Accepted Manuscript

Lipid based nanocarriers: A Translational Perspective

Dinesh K. Mishra, Ruchita Shandilya, P.K. Mishra

PII: S1549-9634(18)30478-7
DOI: doi:10.1016/j.nano.2018.05.021
Reference: NANO 1826
To appear in: Nanomedicine: Nanotechnology, Biology, and Medicine
Received date: 1 May 2018
Accepted date: 28 May 2018

Please cite this article as: Dinesh K. Mishra, Ruchita Shandilya, P.K. Mishra , Lipid based
nanocarriers: A Translational Perspective. Nano (2018), doi:10.1016/j.nano.2018.05.021

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Lipid based nanocarriers: A Translational Perspective

Dinesh K. Mishra1*, Ruchita Shandilya, P. K. Mishra2

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NMIMS, School of Pharmacy & Technology Management, Shirpur (Maharashtra) 425405,

India
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Department of Molecular Biology ICMR-National Institute for Research in Environmental

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Health, Bhopal, India.

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* Corresponding author
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Dr. Dinesh Kumar Mishra

Associate Professor,
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NMIMS, School of Pharmacy & Technology Management, Shirpur (Maharashtra) 425405

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dineshdops@gmail.com; Tel/Fax: +91-2563286545/+91-2563286552

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# The author(s) declare(s) that there is no conflict of interest regarding the publication of this
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article.

Word count:
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Abstract- 146

Manuscript (body text & figure legends)-9025

References- 200

Number of figures-12

Number of tables-05

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Abstract

Over the recent couple of decades, pharmaceutical field has embarked most phenomenal

noteworthy achievements in the field of medications as well as drug delivery. The rise of

Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic,

remedial applications and patient monitoring. The convincing usage of nanotechnology in the

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conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-

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liposomal systems has been discussed. Present review deals with the late advances and updates

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in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical

applications alongside commercially available products and products under clinical trials. This

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exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice
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for the formulation of pharmaceutical products, the challenges looked by the translational

process of lipid-based nanocarriers and the combating methodologies to guarantee the headway
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of these nanocarriers from bench to bedside.

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Key words: Drug delivery, Lipid carrier, Nanotechnology, Nanocarrier, Controlled release
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Abbreviations:

NEMS: Nano electromechanical systems

MEMS: Micro-electromechanical systems
NE: Nanoemulsions
NPs: Nanoparticles
QD: Quantum dots

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PLA: Polylactic acid

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PGA: Polyglycolic acid

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PLGA: Co-polymers of lactic and glycolic acid
PCL: Poly(ε-caprolactone)

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PACA: Poly-alkyl cyanoacrylate
PEI: Polyethyleneimine
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PTX: Paclitaxel
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GIT: Gastrointestinal tract

PEG: Polyethylene glycol
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RES: Reticuloendothelial system

FA: Folic acid
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EPR: Enhanced penetration and retention

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PAMAM: Polyamidoamine
PG: Poly L-glutamic acid
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PPI: Polypropyleneimine
LA: Lactobionic acid
CNTs: Carbon nanotubes
DOX: Doxorubicin
SW: Single walled
MW: Multiwalled
MNPs: Metallic nanoparticles

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LBDDS: Lipid based drug delivery systems

DSC: Differential scanning calorimeter
ME: Microemulsions
MMEs: Mucoadhesive ME
AB: Amlodipine besilate
SEDDS: Self emulsifying drug delivery systems

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ADV: Adefovirdipivoxil

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PE: Pickering emulsions

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PC: Phosphatidylcholine
MLVs: Multilamellar vesicles

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SUVs: Small unilamellar vesicles
LUVs: Large unilamellar vesicles
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HACE: Hyaluronic acid-ceramide
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SF: Sorafenib
Gd: Gadolinium
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MDR: Multidrug resistance

Tf: Transferrin
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DOX: Doxorubicin
OVA: Ovalbumin
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SC: Stratum corneum

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MTX: Methotrexate
LS: Lipospheres
SLMs: Solid lipid microparticles
SLN: Solid lipid nanoparticles
CNS: Central nervous system
NLC: Nanostructured lipid carriers
LDCS: Lipid drug conjugates

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BHT: Butylatedhydroxytoluene
BHA: Butylatedhydroxyanisole
MPS: Mononuclear phagocytic system

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1. Nanotechnology

The journey of drug from its development to its translation into the market is very tedious and

experiences incredibly little accomplishment owing to numerous factors like toxicity of the

therapeutic agents, inadequate solubility leading to lesser bioavailability and consequently

reduced efficiency. In order to combat this, nanotechnology based drug delivery systems is one

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of the approaches that has been investigated for this purpose. Nanotechnology is the science and

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technology of precise manipulation in the materials, devices or systems at nanometer scale

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(usually less than 100 nm) (Figure 1)1, 2. The last several decades have witnessed the emergence

of nanomedicine as one of the major field of academic research providing direct benefit to

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human health through clinical and commercial development. The broadened applications of
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nanomedicine and exploitation of nanotherapeutics in the clinic is only possible due to increased

understanding of the disease and designing of advanced nanoscale materials. Nanomedicines

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include nanopharmaceuticals (i.e. intended for drug delivery), nanodiagnostics (i.e. used for
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imaging and diagnostics), nanotheranostics (i.e. combined therapeutic and diagnostic), and

nanobiomaterials (i.e. medical implants). Among these, nanopharmaceuticals are predominant

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and represent 75% of the market share of approved nanomedicines. The ever growing field of
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development of nanoscale delivery systems for biotherapeutics represents a major sector of

academic research and is beginning to contribute to the future progress in modern health care in
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terms of disease diagnosis, treatment, and prevention. Although significant progress has been

made in these fields but the clinical translation of next-generation nanopharmaceuticals remains

challenging and needs advanced exploration of the manufacturing and regulatory perspectives.

Nanotechnology (nanocarriers) based drug delivery systems may lead to better half-life, precise

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release completed short or extended durations, and identical site specific targeted delivery of

therapeutic compounds3-7.

Attributes of nanocarriers5

 Drugs protection from metabolic degradation.

 Availability of products with superior characteristics.

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 Dosing frequency may be reduced.

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 Efficient and improved treatment with less expense.

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 Increased potential of solubilization.

 Drugs rejected earlier or difficult to administer can be utilized by these carriers.

 Feasibility of drug targeting.

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 Enhanced oral bioavailability of the agents which are not effective after oral

administration.
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 Flexibility of surface manipulation.

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 Capability of designing specific to drug and disease.

2. Classification of nanocarriers
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Nanotechnology basically offers two kinds of nanotools viz. nanomaterials and nanodevices, that
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offer a foremost contribution in the area of pharmaceuticals and related areas (Figure 2).

Nanomaterials can be enriched by addition of functionalities to interface with biological

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molecules or structures. Nanomaterials are subcategorized into nanocrystalline and

nanostructured materials. Nanodevices are minute devices at nanoscale and a few of them

include nano and micro-electromechanical systems (NEMS/ MEMS), microfluidics, and

microarrays. Nanocarrier can be broadly classified as organic-based, inorganic-based or a hybrid

combination of both. Organic nanocarriers comprise of polymeric frameworks, lipid-based

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frameworks e.g., liposomes and nanoemulsions (NE), dendrimers, and carbon-based nanocarriers

e.g., fullerenes and carbon nanotubes. Inorganic nanocarriers comprise of metallic

nanostructures, silica nanoparticles (NPs), and quantum dots (QD)8.

2.1.1 Polymeric NPs:

Polymeric NPs are synthesized by different types of natural and synthetic polymers, which are

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often biocompatible and biodegradable. The merits of these polymeric particles as compared to

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other nanocarriers include stability in various microenvironments, slow release of the drug as a

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function of the polymer degradation, as well as their versatility in terms of polymer type and type

of drug to be encapsulated. The hydrophobicity and hydrophilicity inside the polymeric

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framework can be controlled to suit wide assortment of medication molecules 9,10. Commonly
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employed natural polymers include gelatin, dextran, albumin, chitosan, alginate while synthetic

biodegradable polymers are polylactic acid (PLA), polyglycolic acid (PGA), copolymers of
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lactic and glycolic acid (PLGA), poly(ε-caprolactone) (PCL), poly-alkyl cyanoacrylate (PACA),
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polyethyleneimine (PEI), poly(L-lysine), poly(aspartic acid), etc.1,11.

DOXIL, Abraxane and Genexol-PM exists among these first generation NPs, established for
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therapy of cancer. Abraxane (nab-paclitaxel) is based on the NP albumin-bound (nab) platform

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led to the second class of therapeutic NP which was approved by the FDA in 2005. Abraxane

revealed considerably greater tumour response rates (33% vs. 19%) and elongated times to
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tumour progression (23.0 vs. 16.9 weeks) among metastatic breast cancer patients who did not

respond to combination therapy as compared to paclitaxel (PTX) formulated with Cremophor EL

(Taxol), 12.

Surface manipulation like PEGylation, co-polymerization with functional polymers,

polyelectrolyte coatings and ligand anchoring of polymeric NPs is also done to attain desirable

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characteristics. The hydrophobicity and surface charge of the formulated NPs can be modified to

transform the assimilation energy from the gastrointestinal tract (GIT). It includes surface

functionalization. Peracchia et al. investigated the biodistribution characteristics of polyethylene

glycol (PEG) coated polycyanoacrylate NPs that exhibited prolonged circulation, reduced

hepatic accumulation and in-vitro toxicity. Xie et al. reported a PEG conjugated Fe3O4 NPs that

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demonstrated targeted delivery with concomitant reduction in the macrophage uptake by

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reticuloendothelial system (RES) 13.

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The properties of polymeric NPs could be advantageous for the treatment of several life-

threatening diseases including cancer, neurodegenerative disorders, cardiovascular diseases, and

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even other diseases, such as viral infections and osteoporosis. Dhas et al. investigated a prostate
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cancer targeted delivery systems of bicalutamide-loaded folic acid (FA) conjugated chitosan

functionalized PLGA nanocarriers14.

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2.1.2 Dendrimers:
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Initially proposed by Tomalia in the year 1985, dendrimers are unimolecular, monodisperse,

micellar with well-defined size and structure, which are created from repeating units, like
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polymers, but they basically vary from classical polymers. There are three fundamental reasons
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that legitimize the utilization of dendrimers for drug delivery:

 Firstly, the presence of multiple copies of a drug induce a multivalency effect,

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reminiscent to the polyvalent interactions extensively arising in biological systems.

 Secondly, enhancement of the solubility and thus achieving increased the bioavailability.

 Thirdly, the varying size that may exceeds the renal threshold, and may induce the so-

called enhanced penetration and retention (EPR) effect15.

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However, the deficiency of this carrier is its synthesis because of their complex design. Polymers

that are commonly used in dendrimers for drug delivery are: polyamidoamine (PAMAM),

melamine, poly L-glutamic acid (PG), polyethyleneimine (PEI), polypropyleneimine (PPI), and

(PEG), Chitin etc.16,17. There have been several studies reporting the enhanced therapeutic

efficacy and better targetability of drugs when administered as dendrimers. Fu et al. detailed the

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advancement of a lactobionic acid (LA)-modified multifunctional generation 5 (G5) PAMAM

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dendrimer-based carrier system for targeted therapy of liver cancer cells 18.Cao et al. reported

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doxorubicin encapsulated, folate-functionalized, degradable amphiphilic dendrimer-like star

polymer (FA-DLSP) to be used as a nanoscale carrier for cancer cell targeted drug

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delivery19.Wang et al. reported a targeted anticancer effect via development of multifunctional
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PAMAM dendrimer-based nanocarrier20.

2.1.3 Micelles:
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Micelles have become one of the main players in nanoparticle research to be utilized in advanced
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drug delivery systems. These are supramolecular assembly or systems constituting hydrophobic

core enclosed by hydrophilic corona. For the past several years, polymer-based micelles have
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been the main focus of researchers as carrier systems considering their numerous benefits such as
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better stability, high drug loading capacity, improved solubilization, prolonged circulation,

smaller size and targeting potential. Their small size (1-50 nm) makes them superior for
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intravenous delivery. Additionally they are more stable in comparison to liposomes and

biocompatible. Once ready to be administered, micelles are injected and enter target cells by

endocytosis through ligand-receptor interactions. Targeted delivery of docetaxol, doxorubicin

(DOX) to tumor cells by means of micelles was well demonstrated by Chen et al21.

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2.1.4 Polymer drug conjugates:

Polymer-medicate conjugates are the new medication conveyance frameworks made out of

covalently connected medication particles with the polymer backbone. Apart from drug

molecules, additional purposeful additives like diagnostic agent, targeting ligand, PEG chains to

enhance hydrophilicity can also be housed in the polymer backbone which brings about

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arrangement of nanocargos, specific to disease condition. Further, targeting potential offered by

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polymer-drug conjugate is especially noteworthy if there should be an occurrence of growth

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treatment because of greatly lethal impacts of anticancer agents to the normal tissues of the body.

The classical approach for formulation of polymer–drug conjugates can be comprehensively

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arranged as PEGylation that involves covalent binding of PEG chains with drug molecules. It is
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found that PEGylation may improve solubility, permeability and minimized presystemic

metabolism4, 17, 23. Parvizikhosroshahi and Can developed polymeric drug conjugates to attain
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targeted delivery of bioactive molecules22.

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2.1.5 Carbon nanotubes (CNTs):

CNTs have emerged as a new delivery system and their specific design as well as
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physicochemical properties represents as potential drug carrier system. They belong to fullerenes
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(made up of carbon atom and present as hollow sphere, tube) that are cylindrical in shape and

consist of a hexagonal arrangement. According to structure and arrangement of atoms they are of
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two types: single walled (SW) CNTs and multiwalled (MW) MWCNTs. Depending upon

functionalization they may be further categorized as target oriented, ligand attached, solvent

dispersed and surfactant grafted. They have extensive applications in healthcare sector including

from pharmaceutical companies in developing target oriented drug delivery medicines, biotech

companies in developing numerous novel vaccine and blood products as well as biomedical

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industries in designing nano-sensors (glucose sensors, blood pressure/temperature sensor), nano

diagnostic tools, nano-probes and nano-robots23-25.

A wide array of studies have been put forward proposing CNTs as promising candidates for drug

delivery. Ji et al. attempted to achieve targeted controllable loading/release of anti-cancer agent

doxorubicin (DOX) via construction of chitosan modified folic acid conjugated SWNTs26. Ren et

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al. fabricated a dual-targeting system consisting angiopep-2 functionalized oxidized MWCNTs

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for delivery of doxorubicin for treatment of brain glioma27. Lu et al. developed a magnetic dual-

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targeted nanocarrier combining the advantages of MWCNTs and iron oxide magnetic NPs for

delivery of doxorubicin to the target tumor cells28.

2.1.6 Metallic nanoparticles (MNPs):

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MNPs are very promising as novel carrier and contrast agents for the treatment of cancer. The

unique features of MNPs like high surface-volume ration, wide optical properties, easy synthesis
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and simple surface chemistry and functionalization cling to assurance in the clinical ground for
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cancer treatment. MNPs (gold, silver or blend of two) show highly tunable optical characteristics

which can be easily tuned to required wavelength and enable them for imaging and photothermal
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applications. Current developments have directed to site specific targeting and drug delivery by
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these particles29.

Several studies proving the ability of metallic nanoparticles to achieve improved drug delivery
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and therapeutic efficacy have been reported. Paciottiet al.30 and Maoet al.31 reported targeted and

improved delivery of drugs by means of gold nanoparticle. Hadjipanayis et al. reported the use of

iron oxide NPs conjugated to an anti-synthetic peptide antibody (EGFRvIIIAb) for MRI contrast

enhancement of human glioblastoma cells 32.

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2.1.7 Quantum dots (QDs):

They are inorganic fluorescent semiconductor nanoparticles having size range of 2-10 nm that

comprise a center of hundreds to thousands atoms. QDs with cadmium selenide center and a zinc

sulphide shell, encompassed by a covering of organizing ligand and an amphiphilic polymer are

most extensively used for biological application. They possess certain benefits over conventional

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fluorescent dyes: narrower emission spectra, bigger strokes shift, high quantum yield, greater

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photostability. QDs can release toxic cadmium via photolysis on excitation that is not desirable.

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To overcome this problem system can be coated with biocompatible polymers which may

improve colloidal stability. The surface of QDs can be engineered or manipulated to improve

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solubility, sensitivity, specificity and visualization in target tissue8, 33.
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Many targeted, image-guided drug delivery studies have been reported by Feng et al.34, Justin et

al.35 Muhammad et al.36 and Al-Nahain et al.37 proving the potential of QDs for multimodal
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therapy.
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2.1.8 Silica nanoparticles:

Silica materials are the carriers which mostly preferred for biological purposes among inorganic
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NPs. The mechanism by which drug loading can be done into mesoporous silica material is a
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chemical or physical adsorption. These processes can incorporate various types of drugs,

including anticancer drugs antibiotics, and cardiac drugs into MSNs. These particles have
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applications in catalysis, drug delivery and imaging38. Targeted and improved doxorubicin drug

delivery was reported by Meng et al.39, Pan et al.40 and Meng et al. 41 by means of functionalized

mesoporous silica NPs.

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2.2 Nanodevices:

Microarray is very vital technology in the area of diagnostics, particularly in genetic analysis. It

can be defined as a matrix of numerous entity elements immobilized on a solid support by means

of bulk phase mass transfer approach specifically by direct spotting of biomolecules on the

support. They display persuasive apparatuses for biomedical scientists and medication, as

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exhibits can be designed to look at the event of atomic marks in a to a great degree parallel mold

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and can be arranged to look for either for nucleic acids (DNA microarrays) or proteins (immune

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response based microarrays) and additionally different kinds of cells. On the other hand

microfluidics shows the capability to evaluate miniature volumes (micro, nano or even pico-

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liters) of sample and diminish costly reagent expenditure as well as automatic sample preparation
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with reduced sample processing time. The combination of microarray technologies and rising

area of microfluidics offers numerous benefits like minimization of reagent cost, less time
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requirement for hybridization assay, high-throughput processing of sample, integration and

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automation capacities of the front-end sample processing steps42, 43.

3. Lipid based drug delivery systems (LBDDS)

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Lipids are generally organic compounds which contain hydrocarbons and extracted from plants
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and animals by low polarity solvents. Common examples of lipids are oils, waxes, cholesterol,

sterols, monoglycerides, diglycerides, triglycerides, phospholipids and fat soluble vitamins.

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Recently lipids are becoming very popular as potential excipients for drug delivery as well as

cosmetics44. Among the array of NPs being as of now examined by pharmaceutical researchers,

lipid nanoparticles have led the pack on account of clear preferences of higher level of

biocompatibility and flexibility. These frameworks are monetarily appropriate to define

pharmaceuticals for topical, oral, pneumonic or parenteral organization and delivery. Lipid nano

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formulations can be custom fitted to meet extensive variety of product requirements directed by

disease condition, route of administration and contemplations of cost, product stability, toxicity

and viability. These systems emerge as an alluring candidate for the formulation of

pharmaceuticals, as well as immunizations, diagnostics and nutraceuticals as a result of their

demonstrated safety and efficacy45.

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Based on chemical composition solid lipids can be categorized as:

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a. Homolipids

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Examples: Cerides (Waxes- beeswax, carnauba wax etc.), Glycerides (fats and oils) and Sterides

(esters of cholesterol with fatty acids)

b. Heterolipids
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Examples: Phospholipids (Phosphoglycerides, Phosphosphingolipids-ceramide), Glycolipids and

Sulfolipids
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c. Complex lipids
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Examples: Lipoproteins, Chylomicrons

3.1 Useful properties of lipids in the formulation of LBDDS44

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1. Crystallinity and polymorphism

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Appropriate crystallinity is a criterion for a good quality lipid particulate delivery systems.

Triglycerides, which are principally utilized as lipid networks solidify in various polymorphic
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structures.

2. Melting characteristics

A pure triacylglycerol is having single melting point which occurs at a definite temperature.

However certain lipids contain different types of triacylglycerols with multiple melting points

which results their melting over a broad range of temperatures. It produces a wide endothermic

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transition in differential scanning calorimeter (DSC). Highly pure lipids with sharp melting

transitions do not include drugs on recrystallization.

Solubility is a great challenge for the formulation scientists. Hence, LBDDS have gained much

importance in the recent years due to their capability to improve the solubility and ultimately

bioavailability. As of now huge endeavors have been made to investigate the possibilities of

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LBDDS since it gives the reasonable methods for site specific as well as time controlled delivery

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of drugs with different molecular weight, either little or huge, and furthermore the bioactive

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operators 46 47.

3.1 Reason behind exploration of lipid based systems48, 49:

 Adaptability of lipidic excipients

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 Versatility in designing of formulation

 Low hazard profile

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 Greater oral bioavailability with minimum plasma profile variation

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 Superior permeation in case of topical delivery

 Possibility of commercialization
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 Better representation of lipidic excipients

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 High market appealing qualities for products with innovation

 Improved ability to address the key issues of technology transfer and manufacture scale
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up.

3.2 Attributes of LBDDS

 Controlled and targeted drug release.

 Pharmaceutical stability.

 High and improved drug content as compared to other carrier systems.

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 Capability for incorporation of both lipophilic as well as hydrophilic drugs.

 Biodegradable and biocompatible.

 Better dose uniformity.

 Requirement of low therapeutic dose owing to better drug absorption.

 Low risk profile.

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 Easy scale up and sterilization.

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 Easy validation.

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 Economic than polymeric or surfactant based systems.

 Lowering of therapeutic dose due to improved drug absorption.

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 Administration versatility i.e., can be administered via various routes such as oral,
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parenteral, ocular, intranasal, dermal/transdermal, and vaginal.

3.3 Mechanism of drug transport & Formulation strategies46, 48, 50

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There are numerous factors which needs consideration for the formulation of LBDDS includes
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absorption, compatibility, cost, digestion, dispersion, melting point, purity, regulatory aspect,

solubility, stability, toxicity. Many approaches have been put forward for the formulation of lipid
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based drug delivery systems as shown in Figure 3a.

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Various transfer mechanisms are involved in the transportation of drug across the membrane by

means of lipid based drug delivery systems as shown in Figure 3b. These may include:
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i. Paracellular absorption,

ii. M cell mediated transport,

iii. Fluid phase macropinocytosis,

iv. Endocytosis (clathrin/caveolin mediated),

v. Ligand mediated transport, and

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vi. Enhanced uptake by size regulation.

3.4 Classification of LBDS:

LBDDS are classified as follows Figure 3c& Table 1

3.4.1 Emulsion based systems:

3.4.1.1 Microemulsions (ME)

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The concept of ME was introduced by Hoar and Schulman in the year 1940. They are

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characterized as straightforward, less gooey, thermodynamically steady, optically isotropic

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arrangement of oil and water balanced out by an interfacial film of amphiphilic mixes, for

example, surfactant and co-surfactant. The key difference between emulsion and ME is the size

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and shape of dispersed particles. ME size ranges from 10-200 nm while emulsions size ranges
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from 1-20 µm. ME have created great interest as prospective drug delivery systems as well as

cosmetic and cosmeceutical carriers for skin and hair preparations. Some benefits associated
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with these systems are thermodynamic stability, great solubilization potential, clarity, easy
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preparation and scale up51. Several studies have shown the impact of ME based delivery through

various routes providing better targetability. Topical drug delivery of clobetasol propionate by
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ME based systems was reported by Patel et al.52 ME-base hydrogel formulation for topical
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delivery of ibuprofen. Shah et al. meant to figure ME and mucoadhesive ME (MMEs) of

rivastigmine for nose to brain delivery and to compare percentage drug diffused for the two
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frameworks utilizing as a part of vitro and ex-vivo contemplate 53.

3.4.1.2 Nanoemulsions (NEs)

NEs are emulsions having droplet size in the range of 100 nm. Classic NEs consists of oil, water

and an emulsifier. An emulsifier is very essential for the formation of minute sized droplets

because it reduces the interfacial tension i.e., the surface energy per unit area, among the oil and

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aqueous phases of the emulsion. They also engaged in stabilization of NEs by means of repulsive

electrostatic interactions and steric hindrance. The emulsifier employed is usually a surfactant,

but proteins and lipids are also efficient in the formation of NEs. NEs have been recognized over

few decades owing to their extraordinary characteristics like high surface area, transparent

occurrence, dynamic stability and tunable rheology. NEs are biodegradable, biocompatible, easy

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to prepare and transporters for lipophilic drugs which are susceptible to hydrolysis. NEs have

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been applied in different fields such as drug delivery, food, cosmetics, pharmaceuticals, and

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material synthesis54.

Mahajan et al. developed an intranasal NE for enhanced bioavailability and CNS targeting of

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saquinavirmesylate (SQVM)55. Modi et al. investigated the anti-inflammatory potential of a NE
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formulation for topical delivery of aceclofenac56.Chhabra et al. reported to achieve enhanced

solubility and oral bioavailability of amlodipine besilate (AB) by a development of a targeted NE

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based formulation57.
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3.4.1.3 Self emulsifying drug delivery systems (SEDDS)

They are isotropic mixtures of oil, surfactant, co-surfactant and the therapeutic substance which
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emulsify under gentle agitation. SEDDS quickly distribute in the GIT with moderate agitation
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provided by gastric motility which cause formation of emulsion. SEDDS usually construct

emulsions with cloudy appearance, and droplet size between 200 nm to 5 µm. They are superior
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in comparison to lipid solution due to the existence of surfactants in the preparations leading to a

more uniform and reproducible bioavailability. Specific advantages associated with these carriers

include better steady drug absorption, specific targeting potential, drug protection from the gut

environment, controlled delivery, minimized variability accounting food effects, improved oral

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bioavailability with decreased dose and elevated drug loading capacity. SEDDS is one of the

potential techniques for oral delivery of water insoluble or poorly soluble compounds58.

Chen et al. developed a supersaturatable SEDDS for the enhanced oral bioavailability of

indirubin59.Milovi´c et al. investigated a solid SEDDS, as potential delivery system for poorly

water soluble drug carbamazepine (CBZ)60. To overcome the limitations of poor solubility,

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stability and bioavailability SEDDS of curcumin was developed by Wu et al.61 Balakumar et al.

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developed SEDDS of Rosuvastatin calcium62. Seo et al. investigated the improved bioavailability

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and chemotherapeutic potential of Docetaxel loaded SEDDS when compared with Taxotere®, a

commercial product of docetaxel63. Gupta et al. reported the development of Adefovirdipivoxil

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(ADV) loaded SEDDS exhibiting increased bioavailability due to enhancement of its intestinal
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permeability and minimized effect of pH with improved therapeutic efficacy64.

3.4.1.4 Pickering emulsions (PE)

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PE are very promising preparations owing to its simplicity and similarity to the well-recognized
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surfactant-based emulsions. They may be any type of emulsions either oil-in water (o/w), water-

in-oil (w/o), or even multiple, which is stabilized by solid particles instead of surfactants. The
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main advantage of the stabilization by solid particles is high resistance to coalescence. PE are
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emulsions based on lipid having inner nanostructures stabilized by solid particles like silica,

clays, calcium carbonate, titanium dioxide etc. These emulsions can be substituted for a typical
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emulsion in most of the applications because PE hold the basic properties of typical emulsions.

They are well suited to particular fields like cosmetic and pharmaceutical where surfactant may

cause adverse effects51.

PE with its attractive advantageous attribute of stabilization present an effective strategy to

design potent carriers in biomedical area. The stability and release of curcumin have been

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65
evaluated in nanoparticle stabilized PE by Tikekar et al. and Shah et al.66 during storage and

simulated gastric and intestinal digestion.

3.4.2 Vesicles based systems

3.4.2.1 Liposomes

Liposomes can be defined as microscopic, colloidal, concentric bilayered vesicles comprising of

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an aqueous compartment enclosed by a bilayer of lipids which can be of either natural or

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synthetic lipids (Figure 4a).The essential components of liposomal drug delivery system include

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phospholipids like phosphatidylcholine (PC) and cholesterol where cholesterol acts as a fluidity

buffer. In spite of the fact that cholesterol don't take part in bilayer formation, it can be added to

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PC up to 1:1 or even 2:1 molar ratio of cholesterol to PC. They can be formulated and
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characterized for various sizes, number of lamellae, structure, composition, lipids

physicochemical property and different payloads. As there are numerous types of phospholipids,
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it is feasible to alter the size, charge, surface properties, upon addition of new ingredients to the
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lipid mixture.

They can be categorized in to different types depending on their size and number of bilayers
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includes multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs) and large unilamellar
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vesicles (LUVs). Liposomes contain lipid bilayers which are biocompatible and may improve the

solubility and stability of encapsulated agents, also modify tissue distribution, targeted to
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particular sites, augment therapeutic response and minimize toxicity. They are a versatile tool for

delivery of large array of bioactives ranging from drugs to high molecular weight proteins and

peptides. They can be explored for oral, ocular, pulmonary and transdermal delivery of drugs.

The amphipathic nature of liposomes renders them to be explored as a non-invasive delivery

agent for vaccines. Thus they can be structured to present control over properties like elimination

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half-lives, permeability, biodistribution and targeting specificity67, 68. The last few decades have

witnessed wide array of development in liposomes providing better therapeutic efficacy and

better targetability along with imaging.

Park et al. reported a nanohybrid approach consisting doxorubicin loaded liposomes coated with

amphiphilic hyaluronic acid-ceramide (HACE) for targeted delivery of anticancer drug and in

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vivo cancer imaging69. Ninomiya et al. demonstrated an ultrasound-triggered TSP liposomes for

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drug delivery to HepG2 cancer cells70. Yan et al. reported to achieve enhanced delivery of

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doxorubicin to cells residing in a sub physiologic pH environment through a pH-responsive

liposomal nanocarrier71. Xiao et al. developed a sorafenib (SF) and gadolinium (Gd) co-loaded

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liposomes (SF/Gd-liposomes) with an intent to achieve improved solubility of sorafenib, to
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monitor its distribution and the early feedback effects on its in vivo treatment efficacy72. Meng et

al. first reported a co-encapsulation of Resveratrol with PTX in a PEGylated liposome to

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overcome multidrug resistance (MDR) in tumor cells73. Deshpande et al. reported a R8 and
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transferrin (Tf) modified DOX-loaded liposomes to achieve improved targeting of A2780

ovarian carcinoma cells via the over-expressed Tf receptors (TfRs) with R8-mediated
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intracellular DOX delivery74.

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Many mechanisms are involved in the transportation as well as enhanced availability of drug

when delivered as liposomal and non-liposomal lipid based systems as shown in Figure 4b.
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These may involve

a) Drug free mechanism in which the drug permeates through the membrane independently

after exiting from the vesicles.

b) Penetration mechanism(as in ethosomes), in which a penetration enhancer (like ethanol)

interacts with lipid molecules of the membrane leading to increased fluidity and

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decreased density of the membrane followed by penetration and permeation through

opened new pathways.

c) Ability to deform and pass through narrow constriction and reform, a characteristic

feature of transfersomes without measurable loss.

3.4.2.2 Niosomes

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Niosomes, showing structural resemblance with liposomes, are minuscule multi-lamellar non-

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ionic surfactant vesicles formed as a result of addition of non-ionic surfactants (primarily alkyl or

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dialkylpolyglycerol ether class) to cholesterol with subsequent hydration in aqueous media

(Figure 4c). Niosomes exhibit increased size and charge on the vesicles due to addition of non-

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ionic surfactants which further leads to increase their entrapment efficiency. These systems are
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very close to liposomes in functions and also enhance the bioavailability of the substances with

reduced clearance. They alleviate the limitations related to classic liposomes like chemical
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instability, variable purity of phospholipids and high cost. Additionally, they have more
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penetrating potential than the classic liposomes. He et al. reported to improve the bioavailability

and chemical stability of Paeonol by formation of PEGylated niosomes resulting in its prolonged
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cellular uptake and enhanced synergistic anticancer effects with 5-Fu75. Jyoti et al. prepared
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inhalable curcumin loaded cationic small unilamellar niosomes (Cur-C-SUNS) to surmount the

poor physicochemical and biopharmaceutical limitations for effective drug delivery in lung
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cancer cells76. Mehta et al. reported to prepare biocompatible niosomal formulation of anti-

retroviral drug, Nevirapine by a biological surfactant, tyloxapol for the achievement of for better

patient compliant pharmacotherapy for acquired immune deficiency syndrome77. Auda et al.

developed different niosomal gel preparations of celecoxib that showed significant anti-

inflammatory effect concluding to be as potential carriers78. Qumbar et al. formulated lacidipine

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(LAC) loaded niosomal formulation using transdermal delivery for the management of

hypertension79.

3.4.2.3 Pharmacosomes

They are the colloidal dispersions of drugs with covalent bonding to lipids. Since this system is

developed by a drug to a carrier hence termed as pharmacosomes. They may exist as ultrafine

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vesicles, micelles or hexagonal aggregates depend upon the chemical structure of the drug-lipid

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complex. They could be an efficient tool to acquire desired purposes like drug targeting and

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controlled delivery80. Semalty et al. reported to formulate a diclofenac-phospholipid complex

(pharmacosomes) exhibiting improved solubility improved solubility and dissolution profile with

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reduced gastrointestinal toxicity of the drug81. Kamlesh D et al. formulated ketoprofen loaded
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pharmacosomes to achieve improved solubility, bioavailability, protect active ingredients from

degradation in the gastrointestinal tract and avoid GI disturbance of ketoprofen82. With an

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objective of achieving enhanced solubility, absorption and bioavailability of BCS class III drug,
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Pal et al. formulated and evaluated pharmacosomes of Rosuvastatin Calcium83.

3.4.2.4 Phytosomes/herbosomes
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Phytosomes also known as herbosomes are cell like design which is generated from the
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stoichiometric interaction of phospholipids with standard extract or polyphenolic constituents.

They are well absorbed than traditional herbal extracts. Due to its amphiphilic characteristics
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herbosomal formulations may increase the bioavailability of active phytochemical constituents

since they can readily permeate and cross the lipid membrane. The active constituent of herbal

extract is also secured from enzymatic degradation as well as gut bacteria. These systems have

gained wide attention in various areas like pharmaceuticals, cosmeceuticals and nutraceuticals 67.

Yu et al. a self-assembly technique was employed for the preparation of berberine-phospholipid

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complex loaded phytosomes to cater the limitations of low oral bioavailability and poor

gastrointestinal absorption84. Abdelkader et al. reported to develop hyaluronic acid-phytosomes

loaded with L-carnosine as an alternative approach for the prodrug N-acetyl-L-carnosine as a

novel ocular delivery system85. Mirzaei et al. reported to improve the oral bioavailability of

curcumin by means of phytosomal preparations86.

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3.4.2.5 Elastic liposomes

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A new type of manipulated liposome with an optimum quantity of edge activator or surfactant

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which gives elasticity has been developed (Transfersome ®; Idea AG). This type of novel

vesicular system was initially described by Cevc and Blume (Figure 4d). Elastic liposomes

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(transfersomes) are particularly optimized, ultradeformable lipid supramolecular aggregates
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possessing the ability for drug deliverance into or through the skin and ultimately reaches to the

systemic circulation87. Elastic liposomes were basically designed to get the benefits of
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phospholipids vesicles as transdermal drug carrier. Their transdermal delivery is dependent on

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the choice of administration or application, with high efficiency. Their elastic nature makes him

appropriate for skin delivery and also minimizes the risk of complete vesicle rupture. It follows
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the natural water gradient across the epidermis for skin permeation under non-occlusive
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condition. Elastic liposomes can accommodate hydrophobic as well as hydrophilic moieties due

to its infrastructure. They can go about as a bearer for low and in addition high sub-atomic
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weight substances e.g. analgesic, anesthetic, corticosteroids, sex hormone, anticancer, insulin,

gap junction protein, and albumin. Since, they are made up of natural phospholipids hence

biocompatible and biodegradable in nature. They also possess greater entrapment efficiency and

shield the enveloped moieties from metabolic degradation. They also act as depot therefore

releases their contents slowly. They may be applied for local as well as systemic delivery of

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drugs and easy in formulation. Although it possess numerous benefits but also suffers from

certain limitations like susceptible to oxidative degradation, purity of lipids, and cost of

development88-90.

Transfersomes based transdermal drug delivery system of clindamycin was reported by

Abdellatif et al.91providing good stability characteristics and enhanced transdermal delivery.

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Salama et al. investigated an intranasal formulation of olanzapine encapsulated transfersomes for

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brain targeted drug delivery92. Sarwa et al. investigated the biopotential of an antiarthritic agent,

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capsaicin loaded transfersomes in arthritic rats93. Various formulation parameters and processing

conditions affecting the properties of transfersomes were investigated by Ahmed et al.94

3.4.2.5 Ethosomes
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Ethosomes or ethanolic liposomes, are new lipid based, non-invasive carrier system that helps to

deliver biologically active agents to deeper layer of skin layer and systemic circulation (Figure
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4e). These vesicular systems are mainly consists of phospholipids, higher concentration of
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ethanol (20-50%) and water95, 96. In comparison to well established liposomal system they show

greater transdermal flux. Although the actual mechanism lying behind the transdermal
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permeation of ethosomes is not clear but it is believed that phospholipids and higher percentage
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of ethanol are responsible for efficient skin permeation. Generally ethanol in ethosomal systems

disrupt the skin lipid bilayer organization resulting in enhanced skin penetration. Due to higher
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percentage of ethanol the lipid membrane is less tightly packed as compared to classic vesicles

but stability is same. They are soft malleable vesicles and enhance drug distribution capacity in

skin. These ethanolic vesicles are also able to incorporate hydrophilic, lipophilic or amphiphilic

molecules88, 97.

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Ethosomes have been known to show high transdermal permeability providing better skin

tolerability of drugs like lamivudine, melatonin, and repaglinide as reported by Jain et al.98,

Dubey et al.95, and Bodade et al.99, respectively.

3.4.2.7 Archaeosomes

Archaeosomes are also nothing but liposomes made up of fully saturated bipolar tetra ether

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lipids. They are found to be highly stable as compared to conventional lipids in various

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conditions like high temperature, acidic or alkaline pH, and oxidative stress etc. They are nano

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range vesicles formulated from lipids extracted from Archaeobacteria or synthetic archaeal

lipid100. They provide a promising approach for drug delivery. Alavi et al. provided an

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archaeosomal approach for delivery of paclitaxel in breast cancer cells with increased therapeutic
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efficacy and reduced side effects101. Another approach for in vitro skin permeation was put

forward by Moghimipour et al. of the archaeosomes, prepared using lipid extracted from
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Sulfolobusacidocaldarius102.
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3.4.2.8 Vesosomes

They can be defined as a multi-compartment array frameworks possessing discrete inner

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compartments alienated from the external membrane are the characteristic features of vesosomes.
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Each compartment can incorporate diverse materials and have different bilayer composition.

They can entrap colloidal as well as biomacromolecules effectively. Multiple compartments of

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this framework offer better protection to the encapsulated contents in physiological system and

shows extended release of drug 67.

3.4.2.9 Colloidosomes

These are microcapsules whose cell contains tightly packed colloidal particles. Their physical

characteristics like permeability, mechanical strength, and biocompatibility can be specifically

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controlled by means of proper selection of colloids and formulation conditions for their

assembly. The better control over their physical characteristics makes these system attractive

arrangements for encapsulation and controlled drug release103. Shah et al explained a versatile

technique using stimuli-responsive microgel particles as building blocks, aqueous droplets, and

microfluidic devices for fabrication of stimuli-responsive colloidosomes104. Nan et al. reported to

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prepare monodisperse colloidosomes based on chitosan-coated alginate particles for oral delivery

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of insulin105. Bollhorst et al. reported a synthetic route for synthesis of bifunctional

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colloidosomes from superparamagnetic iron oxide nanoparticles and fluorescent silica

nanoparticles106. Similarly, a straightforward approach was put forward by Zhou et al. for

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fabrication of thermal stimuli based colloidosomes using thermo-sensitive triblock copolymer107.
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3.4.2.10 Aquasomes

Aquasomesor ceramic nanoparticles, self-assembled nanostructures (Figure 4f) as triple layers,

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comprising of a solid phase nanocrystalline core, coated with an oligomeric film (made up of
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carbohydrate) on which biochemically active molecules are adhered with or without

modification. The nanocrystalline core comprises polymers such as acrylate, gelatin, or albumin,
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or ceramic such as diamond particles, brushite (calcium phosphate), and tin oxide that provide
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structural stability. Coating materials commonly used are trehalose, cellobiose, sucrose,

pyridoxal 5 phosphate, citrate, chitosan, and so forth108. Aquasomes are widely utilized for the
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delivery of insulin, haemoglobin109, and enzymes like serratiopeptidase. Pandey et al. reported

the preparation and evaluation of carbohydrate modified ultrafine aquasomes in specific

immunotherapy using ovalbumin (OVA) as an allergen model110.

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3.4.2.11 Cubosomes:

Cubosomes can be characterized as self-assembled, liquid crystalline, thermodynamically stable

nano frameworks, made up of certain amphiphilic lipids in definite proportions, known as

biocompatible carriers in drug delivery. In presence of polar solvents, these particles assemble as

curved bicontinuous lipid bilayers and is divided into two internal aqueous channels that can be

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exploited by various bioactive moieties. Cubosomes have appeared as one of the promising

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vehicles for various routes of administration offering attractive attributes such as the ability to

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encapsulate hydrophilic, hydrophobic and amphiphilic substances, thermodynamic stability,

bioadhesion, and controlled release through functionalization. The term “cubosomes” was coined

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by Larsson, which reflects the cubic molecular crystallography and structural and functional
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resemblance with liposomes108, 111.

Cubosomes have been widely used for enhancement of drug delivery via various routes such as
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oral, topical, ophthalmic etc. For instance, Esposito et al. reported a percutaneous administration
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of indomethacin for anti-inflammatory action via cubosome dispersions112. Ophthalmic drug

delivery with low irritancy and high bioavailability of flurbiprofen and dexamethasone as
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cubosomes was achieved as reported by Han et al.113 and Gan et al114. Cubosomes as an
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alternative approach for the oral drug delivery of amphotericin B was put forward by Yang et

al.115
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3.4.2.12 Sphingosomes.

Sphingosomes can be defined as bilayered vesicles, mainly composed of natural or synthetic

sphingolipids and cholesterol in varying ratio, entirely enclosing an aqueous compartment.

Various types of sphingolipids have been used for the fabrication of sphingosomes such as

sphinganines, hexadecasphinganine, lysosphingomyelins, and lysoglycosphingolipids, n-

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acylsphingosines, gangliosides, glucuronosphingolipids, phosphoglycosphingolipids, and so

forth108. Recently, Tiwari et al. suggested an investigative study of sphingosomes for the delivery

of anti-cancer drug such as Dox116.

3.4.13. Ufasomes:

Ufasomes appears as promising approach for efficient topical/ transdermal delivery of drugs,

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proteins, peptides, hormones, etc. as they enhance penetration of drug into viable skin through

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stratum corneum (SC). Ufasomes containing lipid carriers that attached to the skin surface and

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allows lipid exchange between the outermost layers of the SC.

Initially named as “ufasomes,”reflecting unsaturated fatty acid liposomes was first reported by

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Gebicki and Hicks in 1973. Ufasomes are suspensions of closed lipid bilayers that are composed
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of fatty acids and ionic surfactants108. Cutaneous delivery of dexamethasone loaded ufasomes for

anti-inflammatory activity was reported by Mittal et al117. To overcome the limitations of oral
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administration of cinnarizine, intranasal ufasomes based formulation was reported by Salama et

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al118.

3.4.14. Emulsomes
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Emulsomes are nanocarriers consisting of a solid fat core enclosed by ones or more phospholipid
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bilayers with an integrated properties of emulsion and liposomes. Vyas et al. reported a novel

formulation based on emulsomes for the liver-targeted delivery of anti-viral drug, zidovudine119.
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A chylomicron mimicking carrier based on emulsomal approach was developed by Paliwal et al.
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for oral lymphatic delivery of methotrexate (MTX) . Brain targeted drug delivery via

intranasal route was achieved by oxcarbamazepine loaded lipidic emulsomes by El-Zaafarany et

al.121

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3.4.15. Novasomes

Novasomes, a type of liposomal based nanocarrier with diameter ranging from 0.1 up to 1

micron, consist of a large amphipathic core enclosed by 2-7 bilayers and are produced by

mixture of polyoxyethylene fatty acids (as monoester), free fatty acids and cholesterol. The

surface charge of novasomes could be neutral, positive or negative122. Radwa et al. reported an

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intranasal delivery of a novasomal based formulation encapsulating zolmitriptan for brain

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targeting for management of acute migraine attacks123.

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3.4.3. Particulate system

3.4.3.1 Lipospheres

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Lipid microspheres, also called as lipospheres (LS), are newer type encapsulation based on
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lipidic system comprising of water dispersible solid microparticles, with diameter ranging

between 0.1 -100 μm, developed for delivery of therapeutically active compounds particularly
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lipophilic substances.. These consist of solid hydrophobic core (triglyceride fat) which is
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stabilized by phospholipids embedded in its surface. The innermost core comprises of

therapeutic compound dispersed in the lipid matrix. These are utilized for the controlled delivery
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of various types of drugs including local anesthetics, anti-inflammatory compounds, anticancer,

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vaccines, and antibiotics agents67, 124. LS display better physical stability due to avoidance of

coalescence in the formulation. LS are widely used for parenteral nutrition and possess stability
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over a time period at room temperature and possessed no particular undesirable effects, even at

high dose levels. These can be prepared by melt dispersion technique, solvent evaporation

technique, solvent evaporation method, multiple ME, sonication method and roto evaporation

method125. LS exhibiting attractive attributes such as better stability and sustained release of the

drugs such as carbamazepine126, aceclofenac127 were reported. Attama et al. reported the

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preparation of PEGylated Ceftriaxone sodium loaded LS exhibiting high permeability and better

oral bioavailability128. Acoustically active LS have been reported by Fang et al.129 providing

better therapeutic delivery.

3.4.3.2 Solid lipid microparticles (SLMs)

SLMs are defined as spherical solid lipid particles having size range from 1 to 1000 µm. These

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contain polymeric, biodegradable synthetic polymers or waxy protective materials, and modified

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natural excipients such as gums, starches, fats, waxes and proteins. These are physicochemically

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compatible, physiologically stable and therefore these can be formulated at large scale at a

comparatively low manufacturing cost compared to other vesicular systems or other

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microparticles. These micron sized particles comprised of solid polymeric core based on
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naturally occurring lipids and stabilized by dispersed surfactant molecules. These are having

numerous advantages like controlled drug release, targeting potential, drug protection form
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degradation, and incorporation of both the hydrophilic and/or hydrophobic drugs. These can be
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prepared by: high pressure homogenization; cold homogenization; solvent evaporation and spray

drying techniques. These can be administered via oral route, parenteral route, pulmonary
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administration, topical route, ocular administration and rectal administration124, 125. El-Kamel et
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al. reported the fabrication and characterization of testosterone SLMs for the transdermal

delivery130. Controlled drug delivery via pulmonary route was demonstrated by Jaspart et al.
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taking salbutamol acetonide as a model drug131. The anti-inflammatory effect of curcumin loaded

SLMs was studied by Yadav et al. for the treatment of inflammatory bowel disease132.

3.4.3.3 Solid lipid nanoparticles (SLN)

SLN are novel colloidal delivery systems comprise of biocompatible lipid nucleus and an

amphiphilic surfactant in the outer shell with size range of 50 to 1,000 nm (Figure 4g). These

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symbolize an unconventional carrier system to conventional drug delivery systems, such as

emulsions, liposomes, and polymeric micro- and nanoparticles. In the 1980s, Speiser and co-

workers first reported SLN for drug delivery applications. These are aqueous colloidal

dispersions, comprising matrix made of solid biodegradable lipids and provide dispersion site for

both hydrophilic as well as hydrophobic drug moiety. These solid lipids are used instead of

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liquid oils proffer good drug dispersion and controlled drug release, as the drug mobility in a

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solid lipid should be very much lower contrast to liquid oil68, 133, 134.

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SLN are very much advantageous as in nano-size range these proffer relatively narrow size

distribution requisite for biological prospect for site specific targeted drug delivery; provide

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protection against chemical degradation of drug in formulation, these are free from organic
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solvents and suitable for industrial scale production. These can be formulated by techniques like

high pressure homogenization, cold homogenization, solvent evaporation, supercritical fluid

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technology, ME based techniques and spray drying techniques. Possible routes of administration
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for SLN include peroral administration, parenteral administration and transdermal

administration. The drug distribution in SLN governs the type of release pattern which can be
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achieved by selecting proper ingredient and the type of technique for SLN production. Possibly
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three strategies which offer the drug distribution pattern and consequently the release behavior

patterns includes
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(a) Homogeneous matrix: these are formed when the melting points of drug and lipid becomes in

steady state;

(b) Lipid-enriched core: these are resulting when lipid melts at higher temperature than that of

drug; and

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(c) Drug encapsulated core: these are formed when lipids liquefy at an early point than that of

drug.

Drug loading may bring about strong changes of the SLN attributes (particle size distribution,

zeta potential, lipid modifications etc.). Notwithstanding, a few elective joining locales (micelles,

mixed micelles, liposomes, drug nanosuspensions) exist in addition to the complex

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physicochemical status of the lipid (supercooled melt and several modifications). SLN are

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successfully utilized for cancer therapy, vaccine delivery, drug targeting, gene delivery and it is a

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choice of carrier for central nervous system (CNS) targeting. Various drugs are also utilized for

delivery through SLN and are commercially available for easy and simple delivery43, 97
.

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Sarmento et al. reported the delivery of insulin via oral and pulmonary by means of solid lipid
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nanoparticles with enhanced absorption135. Various anticancer drugs have been delivered by

means of solid lipid nanoparticles such as 5-Flurouracil136, doxorubicin137 etc. There have been
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several reports demonstrating solid lipid nanoparticles used for brain targeting. Dhawan et al.
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and Martins et al. reported the brain targeted delivery of quercetin and camptothecin138, 139. Solid

lipid nanoparticles for topical delivery of drugs have been reported by Bhalekar et al.140.
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3.4.3.4 Nanostructured lipid carriers (NLC)

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This system was developed from SLN and it is advanced form of lipid nanoparticles. They are

colloidal carriers and a combination of solid lipids and liquid lipids which yield lipid matrix.
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This nanostructure enhance drug loading and maintain the drug stability during storage.

Additionally drug release can be modulated by alteration in lipid matrix composition. This

system can be a better alternative than SLN owing to superior controlled drug release and greater

stability profile. There are three possible types of NLC which are imperfect type, amorphous

type and multiple type67, 141. Various routes have been employed for the delivery of drugs via

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nanostructured lipid carriers with improved bioavailability. For instance, ocular drug delivery by

nanostructured lipid carriers was reported by Shen et al.142 and Luo et al.143. Topical drug

delivery of drugs like meloxicam using nanostructured lipid frameworks has been reported by

Khurana et al.144. Delivery of drugs via oral route for enhancement of bioavailability have been

reported by Fathi et al.145, Jawahar et al.146

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3.4.3.5 Lipid drug conjugates (LDCS)

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LDCS, a novel lipid based nanoparticles which have been broadly opted for the delivery through

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site specific targeting. These have been utilized for many features in the field of pharmaceutical

drug therapy. These proffer potential site for hydrophilic and lipophilic drugs, and suitable for

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CNS targeting. The particles were surface modified to target them to the CNS which builds the
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lipid drug conjugates a promising delivery system147. Paliwal et al. reported the development of

lipid drug conjugate of methotrexate to overcome the poor bioavailability and associated
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gastrointestinal toxicity148. Cancer targeting by means of lipid drug conjugates were reported by
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Sharma et al. and Abu-Fayyad et al.149, 150

3.5 Characterization of LBDDS:

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LBDDS can be characterized following methods which are given below (Table 2):
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3.6 Challenges and stability aspect

LBDDS confront various difficulties in the utilization of other targeted nanocarriers. One of the
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real difficulties related with lipids is their helplessness to oxidation particularly for unsaturated

triglycerides and unsaturated fats. It may occur during processing or storage and cause loss in

quality of products. When lipids are encountered with environmental conditions like light, air or

temperature, auto oxidation may occur and lead to changes in texture, color, flavor, low quality

and the formation of toxic compounds with health issues for patients. Other degradation

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pathways are triggered by lipoxygenases enzymes. Metal traces may have a considerable impact

in encouraging oxidation. Nitrogen flushing can be a suitable way to prevent oxidation in closed

systems. Metal based reactions can be evaded by the use of chelating agent (EDTA or citric

acid). Physical and chemical stability of LBDDS that pose challenge of oxidation can be reduced

by the use of saturated triglycerides and suitable antioxidants. Antioxidants can avoid oxidation

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reaction by diversified mechanisms. Some examples of antioxidants include alpha-tocopherol,

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butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHA), and propyl gallate etc. To

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analyze the effects of antioxidants on oxidative stability various analytical approaches can be

utilized like peroxide value, p-anisidine value, thermogravimetry and scanning calorimetry.

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Other challenges imparted by LBDDS are rapid clearance from bloodstream, burst drug release,
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non-specific uptake by the mononuclear phagocytic system (MPS), elevated production cost and

deficient of controlled-release properties. These challenges and stability issues are limiting in
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translation of LBDDS to the clinic151.

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3.7 Clinical applications

LBDDS having applications in various fields like pharmaceuticals, cosmetics, nutraceuticals etc.
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but few of the products has reached to market or still in clinical testing. Some important clinical
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applications are given below (Table 3 and Table 4):

4. Contribution by various researchers in the proposed area

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Various researchers have contributed in the field of drug delivery using lipid system.

Contributions by the researchers using different therapeutic agents are compiled in the given

table (Table 5).

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5. Conclusion

The last few decades have witnessed an intensive increase in interest in nanotechnology,

specifically in the application of nanostructure based system for drug delivery via various routes.

The advances in the diagnosis and therapy along with the possibility of monitoring of drug

distribution, are all the result of fusion of nanotechnology, materials science, and biotechnology.

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Pharmaceutical nanotechnology has offered tweaked finding and centered ailment treatment.

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Still some moral, logical, social and administrative issues are posturing challenges in the

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possibility of pharmaceutical nanotechnology. As such there are no specific guidelines or

directive to control products based on pharmaceutical nanotechnology. Overall these challenges

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needs to be addressed for regulation of these nanotechnology based products and delivery
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devices.

LBDDS have emerged as the most promising candidate of drug delivery and have been the
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longest-studied carriers. LBDDS offer the enormous array of possibilities for safe, economical
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and an encouraging approach for the delivery of hydrophobic drugs having poor bioavailability

that may be largely due to environmentally responsive linkers specifically temperature, pH, ionic
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strength, enzyme or oxidative/reductive environment. The distinctive functioning of target site

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like slightly acidic/alkaline pH, hypoxia (in case of solid tumors), and overexpression of some

enzymes (e.g., sialidase, matrix metalloproteinase) suggests a great array of opportunities for the
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designing of environmentally manipulated delivery systems for drug targeting. They also have

the capability to enhance absorption, sustain the drug release and target at particular site resulting

in improved therapeutic benefits with minimum side effects. The advancement of these

frameworks needs exhaustive comprehension of the physicochemical idea of the medication and

the lipid excipients and gastrointestinal processing. Owing to their biocompatibility, industrial

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scalability and production feasibility, lipid-based nanocarriers provide a great potential of

overcoming various technological and stability limitations of predecessor delivery systems like

liposomes or polymeric NPs, and especially in case of delivery of highly lipophilic and low

soluble actives. The second generation of lipid nanocarriers is emerging day-by-day offering an

awesome potential to speak to a change in outlook in nanomedicine. There are various non-

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liposomal lipidic nanocarriers for example niosomes, transfersomes and ethosomes with

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promising in vitro and in vivo brings about an assortment of utilizations. Currently, there are

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very few non-liposomal lipid based nanocarriers under clinical trials or commercialized, but their

precursors, liposomes, have just demonstrated the maximum capacity as nanocarriers both for

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manufactured medications and biopharmaceuticals deliverance, venturing from the lab seat to the
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clinical practice. Liposomes have also undergone various modifications to prepare targeted,

stimuli-responsive, magnetism activated, and many acoustic signals mediated systems for
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delivery of therapeutic agents. These modified liposomes may include stealth liposomes,
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immunoliposomes, genosomes, marinosomes, ultrasomes etc. Among the non-liposomal lipidic

nanocarriers, sphingosomes and virosomes have appeared to be the first prosperous ones by
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achieving clinical utilize. Apart from second generation non-liposomal carriers, nanocarriers like
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nanocapsules and core-shell NPs have been developed that are a hybrid of lipid and polymeric

carriers, which provide a ‘smart’ environmentally responsive delivery and offering a great
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opportunity of integration of their unique physicochemical properties leading to a lipid-based

polymeric materials.

Commercially available lipid based formulations have been prepared by conventional methods,

yielding final products however their transformation from lab scale to the clinic is often faced by

limitations such as lack of homogeneity, contamination with remaining organic solvents,

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complexity of the scale up process from lab scale to large scale manufacturing along with

variable reproducibility of high-quality products . In this frame, the utilization of novel

technologies such as Pastillation, DepoFoam® technology, AKVANO® technology, lipid

multiparticulate systems, Lipidots®, Lipopearl™ etc. are few venturing stones towards

development of promising alternatives approaches with affordable cost, simplicity of the process,

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high throughputs of lipid based nanoformulations with very much requested physicochemical

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properties and relatively unimportant leftover solvents, and additionally their bewildering

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flexibility and basic adaptability make them perfect skill for pharmaceutical organizations. In

conclusion LBDDS are very promising and can be potential candidates for drug delivery.

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Despite of tremendous efforts, only a few formulations gets promoted for clinical use. Therefore,
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the current approaches and strategies employed for design and development of these LBDDS for

the delivery of hydrophobic drugs must be keenly taken into consideration.

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6. Future prospect/ Translational perspective

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Pharmaceutical industries are more concerned in the designing of an appropriate drug delivery

system that could be adequately versatile and viable for scale up of the formulation. A drug
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delivery system can only be successful when technology transfer will be up-scaled from lab-
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scale to large-scale. Drug delivery is restricted to the academia, which should enter clinical

translation and required to be up scaled to industry. Nanotechnology is fast progressing field and
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has immense potential especially in deliverance of drug. It has bunches of difficulties to

overcome from innovative and regulatory perspective. However the prospective benefits to

enhancing human wellbeing, over an extensive variety of utilizations, are huge. Still

nanotechnology is in initial stages, yet it is significantly watched that NPs are promising

apparatuses for the better targeted delivery. The safety of many of nanotechnological systems is

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yet to be determined. More consideration to be given to the qualities of different lipid based

formulations available, with the goal that reasonable guidelines and methodology can be created.

The need for future research ought to be to direct human bioavailability examines and to

complete more fundamental examinations on the mechanisms of action of this captivating and

distinctive kind of formulations. There are numerous treatments available today that take a

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considerable measure of time and exorbitant too. Using nanotechnology based LBDDS, faster,

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patient friendly and economic treatments can be established. Usually, drugs work through the

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entire body before they reach to the affected part but by the use of these systems drug can be

effectively targeted to specific location. It will lead to efficient drug delivery with minimum side

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effects. In the blink of an eye present day advancement, showcase acknowledgment of an
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assortment of pharmaceutical nanotools and all inclusive intrigue appeared by researchers,

governments and businesses ensure that there is momentous potential and probability of nano
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lipid based medication conveyance framework in not so distant future. For the translation of lipid
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based nanocarriers to the clinic, the various critical aspects such as formulation issues,

toxicological aspects related to the use of nanomaterials, accurate evaluation of absorption,

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biodistribution, metabolism and degradation, accumulation and potential negative effects must be
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taken into consideration and steps to develop triggering modalities amenable to human

applications and alternative strategies for in vivo stabilization of drug nanocarriers must be
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taken. Further functionalized nanocarriers for targeted and triggered release as well as

technological improvements in nanocarrier composition can be expected in the upcoming years.

There is no dithering to accept that in coming years market will be overflowed with these

frameworks and gadgets. However, the clinical evaluation of LBDDS is still in its “infancy.”

Future refinements related to issues in constitution, methodology, characterization, and stability

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at product development stage will unwrap new avenues for lipid based system as a potential

molecular vector for clinical translation.

Figure legends:

Figure 1 Nanotechnology dimensions

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Figure 2 Classification of nanocarriers

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Figure 3a Formulation strategies of lipid based drug delivery systems

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Figure 3b Mechanism of transport of drugs by lipid based drug delivery systems

Figure 3c Classification of lipid based systems

Figure 4a Structure of liposomes

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Figure 4b Mechanism of transport of drug via liposomal and non-liposomal drug delivery

systems
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Figure 4c Structure of niosomes

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Figure 4d Structure of elastic liposomes

Figure 4e Structure of ethosomes

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Figure 4f Structure of aquasomes

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Figure 4g Structure of SLN

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196. Aditya NP, Macedo AS,Doktorovova S, Souto EB, Kim S, Chang PS, et al. Development

and evaluation of lipid nanocarriers for quercetin delivery: A comparative study of solid

T
IP
lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid nanoemulsions

CR
(LNE). FoodSciTech 2014;59:115-21.https://doi.org/10.1016/j.lwt.2014.04.058

197. Gautier J, Allard-Vannier E, Munnier E, Souce M, Chourpa I. Recent advances in

US
theranostic nanocarriers of doxorubicin based on iron oxide and gold nanoparticles. J
AN
Control Rel 2013;169(1-2):48-61.https://doi.org/10.1016/j.jconrel.2013.03.018

198. Lacatusu I, Badea N, Badea G, Oprea O, Mihaila MA, Kaya DA, et al. Lipid nanocarriers
M

based on natural oils with high activity against oxygen free radicals and tumor cell
ED

proliferation. Mater Sci Eng C 2015;56:88-94.https://doi.org/10.1016/j.msec.2015.06.019

PT

199. Li L, Jiang G, Yu W, Liu D, Chen H, Liu Y, et al. A composite hydrogel system containing

glucose-responsive nanocarriers for oral delivery of insulin. Mater Sci Eng C 2016;69:37-
CE

45.https://doi.org/10.1016/j.msec.2016.06.059
AC

200. Du F, Honzke S, Neumann F, Keilitz J, Chen W, Ma N, et al. Development of

biodegradable hyperbranched core-multishell nanocarriers for efficient topical drug

delivery. J Control Rel 2016;242:42-49.https://doi.org/10.1016/j.jconrel.2016.06.048

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Table 1: Lipid based nanocarriers with their salient features and limitations

Lipid based Composition Salient features Benefits Limitations/chall

carrier system enges

Emulsion based

ME Water, oil  Transparenc  Thermodyn  Thermal

and y amic stress can

T
amphiphile stability break the
 Less ME

IP
viscosity  Great
solubilizati  High

CR
 Thermodyna on potential surfactant
mic stability levels are
 Clarity required

US
 Easy  Higher
preparation costing
AN
and scale
up  Elevated
risks of
M

 Increased adverse
solubilizati events
ED

on such as
 Improved irritation
and/or
PT

bioavailabil
ity and poor taste
efficacy  Cosolvent
CE

 Improved s may be
physical costly and
AC

stability have
unwanted
 Reversible toxicities
under
thermal  Affected
stress by the
conditions ionic
strength
of the GIT

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 ACCEPTED MANUSCRIPT

NE Oils Submicron  Lack of  Manufact

(acylglycerol emulsion flocculation uring via
s) and other , high
bioactive sedimentati energy
components, on & methods
Surfactants creaming utilize
(phospholipid costly and
s, proteins,  Reduced complicat
dosing

T
polysaccharid ed
es, or frequency equipment

IP
minerals),
 Sustained ’s like
aqueous

CR
and homogeni
component zer,
controlled
(water), microfuidi
release

US
texture zer, which
modifier,  Manufactur adds to
weighting ed by manufactu
AN
agent, and minimum ring cost.
ripening amount of
retardant surfactant,  Still better
M

hence less understan

toxic to ding of
ED

biological droplets
membranes generation
mechanis
PT

 Nanosize m using
droplets various
makes them methods
CE

resistant is required
towards to
AC

destabilizin efficiently
g place this
phenomeno system in
n market

 Used in  Stability
replacemen is of short
t for term due
liposomes to less
and amount of
vesicles as surfactant

72
 ACCEPTED MANUSCRIPT

they are used

more
stable.  lack of
understan
ding of
basic
chemistry
involved
in

T
productio

IP
n of NE
has

CR
created
misconcep
tions in

US
mind of
researcher
AN
s leading
to
avoidance
M

in
working
ED

on NE or
terminatio
n of
PT

ongoing
works
CE

SEDDS Mixture of  GRAS  Improved  Lack of

oil & status oral robust in
surfactants bioavailabil vitro
AC

 Simple ity model

 Excellent  Selective  Oxidation
capsule targeting potential
compatibilit of lipid
y  Drug componen
protection t
 Unlikely to from the
lose solvent hostile  High ratio
capacity on environmen of lipid
and

73
 ACCEPTED MANUSCRIPT

dispersion t in gut surfactant

may lead
 Drug  Reduced to
absorption dosing complex
without reactions
digestion and
ultimately
serious in-

T
vivo
issues

IP
 High

CR
concentrat
ion of
surfactant

US
may lead
to serious
AN
toxicity
by
altering
M

the
protein
ED

structure
and
malfuncti
PT

oning the
enzyme
and
CE

phospholi
pid
membrane
AC

PE Water, oil  Emulsifiers  Formulatio  Nanostruc

and used are of n at ture get
amphiphile nanometric nanoscale severely
size structures affected
are possible on higher
 The surfactant
stabilization  Recently concentrat
through manufactur ion
surface ed as

74
 ACCEPTED MANUSCRIPT

adsorption. magnetic  When the

balls particle
size
 Easy distributio
preparation n is very
and scale broad and
up particles
 Lack of are used

T
flocculation at a non-
limiting

IP
,
sedimentati amount,

CR
on & only a
creaming small
fraction

US
of
particles
could
AN
actually
act as
Pickering
M

emulsion
stabilizers
ED

, whereas
broader
fractions
PT

would
remain
CE

non
adsorbed

Vesicles based systems

AC

Liposomes Phospholipid  Biological  Offer targeted  Less

s, ly inert drug delivery stability

cholesterol,  Biodegrad  Increase  Low

able and efficacy and solubility
water
weakly therapeutic
immunog index of drug  Short
enic half-life
 Non-toxic,
 Phospholi

75
 ACCEPTED MANUSCRIPT

 Passive flexible, pids

targeting biocompatible undergoes
to REC by , completely oxidation,
pegylation biodegradable hydrolysis
possibility
 Help reduce  Leakage
to avoid
RES by exposure of and fusion
pegylation sensitive
tissues to  High

T
 Increased toxic drug productio

IP
plasma n cost
circulatio  Size can be


CR
varied to Allergic
n and reactions
increased incorporate
smaller or may occur
half life

US
larger drug to
 Active molecules liposomal
targeting constituen
AN
reduced  Can ts
toxicity incorporate
both water  They are
and
M

and lipid not

increased suitable
efficacy soluble drugs
ED

for
 Can be transderm
administered al delivery
PT

through
various routes
CE

Niosomes Non-ionic  Osmotical  Niosomes are  Physical

surfactant ly active. osmotically instability
and active,
AC

cholesterol  Site  Aggregati

specific  Chemically on
delivery stable and
have long  Fusion
 Biocompa storage time
tible,  Leaking
compared to of
biodegrad liposomes
able and entrapped
non-  They have drug
immunog high  Hydrolysi

76
 ACCEPTED MANUSCRIPT

enic. compatibility s of
with encapsulat
 Less toxic biological ed drugs
and systems which
improves limiting
the  Low toxicity the shelf-
therapeuti because of life of the
c index of their non- dispersion
drug ionic nature

T
 They are


IP
Biodegradabl not
e and non- suitable

CR
immunogenic for
 They can transderm
al delivery

US
entrap
lipophilic
drugs into
AN
vesicular
bilayer
membranes
M

and
hydrophilic
ED

drugs in
aqueous
compartments
PT

 Sustained
release drug
CE

delivery
possible
AC

 Access to raw
materials is
convenient

Pharmacosomes Drug, lipid,  Physical  Less time  A

and required for compound
High purity
chemical formulation can be
solvents
stable than other synthesise
system vesicular d
systems depending

77
 ACCEPTED MANUSCRIPT

 Consist of  The process on the

both of drug amphiphil
hydrophili release is ic nature
c and hydrolysis
hydropho rather than  They
bic drugs bilayer require
diffusion, superficial
 Can surface as well as
permeate mass

T
desorption, or
through degradation drug-lipid

IP
the cell as in case of interaction
membrane .

CR
liposomes.
, walls, or
tissues  The  Covalent
entrapment type of

US
 The rate efficiency of bond is
of pharmacosom required
degradatio to restrict
AN
es remain
n relies on unaffected by drug
size, the volume of leakage
nature of
M

inclusion  Pharmaco
functional
group  The somes are
ED

present in membrane susceptibl

the drug fluidity of e to get
fused,
PT

molecule pharmacosom
es is aggregate,
 Can be dependent on or
CE

administer conjugate hydrolyse

ed via phase by
topical, transition chemicals
AC

oral, temperature. on storage

extra- or
intravascu  There is no
lar route drug leakage
or
sedimentation
due to
covalent
binding of the
drug to the

78
 ACCEPTED MANUSCRIPT

carrier

Phytosomes/her Herbal  Better  Phosphatidylc  Bioavaila

bosomes extracts, PC bioavailab holine acts a bility is
ility carrier as well limited in

T
andabsorp as has case of
tion hepatoprotecti orally or

IP
ve effect topical
 Easy applicatio

CR
manufactu  The ns
ring absorption
processes and  Require

US
bioavailabilit superficial
 Ingredient y of water as well as
s are of soluble mass
AN
natural phytoconstitu drug-lipid
origin ents is interaction
M

increased.
 Covalent
 Better type of
ED

therapeutic bond is
effects required
to restrict
PT

 Drug drug
targeting leakage
CE

 These are
susceptibl
AC

e to get
fused,
aggregate,
or
hydrolyse
by
chemicals
on storage

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 ACCEPTED MANUSCRIPT

Elastic Phospholipid  These can  They have  Unable to

liposomes s, surfactants accommo higher deliver
and edge date entrapment high-
activators hydropho efficiency molecular
bic as -weight
 They allow
well as complex
hydrophili enhanced molecules

T
c moieties permeation of to the

IP
drug through inner
 Due to skin layers of

CR
their skin
 They can
deformable
nature they increase the  Resistance

US
can transdermal to deliver
squeeze flux hydrophili
through  Prolonging c drug
AN
narrow the release moiety
constriction and  SC the
without
M

improving the outermost

measurable site-
loss layer and
specificity of
ED

interface
 Give bioactive with the
better molecules outside
PT

penetratio  They can world – is

n of intact accommodate considere
vesicles. d a major
CE

drug
molecules hydropho
 Can act as a
with a wide bic
carrier for
AC

range of crystalline
low as barrier to
well as solubility
TD. Thus,
high it is even
molecular more of a
weight hurdle to
substance deliver
s hydrophili
 Are made c and
up of high-

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 ACCEPTED MANUSCRIPT

natural molecular
phospholi -weight
pids hence complex
are molecules
biocompat to the
ible and inner
biodegrad strata of
able the skin

T
 Higher

IP
entrapmen
t

CR
efficiency

Ethosomes Phospholipid  Permeatio  Can deliver to  Poor yield

US
s,water, high n of drug targeted site
 In case if
quantity of through by non-
ethanol skin invasive shell
AN
means locking is
 Can ineffective
deliver  Large mol. then the
M

large wt.
molecules compounds ethosomes may
coalescence and
ED

(peptides, can be deliver

protein fall apart on
 High transfer into
molecules
PT

) is permeation water
possible rate observed
 Loss of
CE

 Ethosoma product
l system is during
passive, transfer
AC

non- form
invasive organic to
water
media

Transfersomes Phospholipid  These are  Large mol. wt  These are

s and edge self compounds chemicall
activators aggregates, can be deliver y unstable
(EAs) like with an at efficient because of
sodium ultra rate their

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 ACCEPTED MANUSCRIPT

cholate flexible  Due to its predisposi

(NaCo), membrane elastic nature tion to
sodium which leakage of oxidative
deoxycholate delivers the drug is degradatio
drug minimum n
reproducibl
 Efficient  Expensive
y into or
through the transdermal manufactu
delivery ring

T
skin

IP
 More elastic
than the

CR
standard
liposomes

US
 Suitable for
peptides
delivery
AN
Arachaeosomes Archaeal  Can be  The archaeal  Less pH
lipids sterilized lipids are stability
M

by more stable
 Expensive
autoclavin than other
manufactu
ED

g phospholipids
ring
 Have  Stability
PT

more toward
thermo- oxidative
labile degradation
CE

stability in would be
environm improved by
ent saturated
AC

alkyl chains
 Archaeal
lipids act  It does not
as self- require
adjuvant cholesterol in
drug the
delivery formulation
systems

Vesosomes Aqueous core  Multi-  Steric  Premature

82
 ACCEPTED MANUSCRIPT

containing compartm stabilization contents

unilamellar ent release in
 pH loading of
vesicles structure physiologi
that drugs cal
function  Intrinsic environme
as internal biocompatibil nts. This
compartm ity premature
ents release is
 Better

T
which likely
contain protection to due to

IP
the drug the interior enzyme
and which contents in degradatio

CR
can vary serum, n or
in leading to protein
extended

US
compositi insertion
on from release of into the
each other encapsulated liposome
AN
drug membrane
 Easy to , which
produce significant
M

and offers ly
the increases
flexibility
ED

the bilayer
to deliver permeabili
multiple ty.
PT

drugs
within a
single
CE

carrier

Colloidosomes Microcapsule  Excellent  Offers great  Poor yield

AC

s control of potential in of
sizing controlling particles
Colloidal
the
particles  Flexible permeability  If shell
and of the locking is
adjustable entrapped insufficien
yield species and t then the
strength to allows the colloidoso
withstand selective and mes may
varying collapse

83
 ACCEPTED MANUSCRIPT

mechanic time release and fall

al loads apart on
 Control of transfer
 Easily compactibilti into water.
constructa y allows
ble encapsulation  Large
of fragile and proportion
sensitive of
ingredients, colloidoso

T
such as mes

IP
biomolecules seems to
and cells. be lost on

CR
the
transfer
from

US
organic to
water
AN
media.

Lipospheres Tri Caprin,  Better  Extended  Low drug

Tri Lauren, physical release of loading
M

Stearic acid, stability loaded drug. capacity

of
ED

Hydrogenate  Low cost  High lipophilic

d vegetable of its entrapment of proteins.
oil, Tri componen hydrophobic
PT

Stearin, Ethyl ts. drug.  Variable

kinetics.
Stearate.  Ease of  Reduced
CE

preparatio mobility of  Drug

n. entrapped degradatio
AC

drug. n due to
 High high
degree of  Offers better pressure.
dispersibil biocompatibil
ity in ity and being  Insufficie
aqueous physiological nt
medium substance. stability.
loading of
lipophilic  Offers high  Different
drug. degree of lipid
variability modificati

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 ACCEPTED MANUSCRIPT

due to ons and

different colloidal
degree of species
esterification coexist
and chain that may
lengths or cause
even mixtures different
of lipid solubility

T
components. and
melting

IP
 Administrable point of
by various active and

CR
routes such as auxiliary
oral, I.V, I.M species.
and topical

US
route.

SLM Solid  Use of  Possibility of  Possibility

AN
hydrophobic biodegrad controlled of particle
fat core able lipids drug release growth
(triglyceride) and drug
M

 Allows targeting  SLMs

hydrophili dispersion
ED

c and/or  Protection of s have

hydropho incorporated high water
bic drugs labile drug content
PT

to be against
incorporat chemical  They
adjust the
CE

e degradation
release
 There is profile of
AC

chemical and the

physical incorporat
storage ed drug.
stability (for
both drug and  Safety
carrier profile
system) may be
uncertain

 Drug
loading

85
 ACCEPTED MANUSCRIPT

may be
limited
due to the
solubility
and
miscibility
of the
drug in

T
the melted
lipid,

IP
chemical
and

CR
physical
structure

US
of lipid
materials,
and their
AN
polymorp
hic state.
M

SLN Physiological  Avoidanc  Organic  Low drug

lipid, e of solvents not loading
ED

dispersed in organic required for capacity

water or in an solvents formulation
aqueous  Drug
 Potential  Greater expulsion
PT

surfactant
wide stability and during
solution applicatio bioavailabilit storage
CE

n y
spectrum(  High
dermal, water
AC

per oral, content

intraveno  Low
us) and capacity
 High to load
pressure hydrophili
homogeni c drug
zation as
an
establishe

86
 ACCEPTED MANUSCRIPT

d
productio
n method

T
IP
CR
US
AN
M
ED
PT
CE
AC

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 ACCEPTED MANUSCRIPT

Table 2 Characterization of nanocarriers

S.
Characterization parameters Instrumentation/ Analytical methods
No
Transmission electron microscopy (TEM)
Scanning electron microscopy (SEM)
1 Shape and surface morphology Phase contrast optical microscopy (PCM)
Atomic force microscopy (AFM)

T
Freeze fracture microscopy (FFM)

IP
2 Molecular weight Gel permeation chromatography (GPC)

CR
3 Surface charge and electrophoretic mobility Laser light scattering technique
Electron microscopy (SEM/TEM)

US
4 Vesicle size and size distribution Optical microscopy
Photon correlation spectroscopy (PCS)
Hydrophobic interaction chromatography
AN
Two phase partition
5 Surface hydrophobicity Radiolabel probe
M

Contact angle measurement

X-ray photoelectron spectroscopy
ED

Zeta potential measurement

6 Electrical surface potential and surface pH
pH sensitive probes
PT

7 Density Gas pycnometer

8 Rheology Viscometer
CE

Dialysis membrane
9 In-vitro release
Dissolution test apparatus
AC

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Table 3 Lipid based formulation under clinical trials (CT)

Product name Phase of Drug delivered Indication Reference

CT
151
Alocrest Phase I Vinorelbine NSCLC and breast cancers,
(Optisomes) non-Hodgkin’s lymphoma,
Hodgkin’s disease

T
152
ATI-1123 Phase I Docetaxel NSCLC, gastric, pancreatic

IP
(Protein stabilized cancer, and soft
Liposomes) tissue sarcoma

CR
153,154
Aroplatin Phase I/II Analog of Advanced pancreatic and
(MLVs) cisplatin colorectal cancer,

US
malignant pleural
mesothelioma, advanced
AN
solid malignancies
155,156
MCC-465 Phase I Doxorubicin Stomach cancer
M

(Antibody
conjugated
ED

PEGylated
liposomes)
PT

157-159
SGT-53 Phase I p53 DNA plasmid Solid tumors
(Anti-TfR
CE

conjugated
cationic liposomes)
AC

TKM-080301 Phase I/II PLK1 siRNA Gastrointestinal 160,161

(TKM-PLK1) neuroendocrine tumors,

(Cationic adrenocortical carcinoma,
PEGylated hepatocellular carcinoma
Liposomes)
162-164
Liposome- Phase I/II annamycin breast cancer, acute
annamycin lymphocytic leukemia

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 ACCEPTED MANUSCRIPT

NanoVNB Phase I Vinorelbine Advanced solid tumors

(PEGylated
liposomes)
165
Anti-EGFR Phase I Doxorubicin solid tumors
immunoliposomes
166-167
MBP-426 Phase II Oxaliplatin Gastric, gastroesophageal,
(Tf-conjugated esophageal

T
IP
liposomes) adenocarcinomas
168-170
EndoTAG-1 Phase II Paclitaxel Solid tumors

CR
(Cationic
liposomes)

US
171
OSI-211 Phase II Lurtotecan NSCLC, breast, colorectal,
(SUVs) ovarian, head and neck
AN
cancers
172
CPX-1 Phase II Irinotecan and Advanced solid tumors,
M

(ULVs) floxuridine (1:1) including

colorectal cancer
ED

173
LEP-ETU Phase II Paclitaxel Metastatic breast cancer
(Anionic liposomes)
PT

174
Pulmaquin/Lipoquin Phase II/III ciprofloxacin non-cystic fibrosis
bronchiectasis
CE

175-177
MM-398 (PEP02) Phase III Irinotecan Metastatic pancreatic
(PEGylated cancer
AC

liposomes)
178, 179
CPX-351 Phase III Cytarabine and Acute myeloid leukemia
(Bilamellar daunorubicin (5:1)
liposomes)
180
Thermodox Phase III Doxorubicin Hepatocellular carcinoma
(Lyso-lipid and breast cancer
temperature
sensitive liposomes)

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 ACCEPTED MANUSCRIPT

181,182
Lipoplatin Phase III Cisplatin NSCLC, gastric,
(PEGylated pancreatic, breast, head and
liposomes) neck cancers
183
Arikace Phase III amikacin lung infection

T
IP
CR
US
AN
M
ED
PT
CE
AC

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Table 4 List of marketed nanocarrier products

Nanocarrier
Active ingredient Indication Trade name Company
system
Enzon
P T
Pharmaceuticals Inc., Bridgewater, NJ,
Amphotericn B Fungal infections

Lymphomatous
Abelcet
USA
R I
Cytarabine
Meningitis
Depocyt

S CEnzon Pharmaceuticals Inc., NJ, USA

Amphotericn B

Daunorubicin
Fungal infections

Kaposi’s sarcoma
AmBisome

Daunoxome
N U Gilead Sciences Inc., Foster City, CA, USA

Gilead Sciences Inc., CA, USA

Doxorubicin Advanced breast Myocet
A Zeneus/Cephalon, Inc., Frazer, PA, USA
Inactivated Hepatitis cancer M
A virus
Hepatitis A

E D Epaxal Berna Biotech, Bern, Switzerland

T
Inactivated influenza
Influenza Inflexal V Berna Biotech, Bern, Switzerland
surface antigen
Morphine
E P
Analgesia DepoDur EKR Therapeutics, Bedminster, NJ, USA

Verteporfin
C C Age-related macular
degeneration
Visudyne
QLT Inc., Vancouver, British Colombia,
Canada; Norvatis, Basel, Switzerland

Liposomes
A
Doxorubicin
Ovarian cancer &
Kaposi’s sarcoma
Doxil Ortho Biotech, Bridgewater, NJ, USA

Ovarian cancer,
Doxorubicin Kaposi’s arcoma & Caelyx Schering-Plough, Kenilworth, NJ, USA
breast cancer

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 ACCEPTED MANUSCRIPT

Menopausal Hot
Estradiol Estrasorb Novavax, Rockville, MD, USA
flushes
Beractant (bovine Respiratory distress
Survanta Abbott Laboratories, IL, USA
lung homogenate) syndrome
Bovactant(bovine Respiratory distress
P T
Boehringer Ingelheim GmbH, Ingelheim
lung lavage)
Poractant
syndrome
alfa Respiratory distress
Alveofact
I
Germany
R
(porcine lung syndrome Curosurf
S C Chiesi Farmaceutici SpA, Parma, Italy

Polymeric
homogenate)
Paclitaxel
Cancer
Genexol-PM
N U Samyang Pharmaceutical, Daejeon City, Korea
micelles chemotherapy
A
Rapamune Sirolimus
M
Immuno suppressant
Elan Corporation, Dublin,
Pharmaceutical, Madison, NJ, USA
Ireland; yeth

Emend Aprepitant
E D Antiemetic
Elan Corporation, Dublin, Ireland; Merck and

P T Co., Inc. Whitehouse Station, NJ, USA

Elan Corporation, Dublin, Ireland; Abbott Labs,
Nanocrystalline
Drugs
Tricor

C E Fenofibrate Hyperlipidemia
Illinois, USA

Megace

A C Megestrol acetate Anorexia, Cachexia

Elan Corporation, Dublin,
Pharmaceuticals, Woodcliff Lake, NJ, USA
Ireland;

Protein
Abraxis BioScience, Los Angeles, CA, USA;
(albumin) Abraxane Paclitaxel Metastatic breast cancer
Astra Zeneca, London, UK
nanoparticles

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 ACCEPTED MANUSCRIPT

Lipid colloidal
Amphotec Amphotericin B Fungal infections InterMune, Brisbane, CA, USA
dispersion
Lidocaine &
ORAQIX® prilocaine Periodontal Anesthesia Dentsply Pharmaceutical

T
Microemulsion
periodontal gel
Neoral Cyclosporine Anticancer
I P
Wolters Kluwer

Lesion-directed
Aminolevulinic acid field-directed
and

C
treatment
R
Nanoemulsion AMELUZ
hydrochloride of actinic
U S
keratoses
Biofrontera

Phytosome Greenselect®
(AKs)

A
Complex of green Antioxidant, N liver
thermogenic Thorne Research
M
tea polyphenols & protective,
phosphatidylcholine (fat burning) effects

Transfersomes Diractin
Ketoprofen
E D in
Analgesic Idea AG

P T
Transfersome gel
Vitamin C and E Used in skin care and
Aquasome Aquasome EC-30

C E
derivatives anti-aging agent
Nikkol

A C

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Table 5 Contribution in the proposed area

Therapeutic
Nanocarriers Disease Contribution References
agent

Breast

P T
cancer  Comparative evaluation based on tissue distribution,

I
184
Nanospheres Mitoxantrone and lymph node acute toxicity, therapeutic efficacy against breast
metastases.
R
cancer and its lymph node metastases.

C
 Exploration of novel methods for selective drug
Folate-hapten
conjugate
Hapten Mice liver delivery
U S 185

 Investigation
N
 Identification of optimal targeting ligand

A of functionalized SWCNTs for

M
tumour targeting

D
Murine 4T1
SWCNTs PTX  CNTs as promising carrier with high entrapment 186
breast cancer

T E and less side effects

E P  Possibility of future cancer therapy

 Potential results in phase I clinical study of

C C escalating doses of the lapatinib in patients with

Albumin
NPs
bound
PTX
A Advanced solid
malignancies
advanced solid tumors
 Dynamic contrast enhanced magnetic resonance
187

imaging studies in a subset of patients confirmed a

decrease in tumor vascular permeability
 Formulation of thermosensitive magneto-liposomes 188
Thermo-sensitive MTX Skeletal

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magneto- muscular tissue (TMs) containing MTX

liposome  Superior magnetic targeting effect and rapid drug
release in response to hyperthermia
 Potential for cancer therapy
HER-2 over
P T
Albumin bound Carboplatin/ expressing
paclitaxel nanoparticles
R I
 Evaluation of efficacy and safety of albumin-bound
189
NPs trastuzumab metastatic breast
cancer C
 High activity in HER2-overexpression
S
Metastatic
N U
 Development of doxorubicin loaded SLN
 Assessment of in vitro haemolytic effect
SLN DOX
breast cancer A
 Enhanced apoptotic cell death through higher
190

M
accumulation of doxorubicin in cancer cells

E D  Formulation of novel nanocrytals for hydrophobic

Pluronic
polymer
F127
PTX and Murine
P T breast
drugs
 Excellent antitumor activity 191

nanocrystals
camptothecin

C E
cancer
 Low toxicity

Aerosol-OT A C Balb/c mice

 Easy scale-up

 Reported combinatorial anticancer activity of DOX

bearing Drug
(surfactant) and methylene blue 192
DOX Resistant
(AOT), and  Enhanced tumor accumulation of both DOX and
syngeneic JC
Sodium alginate methylene blue
tumors

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 Considerable inhibition of tumor cell proliferation

For co-delivery  Formulation of cationic SLN for co-delivery of PTX
Epithelial 193
Cationic SLN of PTX and and siRNA
carcinoma
siRNA  Enhanced tumor inhibition

P T
Exploration of nanocarrier mediated transdermal

Lipid based Topical

R I
delivery of Huperzine A (HupA) for the treatment

C
194
Huperzine A of Alzheimer's disease
nanocarriers administration

S
Formulation and characterization of ME, SLNs,
and NLCs
U

 A N
Designing of nanocarrier
Soft
nanocarriers
lipid Bioactive
vegetable oils
Antioxidant
activity M
Superior in vitro antioxidant activity mediated by
nanocarrier
195

ED Improved photoprotective effect

SLN, NLC, and T

Nutraceutical
P  Fabrication of lipid carrier as SLN, NLC and NE 196
lipid NE
Quercetin

C E
compound
delivery
 Greater entrapment & maximum bioaccessibility

Nanocarrier- A C  Emergence of hybrid (organic/inorganic)

nanoparticles to build “theranostic” systems
Cancer

197
Plasmonic gold DOX Highlighted superparamagnetic iron oxide
treatment
NPs nanoparticles (SPIONs) and plasmonic gold
nanoparticles (Au-NPs) for cancer treatment

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High activity
 Formulation of functional lipid nanocarriers with
against oxygen
Lipid unique features 198
natural oils free radicals and
nanocarriers  Greater antioxidant activity with nanocarrier
tumor cell
proliferation
 Better therapeutic effect

P T
Glucose 
 R I
Preparation of glucose-responsive nanocarriers
responsive
hydrogel- Insulin
Oral delivery of
insulin
Encapsulation of

S C insulin-loaded
responsive nanocarriers into a HA hydrogel
glucose-
199

nanocarriers
system

U
Better option for diabetes treatment via oral
ingestion
N
Biodegradable A
hyperbranched For efficient

M
Formulation of nanocarrier for topical delivery

core-multishell Dexamethasone topical drug

E D 

Better skin permeation by nanocarrier
Improved stability, low cytotoxicity, and easy
200

nanocarriers
(CMS)
delivery

P T scale up

C E
A C

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Highlights:

 Nanotechnology is the science and technology of precise manipulation in the materials,

devices or systems at nanometer scale.
 Pharmaceutical nanotechnology has offered fine-tuned diagnosis and focused disease
treatment.

T
 Recently lipids are becoming very popular as potential excipients for drug delivery as

IP
well as cosmetics.

CR
 Using nanotechnology based LBDDS, faster, patient friendly and economic treatments
can be established.


US
In recent years significant efforts have been made to explore the potentials of LBDDS.
 LBDDS having applications in various fields like pharmaceuticals, cosmetics,
nutraceuticals.
AN
 One of the major challenges faced by LBDDS is their susceptibility to oxidation.
 Pharmaceutical industries are more concerned in the designing of an appropriate drug
M

delivery system that could be adequately versatile and viable for scale up of the
ED

formulation.
 The safety of many of nanotechnological systems is yet to be determined.

PT

Lipid based system could be a potential molecular vector for clinical translation.
CE
AC

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Graphics Abstract
Figure 1
Figure 2
Figure 3ab
Figure 3c
Figure 4ad
Figure 4eg