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Current Applied Polymer Science, 2020, 4, 1-9 1
REVIEW ARTICLE

Lipoidal-Nano Architecture for Parental Drug Delivery: Formulation De-

velopment and Regulatory Concerns
Vikas Jhawat1,*, Anil Kumar Sharma1, Vandana Garg2, Monika Gulia1 and Rohit Dutt1

1
School of Medical and Allied Sciences, GD Goenka University, Gurugram, Haryana, India; 2Department of Pharma-
ceutical Sciences, Mahrishi Dyananad University, Rohtak, Haryana, India

ARTICLE HISTORY
Received: April 10, 2020
Revised: June 09, 2020
Accepted: June 11, 2020
DOI:
10.2174/2452271604999200706014809
Abstract: The nanoparticles as drug carriers have demonstrated enhanced targeting, and sustained/-
controlled drug release, as evident from numerous investigations that have shown promising out-
comes facilitating the wellbeing of humans in the desired manner. The lipid-based nanoparticles
are biodegradable and considered biocompatible by virtue of being composed of lipid moieties
mimicking physiological lipids of biological systems which is their prime advantage over the other
polymeric systems. A variety of such lipid carriers have been reported to be delivered from the par-
enteral route. However, there are certain pitfalls which are associated with lipid nanoparticles such
as toxicity, poor scale up potential, immunological reactions and absence of straight forward regula-
tory guidelines that address the issues of lipoidal nanocarriers such as their classification, approval
and compliance of governmental policies. Therefore attention must be given to address the techno-
logical and regulatory challenges associated with lipoidal nano-formulations for parenteral adminis-
tration to smoothen the approval process throughout the world and bringing the same to the termi-
nal users on time.

Keywords: Lipids carriers, nanotechnology, parenteral route, regulatory challenges, lipid nanoparticulates, lipoidal nanocarri-
ers.

1. INTRODUCTION
The parenteral route has been considered as the most ef-
fective and fastest route for drug delivery and action of a
drug inside the body because of many reasons such as no
need for drug absorption phase, hundred percent bioavailabil-
ity, no first-pass effect and formulation advantages. But de-
spite many advantages, this route also has some limitations
related to the physicochemical properties of drugs such as
the problem of solubility in blood components, drug release
from the formulation, non-target adherence of drug
molecules, drug toxicity, burst effect and many more. The
majority of the newly discovered drug molecules being hy-
drophobic in nature have low aqueous solubility, low bioa-
vailability, and impaired pharmacokinetic behavior inside
the body and tissue toxicity [1, 2]. During the drug develop-
ment phase, we cannot make a choice for the lead molecules
to be hydrophilic or lipophilic and as per a study; there are
more chances of the drug molecules being lipophilic which
further may become the reason of rejection in later stages of
the drug development due to poor water solubility [3, 4].
Therefore to avoid such problems, we need some modifica-
tions in the drug formulation to get the desired effect with
minimum adverse events. Nanotechnology can be of great
importance in developing the desired formulation utilizing
various synthetic and natural polymers carriers. Lipoidal
* Address correspondence to this author at the School of Medical and Al-
lied Sciences, GD Goenka University, Gurugram, Haryana, India;
Tel: +91-9729216101; E-mail jhawat231287@gmail.com
carriers are one among them which, when processed at the
nano scale can result in biocompatible drug carriers. In
the present manuscript, we reviewed the applications of
nanotechnology in the area of parenteral drug delivery using
lipoidal carriers for improved drug delivery.
2. NANOTECHNOLOGY
Application of nanotechnology in the area of drug deliv-
ery (nanocarrier drug delivery) could be considered promis-
ing in circumventing above mentioned problems. Nanotech-
nology is the science which deals with the molecules at the
nano scale (1-100 nm) where molecules exhibit some specif-
ic size and shape-dependent magnetic, electrical and optical
properties that are not generally observed in the bulk mate-
rial of the same compound [5, 6]. Nanotechnology allows us
to manipulate physicochemical properties in such a manner
that the molecule (nanoparticles) behaves as per the require-
ments under different environmental conditions [7, 8]. Nano-
carrier drug delivery systems are of various types based on
the polymeric systems utilized in the manufacturing and can
be administered via different routes such as oral, nasal, ocu-
lar, intraperitoneal, rectal, transdermal and parenteral route
[9-12].
2.1. Parenteral Route
The focus of the current review is on drug delivery
through the parenteral route. This route offers several advan-
tages over other routes such as [13]:

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2 Current Applied Polymer Science, 2020, Vol. 4, No. 0
Dose accuracy with immediate onset of action
Pain-free delivery of larger doses
Easy to administer in unconscious and non-coopera-
tive patients.
The unpleasant and bitter taste of the drug is no
problem.
Nanocarrier drug delivery systems play an important
role in improved parenteral administration of the drugs for
the specific need. Nanoparticles delivered through parenteral
route have additional advantages such as [14]:
Enhanced drug circulation time in the body which
prolongs the residence time of the drug for pro-
longed therapeutic effect
Targeting and release of the drug at the desired site
Improved physicochemical properties of drugs
Bypassing the first-pass effect of drugs via oral ad-
ministration.
Nanocarriers can be prepared using different biodegrad-
able and biocompatible polymers such as [15, 16]:
[a] Natural lipids e.g. triglycerides, fatty acids, partial
glycerides, steroids and waxes.
[b] Hydrophilic polymers from natural origin e.g. ge-
latin, albumin, lecithin, legumin, alginate, dextran,
chitosan, agarose and pullulan.
[c] Synthetic hydrophobic polymer e.g. polyesters, poly
(lactic acid), poly (lactide-co-glycolide), polystyrene,
Fig. (1). Lipoidal nanoarchitecture that can be used for a novel drug delivery system through parenteral route.
Jhawat et al.
poly (alkyl cyanoacrylates), poly (isobutyl cyanoacry-
lates), poly (butylcyano acrylates), poly methyl
(methcyanoacrylates).
2.2. Lipoidal Nanocarriers for Drugs
Lipoidal nanoparticulate delivery system can deliver the
drug in such a manner that it may overcome the problems as-
sociated with the new drug candidates such as drug transpor-
tation problem, first pass metabolism, short residence time,
poor absorption and permeation of the drug from blood ves-
sels to the tissues [17, 18]. When these lipid carriers are ad-
ministered through the parenteral route, it provides an excel-
lent opportunity to inject the drug directly into the blood
stream for faster onset of action, site-specific delivery of the
drug and encapsulation of both hydrophilic and lipophilic
drugs [19, 20]. Lipoidal nanoparticles have demonstrated bet-
ter biocompatibility with the biological system than the or-
ganic nanoparticles because of the lipid nature of the biologi-
cal membranes [21]. Lipoidal nano-carrier drug delivery sys-
tem for parenteral administration can be formulated into dif-
ferent types of assemblies such as solid-lipid nanoparticles
[16, 21, 22], nanoemulsions [23, 24], nanosuspensions [25],
niosomes [26], liposomes [27], lipid nanocapsule [28], lipid
core micelles [29, 30], and nanostructured lipid carriers [31].
The purpose of all the drug delivery systems is to maximize
the efficacy of the drug at lower doses and to minimize the
side effects. Therefore, a suitable drug delivery system is de-
signed based on the physicochemical properties of the drug
molecules. Diverse lipid nanocarrier systems suitable for par-
enteral administration are given below (Fig. 1):
Lipoidal-Nano Architecture for Parental
Solid lipid nanoparticles (SLN): Solid lipid nanoparti-
cles are made up of a mixture of solid lipids and liquid
lipids, which is stabilized by the addition of emulsifying
agents. SLNs have unique properties such as small size (10
nm to 1000 nm), large surface area, biocompatible and
biodegradable, high drug loading capacity, and can load
both hydrophilic and lipophilic drugs [32, 33]. SLNs are pre-
pared from fatty acids, triglycerides, steroids and waxes us-
ing soybean lecithin, phosphatidylcholine, and sodium gluco-
nate as emulsifying agents [34].
Nanoemulsion: Nanoemulsion is a fine to ultrafine ther-
modynamically stable dispersed system which is made up of
water in oil (w/o) or oil in water (o/w) emulsion stabilized
by emulsifying agents and have a size range of 50nm to
1000nm [35]. Nanoemulsions, when seen through the naked
eye, appear transparent as fine globules in the emulsion, can-
not scatter the light rays [36]. Nanoemulsion is non-toxic
and non-irritant to the biological system and can be utilized
as the drug carrier for a number of drugs [37]. Nanometric
size of the dispersed phase in the nanoemulsion confers it
least chances of cracking, coalescence, flocculation, cream-
ing and sedimentation of the emulsion.
Nanosuspension: It is the biphasic dispersion system in
which nano-sized particles (200nm-600nm) of the pure drug
are uniformly dispersed in the aqueous vehicle stabilized by
the surfactants. Reduction in the particle size of the drug to
nanoscale increases the surface area and saturation solubility
of the drug particles and therefore, poorly water lipid-solu-
ble drugs can be easily formulated with high bioavailability
profile [38-40].
Niosomes: Niosomes are unilamellar or multilamellar
vesicles formed by the non-ionic surfactants with the combi-
nation of cholesterol or other lipids [41]. Cholesterol forms
the hydrogen bond with the hydrophilic head of the non-ion-
ic surfactant, which impacts the physical properties of the
vesicles such as entrapment efficiency, stability, and drug re-
lease characters [42, 43]. These have the size range of 20 nm
to 200 nm and can encapsulate both hydrophilic and lipophil-
ic drugs for delivery to the human body. Niosomes are a sta-
ble, low cost, material easily available for preparation [44].
These prolong the circulation time of the drug in the blood
and can easily penetrate the cells through different peptide
channels, having a higher distribution rate [45].
Liposomes: In contrast to the niosomes, liposomes are
vesicular structure made up of phospholipids or sphin-
golipids, which contain an inner hydrophilic core protected
by an external hydrophobic lipid bilayer. Because of the
presence of dual moieties, liposomes can be utilized for the
delivery of both hydrophilic and lipophilic drugs [46]. Based
on the arrangement of lipid bilayers, liposomes can be classi-
fied into unilamellar (containing single bilayer) and multil-
amellar (more one lipid bilayer separated by aqueous space)
[47]. The structure and composition of the lipid bilayer of li-
posomes are almost similar to that of the biological mem-
branes, which makes liposomes more biocompatible and
safer as compared to niosomes and other vesicles. Because
of the structural similarity, liposomal bilayer can easily fuse
Current Applied Polymer Science, 2020, Vol. 4, No. 0 3
with the cell membranes and release its content where re-
quired [48, 49].
Lipid nanocapsule: Lipid nanocapsules are the vesicu-
lar structure made up of three components namely; oily
phase such as triglycerides, aqueous phase such as purified
water containing sodium chloride salt and non-ionic surfac-
tants for the stabilization of the nanocapsule [50-52]. The
vesicles of lipid nanocapsule form an inner lipid core that en-
traps the drug molecules and an open hydrophilic surfactant
tail outside. Nanocapsules can be used for sustained or con-
trolled delivery of the drug [53]. Lipid nanocapsules reduce
the drug degradation and increase the drug’s stability and wa-
ter solubility [54, 55], and when administered through the
parenteral route, lipid nanoparticles provide the direct access
of the drug into the blood which enables quick action and tar-
geting of the drug at the desired site [56].
Lipid core micelles: Along with the polymeric micelles,
lipid core micelles formed by the phospholipids can also be
utilized as the drug delivery carrier for poorly water-soluble
drugs. The long-chain fatty acyl group present in the phos-
pholipid can be formulated into a hydrophobic micelle core
capped by the hydrophilic polymer such as PEG, which
forms the external hydrophilic part of the lipid micelle
[57-59]. Phospholipids are a biocompatible and biodegrad-
able carrier and considered as safe drug delivery systems as
compared to polymeric systems. Therefore lipid-polymer
conjugate micelles prepared from phospholipids-PEG have a
size range of 7nm-35nm and at Critical Micelle Concentra-
tion (CMC), the hydrophobic part forms the core of the mi-
celles that can uptake the poorly soluble drugs surrounded
by the polymeric hydrophilic part. This type of micelles can
also be attached with the targeting moieties for a particular
type of organ, tissue or cells to achieve the maximum con-
centration of the drug at that particular site [60].
Nanostructured lipid carrier: Nano-Structured Lipid
Carriers (NLC) are similar in composition to the Solid Lipid
Nanoparticles (SLN) but NLCs have been designed to over-
come the limitations of SLN such as poor drug loading due
to crystalline nature of SLN, drug expulsion from the SLN,
and up to 30% particle concentration in the aqueous environ-
ment [61-63]. The NLCs are composed of surfactants, solid
lipidse.g., fats and liquid lipid e.g., oils complex at the room
temperature that has the size in the nanometer range. The
SLN contains up to 30% w/w of solid lipids content dis-
persed in liquid aqueous part, but in NLC, solid lipid content
may increase up to 95% w/w [64]. The NLC formulation
contains liquid lipid (oil) in the core of the particles, which
increases the solubility and loading capacity of drugs. More-
over, complex lipids of NLC have very slow polymorphic
transitions, therefore lower chances of crystallization [65,
66]. The lipid complexity of NLC improves the encapsula-
tion efficiency, drug loading capacity, bioavailability along
with the physical stability and chemical stability of the drugs
[64, 67]. NLCs, when administered through the parenteral
route, provide higher bioavailability and pharmacological ac-
tivity as compared to plain drug and provide protection to
the encapsulated drugs [68].
4 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Jhawat et al.

Table 1. Drug delivery through different kinds of lipoidal nano architect systems

Sr. No. Drug Polymer carrier Formulation Ref

1. Doxorubicin Phosphatidylcholine Liposomes 72
2. Zidovudine Phosphatidylcholine, Cholesterol Liposomes 73
3. Clobetasol propionate Monostearin SLN 74
4. Cortisone Trimyristin-phospholipid mixture SLN 75
5. Itraconazole Tristearin and triolein Lipid nanoparticles 76
6. All-trans retinoic acid (ATRA) or Cetyl palmitate and soybean oil NLC 77
Tretinoin
7. Silybin Glycerol monostearate-triglyceride NLC 78
8. Docetaxel Stearic acid, glyceryl NLC 79
monostearate, soya lecithin and oleic acid
9. Paclitaxel - Nanoemulsion 80
10. Thalidomide Olive oil, soybean oil and soybean lecithin Nanoemulsion 81
11. Docetaxel Soya lecithin, Glycerol, ceramide Nanosuspension 82
12. Docetaxel Soya lecithin, DSPE-PEG-2000-amine and DSPE-PEG-2000-methoxy Nanosuspension 83
13. Zidovudine Cholesterol, Tweens, Spans, dicetylphosphate Niosome 84
14. Tamoxifen Caprylic-capric acid triglyceride and Soybean lecithin Lipid nanocapsule 85
15. Tretinoin Caprylic-capric acid triglyceride and Polycaprolactone Lipid nanocapsule 86
16. Docetaxel PEG 660 12-hydroxy stearate, Hydrogenated soybean phosphatidylcholine Lipid nanocapsule 87
17. Taxol Sodium glycocholate, phosphatidylcholine Lipid core micelle 88
18. Lipid core micelle Phosphatidylcholine and bile salt Lipid core micelle 89

2.3. Lipid Nano Carrier Delivery
Lipid nanocarriers, as discussed above, have the im-
mense potential to deliver the variety of molecules for differ-
ent purposes inside the body e.g., delivery of hydrophilic
and hydrophobic drugs, gene, DNA, vitamins, hormones,
proteins, peptides and nutrients [69]. Lipoidal drug delivery
systems are preferred over the polymeric system because
lipid content of the delivery system resembles the lipid con-
tent of biological cell membranes, which provides easy ac-
cess to the drug delivered through the different barriers [70,
71]. However, lipoidal systems have their own limitations,
which pose a hindrance in the way of the lipoidal drug deliv-
ery system to become the universal carrier. These limitations
can be overcome using an alternate lipoidal carrier or by in-
corporating synthetic polymers in the lipoidal system. Differ-
ent types of molecules delivered using the lipoidal carrier
through the parenteral route are given in the below Table 1:
2.4. Challenges in the way of Lipodal Nano Architect Sys-
tems
2.4.1. Toxicity and Side Effects
Nanotechnology has wider applications in the area of
drug delivery, which offers many advantages over conventio-
nal drug delivery systems. It also has become successful to
some extent and few nanotechnology-based products have
been introduced in the market [90, 91]. Scientists from all
over the world are working continuously on this novel sci-
ence with the hope of developing more efficient and safer
drug delivery systems [91]. As nanoparticulate drug delivery
systems have been altered at the molecular level to alter the
physico-chemical (particle size, shape, composition, surface
area, charge), pharmacokinetic (ADME) and pharmacologi-
cal properties of the drug and polymers so that these can inte-
grate into a complex system in a manner to target the drug at
a specific site crossing the different biological barriers and
deliver the drug at a specific rate [92, 93]. But along with
many advantages, nanotechnology-based modified products
being at nano-size range have direct interaction with the hu-
man biological system and living cells which may prove
lethal because the body’s response to the nanoparticulate sys-
tems cannot be foreseen and it may also induce an immuno-
logical and inflammatory reaction, toxicity and oxidative
stress [94, 95], accumulation of nanoparticles in the liver,
kidney or other organs [96], risk of dose dumping from the
nanoparticles, leakage of a drug at the undesired site, escape
of the nanoparticulate system form the circulation, and im-
proper release of a drug from the nanoparticles [94]. Lipid
content of the lipoidal nanocarrier system (cationic lipids)
can be toxic for the organ systems in which these accumu-
late by interfering in the normal functioning of the cell mem-
brane. Nanoparticles administered via the intravenous route
get absorbed into the lymphatic system at the injection site
and the situation worsens when cationic nano lipids adminis-
tered via parenteral route initiate inflammation-induced im-
munological reaction via activation of the phagocytic
macrophages [97-99].
2.5. Technology Transfer Related Challenges
Technology transfer from the laboratory scale to the in-
dustrial scale for mass production of the nanoparticulate
products is also a big problem as it is very difficult to pro-
cess the materials at the nano scale without any variation
[90]. Nanoparticles are refined entities that have some specif-
Lipoidal-Nano Architecture for Parental
ic predefined features for which these are designed, such as
the size, shape, surface area, integrity, toxicity, biodegrada-
bility, drug loading capacity, controlled drug release and in-
tegrity of the multicomponent system. There are higher
chances of these features to be lost at large scale production
which makes the product unacceptable for physicians and pa-
tients. Therefore, the selection of polymers, solvents, meth-
ods of preparation and processing parameters needs to be re-
addressed during scaling up operations, which is a challeng-
ing task [100, 101]. Other than technical challenges, there
are many other challenges in technology transfer from labo-
ratory to the industry such as lack of funds, lack of adequate
laboratory setup, lack of marketing of the product, lack of
consumer for the product, lack of skilled manpower because
of nanotechnology being multidisciplinary, lack of analyti-
cal instruments, lack of knowledge on Intellectual Property
Rights (IPR) to protect the product, lack of infrastructure re-
quired and sustainability of the product in the market
[102-106].
2.6. Regulatory Challenges
To get the approval of any new product, its quality, safe-
ty and efficacy parameters must comply with the guidelines
of the regulatory agency and must be supported with docu-
Fig. (2). Challenges for the approval of lipid nanoachitect drug delivery systems from the regulatory body.
Current Applied Polymer Science, 2020, Vol. 4, No. 0 5
mented evidence. But the approval of the novel nanoparticu-
late drug delivery systems is a major concern which the regu-
latory agencies are facing due to lack of data regarding the
classification of the new product, the chemistry of the prod-
uct, manufacturing process and control parameters of the
product [107]. For approval, a product must be categorized
as either a medicine or a medical device. A medicine is an
entity that shows its intrinsic metabolic, pharmacological
and immunological activity while a medical device acts via
providing physical support or initiating chemical reaction
and may be a drug delivery carrier [108]. But the nanopartic-
ulate drug delivery systems may have both types of activi-
ties as the drug contained in it performs pharmacological ac-
tivity and the delivery system itself may act as a device
which helps the drug to traverse across the body, providing
targeting potential and also acting as the diagnostic agent
(Fig. 2).
Therefore, for the regulatory agencies, it would be very
difficult to categorize the nanoparticulate system. Likewise,
the chemistry of the drug in the formulation determines its
quality, safety and efficacy. So a novel nanoparticulate
based product is expected to have a similar quality, safety
and efficacy parameters to get approval from the regulatory
6 Current Applied Polymer Science, 2020, Vol. 4, No. 0
authority but the technical conditions of the nanoparticulate
system with respect to chemistry, manufacturing method
and its controlling parameters are different from the conven-
tional formulations which are difficult to comply as per cur-
rent regulatory conditions and therefore pose a problem in
getting approval [107]. Regulatory authorities also require
data from toxicological studies, preclinical studies and clini-
cal studies as proof of desired quality, safety and efficacy,
but the assessment of novel nanoparticulate system is not
conducted in a manner as in conventional systems. Nanopar-
ticles are reported to interfere with the normal physiological
system of the body, such as the administration of nanoparti-
cles induces immune-inflammatory and immune-modulatory
responses, increases the cytokine release [94, 95] and even
some nanoparticles may affect gene or gene expression and
induce cytotoxicity in the normal cells. So, the current regu-
latory requirement for the conventional system cannot pro-
vide the approval to the nanoparticulate delivery systems. In
the same way, the limited knowledge about the clinical out-
comes of the nanoparticulate system restricts the regulatory
authority to approve these products. It is very difficult to de-
sign a clinical study and bioequivalence study for new prod-
ucts due to the lack of prior knowledge about the number of
patients required, study protocol, the initial dose required,
unavailability of biosimilars for comparison. Another most
important hurdle in the way of nanoparticulate drug delivery
systems is its size. The behavior of any chemical entity
varies from macromolecular state to nano molecular state
but as per the regulatory guidelines, if any substance has a
similar molecular and chemical features (i.e. number of
atoms, atomic and molecular arrangement of bonds and pat-
tern of bonding), it will be considered as the existing
molecule irrespective of the difference in the physical and bi-
ological activities which may place the nanomaterial at a
greater risk than its macromolecular form. Moreover, high
surface area to volume ratio of nanomaterialsrenders them
highly reactive as they can pass through living biological
membranes easily in high concentration and may cause sys-
temic toxicity in the doses similar to that of the macromolec-
ular form [109]. One such example is of iron oxide, which
has been used in the form of parenteral iron colloidal as a
conventional dosage form, but the competitors launched a
nanotechnology-based iron oxide parenteral product, which
is not therapeutically equivalent to the conventional form at
same dose strength. But conventional regulatory guidelines
cannot deal with this kind of situation which compromises
the quality, safety and efficacy of the same drug in the same
dose but at different size scales of the system [110, 111]. Dif-
ferences in the nature of material required for conventional
dosage forms and novel nanotechnology-based dosage
forms also create problems as the fate of new biodegradable
and non-biodegradable polymers inside the body is un-
known. Therefore, differences in the technical requirement
of conventional and novel drug delivery systems make the
approval of the novel products challenging with the regulato-
ry guideline of the conventional system.
Jhawat et al.
CONCLUSION
Nanotechnology has the potential to deliver drugs
through different routes to serve the purpose of effective and
safe delivery. Different types of nanoformulations have been
developed throughout the world to target the drugs at a spe-
cific site and to avoid problems encountered in conventional
systems. Lipid-based nanoformulations are one of them
which have been developed in recent years due to their bio-
compatibility with living system and biodegradable nature.
Though nanotechnology offers several advantages over con-
ventional drug carriers, yet it is not entirely devoid of nega-
tive effects and poses many technical and regulatory chal-
lenges that need to be addressed. The technical complexity
to manufacture and administer lipoidal nanoarchitecture
through the parenteral route requires special attention. Apart
from the technical difficulties, the unique attributes of these
dosage forms have resulted in non-uniformity of regulations
as the regulatory bodies across the globe have found it diffi-
cult to categorize these lipoidal nanoarchitectures, formulate
user guidelines and comply governmental policies. There-
fore, there is a need to address these challenges in the devel-
opment of lipoidal nano-formulations so as to facilitate drug
delivery in a safe and effective manner and to bring these for-
mulations in the market on time for the betterment of
mankind.
LIST OF ABBREVIATIONS
SLN = Solid Lipid Nanoparticles
CMC = Critical Micelle Concentration
NLC = Nano Structured Lipid Carriers
ATRA = All-trans Retinoic Acid
IPR = Intellectual Property Rights
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors have no conflicts of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
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