Recent Patents on Biomedical Engineering 2008, 1, 43-59 43

Polymeric Nanocarriers: New Endeavors for the Optimization of the

Technological Aspects of Drugs
Alejandro Sosnik1‡*, Ángel M. Carcaboso2 and Diego A. Chiappetta1
Departments of 1Pharmaceutical Technology and 2Pharmacology, Faculty of Pharmacy and Biochemistry, ‡National
Science Research Council (CONICET), University of Buenos Aires, 956 Junín St., 6th Floor, Buenos Aires CP1113,
Argentina

Received: September 28, 2007; Accepted: November 13, 2007; Revised: November 15, 2007
Abstract : Drug low solubility and stability in physiological environment constitutes a main hurdle in attaining the
appropriate bioavailability. Several polymer-based nanotechnologies are being intended in order to optimize the
technological (e.g., solubility, stability, bioavailability, etc.) aspects of drugs. Among them, polymeric nanoparticles,
dendrimers, polymeric micelles and polymersomes appear as the most attractive and promising. Concomitant with efforts
in the academic arena that aim at overcoming these drawbacks and, strongly motivated by a constant search for innovative
therapeutic strategies, a very rich intellectual property has been produced in the last years. This phenomenon has been
moved forward by the fact that aiming at registering off-patent or about to be off patent products, pharmaceutical
companies develop new formulations of old products. Another ambit of research is the design of more sophisticated drug
delivery devices (e.g., targeting, localized delivery) in order to minimize adverse effects that make the administration of
certain drugs risky or to enhance the patient compliance. A recent report by Cientifica Ltd. foresees a critical expansion in
the nano-based drug delivery market from its current $3.4B (about 10% of the total drug delivery market) to about $26B
by 2012, being this only a promising beginning for the $220B forecasted by 2015. Given the present circumstances, we
are probably witnessing a new revolution in therapeutics that will take treatment to a different dimension. The goal of the
present review is to provide a comprehensive and updated patent compilation of the most recent inventions relying on
polymer-based nanoparticulated carriers (polymeric nanoparticles, dendrimers, polymeric micellles and polymersomes)
for the optimization of the technological aspects of therapeutic agents. This article also includes a thorough review of the
patents made public in recent years (2003-2007).
Keywords: Pharmaceutical nanotechnology, polymeric nanocarriers, polymeric nanoparticles, dendrimers, polymeric micelles,
polymersomes, drug solubilization and stabilization, enhanced bioavailability.

1. INTRODUCTION these therapeutic agents usually correlates well with

improved bioavailability [3,4]. Class IV comprises poorly
The last century has witnessed a pronounced increase in water-soluble molecules with low permeability. In this case,
lifespan. This revolution was mainly led, in early stages, by
a further modification is required to attain appropriate
the discovery of drugs for the treatment of incurable patho-
transfer through body membranes. Thus, limited water-
logies. An example worth to be stressed was the break-
solubility represents a serious drawback in the design of
through in therapeutics due to the discovery of penicillin by
formulations not only for oral but also for parenteral and
1928 and the later fast expansion in the design of broad
topical administration. Another aspect of concern stems from
spectrum antibacterial, antiviral and antifungal agents. Later the limited chemical or biological stability of the drugs in the
on, this progress was sustained by the rational design and
physiological environment. An example worth to be men-
search of novel therapeutic alternatives. Technological and
tioned is the antitumoral drugs of the camptothecin family
industrial developments allowed the massive production and
[5]. These drugs display a very short t1/2 in vivo due to the
distribution of formulations and made drugs commercially
hydrolysis of a lactone group that results in their inacti-
available to almost every social stratus. However, due to
vation. Thus, different technological strategies have been
their high hydrophobicity, more than 50% of the drugs investigated in order to prolong the exposure to the drug [6].
approved for use display low aqueous solubility, constituting
nowadays one of the main hurdles to attain convenient Nanotechnology has opened the possibility of controlling
absorption and bioavailability. Based on their permeability and manipulating structures at the molecular level and led to
characteristics, the Biopharmaceutic Classification System the creation of novel surface architectures and materials.
(BCS) categorizes hydrophobic drugs for oral administration Traditional biomedical applications incorporated the use of
in two major groups: (1) Class II and (2) Class IV. Class II nanotechnology in a broad spectrum of areas. Among them,
drugs are poorly water-soluble entities with high permea- biosensors, tissue engineering, intelligent systems and
bility [1,2]. In this context, enhancement of the solubility of nanocomposites are used in implant design and controlled
release systems [7]. Several nano-oriented approaches are
being intended (e.g. nanoparticle engineering [8-11]) in order
*Address correspondence to this author at the Department of Pharma-
ceutical Technology, Faculty of Pharmacy and Biochemistry, University of
to optimize the technological aspects of drugs. The use of
Buenos Aires, 956 Junín St., 6th Floor, Buenos Aires CP1113, Argentina; these processes has dramatically enhanced dissolution rates
Tel: +54-11-4964-8273; E-mail: [email protected] in vitro and bioavailabilities in vivo of many drugs. Another

1874-7647/08 $100.00+.00 © 2008 Bentham Science Publishers Ltd.

44 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

important strategy is the design of nanocarriers. From the where the molecules are homogeneously distributed across
first liposomes developed by Gregoriadis and colleagues the bulk or attached to the surface The different aspects of
more than three decades ago [12] until the current state-of- nanoparticles as well as the biomaterials employed for their
the-art, a pronounced increase in the variety of production have been comprehensively reviewed by several
macromolecular-based approaches for drug delivery was research groups [19]. The most broadly investigated
observed [13]. Among the technological alternatives, the polymers include the natural chitosan [20,21], alginate [22],
most broadly implemented are polymeric nanoparticles, gelatin [23] and albumin [24,25] and the synthetic polylactic
dendrimers, polymeric micelles and polymersomes. acid (PLA) [26], poly(lactic-co-glycolic) acid (PLGA) [27],
polycaprolactone (PCL) [28], poly(cyanoacrylate) (PCA)
Several facts have contributed to the generation of a
[29], poly(methacrylic acid-co-ethylacrylate) block copoly-
broad and rich intellectual patrimony available and worth to
be revised in the area of polymeric nanocarriers: (1) a mer [15,16] as well as combinations with other materials
such as poly(ethylene glycol) (PEG) [30]. Also, inorganic
constant search for innovative therapeutic strategies aiming
nanoparticles have been developed [31,32]. In the case of
at improving not only technological features (e.g. higher
highly hydrophobic drugs, increased entrapment can be also
patient compliance, targeting, etc.) of a drug but also in order
attained [13]. From a pharmaceutical perspective, the appli-
to add technological value to the products and differentiate
cation has been extended to formulations for a broad
from the competitors, (2) stronger academia-industry interac-
tion mainly founded on a more compromised involvement of spectrum of administration routes including intravenous
injection and pathologies (e.g., cancer [33,34]). It is worth
academic scientists as scientific directors and advisors and
stressing that microparticles do not enable i.v. adminis-
(3) the high economic impact that a broader intellectual
tration. Especial emphasis was dedicated to the design of
property portfolio has nowadays on a company positioning
orally administered peptide and protein-loaded preparations
in the market. This process has gained impulse because in
[35]. The main advantage stems from the improved stability
order to register and license off-patent or about-to-be-off-
patent products, pharmaceutical companies develop new and absorption of these biologically active molecules in the
GI tract. Another area of interest is the drug delivery to the
formulations of old products. Also, the design of more
brain. Nanoencapsulation enhances the transfer across the
sophisticated drug delivery devices (e.g., targeting, localized
main hurdle: the brain blood barrier (BBB) (for recent
delivery) enables administration of certain drugs that display
reviews read [36,37]). However, nanoparticles are removed
high toxicity or to enhance the patient compliance by the
from the body by opsonization and phagocytosis [38]. Thus,
modification of disadvantageous characteristics like
bitterness. A recent report by Cientifica Ltd. foresees a the modification of the surface with highly hydrophilic
chains (e.g., polyethylene glycol) that results in lower recog-
critical expansion in the nano-based drug delivery market
nition by the host and longer circulation times was perfor-
from its current $3.4 billion (from about $33 billion of the
med. The profuse academic literature found its parallelism in
total drug delivery market) to about $26 billion by 2012,
the patent arena. Prokop patented particles made of
representing a ~ 37% annual growth and a promising
oppositely charged polymers such as dextran, derivatives of
beginning for the $220B forecasted for 2015 [14]. Given the
present circumstances, we are witnesses of a revolution in poly-methacrylamide, PEG and maleic acid [39,40]. Slower
release rates are attained by covalently binding the drug to
therapeutics. The goal of the present review is to provide a
the matrix. Desai and co-workers designed nanoparticles of
comprehensive and updated patent compilation of the most
water insoluble drugs stabilized with a protein coating
recent developments on polymer-based nanoparticulated
[41,42]. Oh et al. developed a series of drug-polyester
carriers (polymeric nanoparticles, dendrimers, polymeric
complexes obtained by the conjugation of the drug with the
micellles and polymersomes) for the improved solubility,
stability and bioavailability of therapeutic agents. Every polymer, attaining a zero order release profile and preventing
the burst effect [43]. Other groups produced biodegradable
section contains a general descrip-tion and then a table
nanoparticles for local delivery (e.g., bladder [44]) and cell
summarizing the most relevant inventions in the period
targeting [45-47]. These systems were also investigated in
2003-2007 is included.
diagnostics, detection and purification of biologically active
2. POLYMERIC NANOPARTICLES (NP) agents. For example, the group led by Mirkin patented
several inventions based on surface-modified gold nanopar-
The application of polymer made particles (micro and ticles containing oligonucleotides with sequences comple-
nano) as means for drug vehiculization was one of the most
mentary to portions of the sequence of a nucleic acid to be
broadly investigated strategies during the last decades.
detected [48]. Table 1 summarizes the most recent patents
Particles display interesting features related to the protection/
pursuing this approach [49-61].
stabilization of sensitive active compounds and their delivery
profiles [15,16]. Due to the higher surface area leading to 3. DENDRIMERS
faster solubilization rates, nano-sized structures usually show
higher plasma concentrations and AUC values [17]. How- Dendrimers are macromolecules combining a number of
unique characteristics: (1) a well defined, regularly hyper-
ever, this phenomenon also depends on the properties of the
branched and three-dimensional architecture, (2) a relatively
drug and some studies did not show statistically significant
low polydispersity and (3) a high and tunable functionality.
differences [18]. Depending on the production methodology,
This molecular structure confers the molecule properties
nanocapsules or nanospheres can be obtained. While the
substantially different than the linear counterparts. The first
former are vesicular systems where the solid or solubilized
drug is surrounded by a polymeric membrane, the later family was described by Tomalia et al. during the early ´80s
and stemmed from a step-by-step synthetic path-
comprise a solid matrix with different levels of porosity
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 45

Table 1. Patents Describing the Development of Polymeric Nanoparticles for the Improvement of Technological Aspects of Drugs
(Refs 39-61)

Inventors Patents No. [Ref.] Polymers Title Observations

Enzymatically degradable polymers can

Dextran, derivatives of poly- be incorporated in otherwise
US20036589563 methacrylamide, PEG, maleic Drug delivery system exhibiting hydrolytically stable particles to provide
Prokop, A.
[39] acid, malic acid, and maleic acid permeability control drug release at particular sites within the
anhydride body where the enzyme of interest is
present.

US20046726934 Micro-particulate and nano- A method of making a nanoparticle that

Prokop, A. Polyanions and polycations particulate polymeric delivery is stable in a physiological environment
[40] system for at least a day.

A formulation useful for the in vivo

delivery of water insoluble
Compositions and methods for
US20036537579 pharmacologically active agents (such as
Desai, NP. et administration of
Proteins (albumin) the anticancer drug paclitaxel) in which
al. [41] pharmacologically active
the drug is delivered in the form of
compounds
suspended particles coated with protein
(albumin).

A formulation useful for the in vivo

Novel formulations of delivery of water insoluble
US20070092563 pharmacological agents, pharmacologically active agents (such as
Desai, NP. et
Proteins (albumin) methods for the preparation the anticancer drug paclitaxel) in which
al. [42]
thereof and methods for the use the drug is delivered in the form of
thereof suspended particles coated with protein
(albumin).

Poly(lactic acid), poly(glycolic Sustained controlled release system

acid), poly(D-lactic-co-glycolic constructed by the conjugation of drug
US20036589548 acid), poly(L-lactic-co-glycolic molecules with biodegradable polyester
Controlled drug delivery system
Oh, JE., et acid), poly(D,L-lactic-co- polymer. The drug release rate can be
US20077163698 using the conjugation of drug to
al. glycolic acid), regulated, resulting in near zero order
[43] biodegradable polyester
poly(caprolactone) kinetic profile of release without
poly(valerolactone) showing a burst effect.
poly(hydroxybutyrate)

Homopolymer or copolymer The biocompatible microparticles or

comprising one or more nanoparticles are non-invasively instilled
US20046797704 monomer repeat units selected Systemic delivery of compounds into the bladder and subsequently
Leong, KW.
from lactic acid, glycolic acid, through non-invasive bladder localized to the lymph node whereupon
et al. [44]
lactide, lactone, poly(ethylene administration the therapeutic agent is released from the
oxide), and poly(propylene polymer matrix.
oxide)

The invention discloses the nanoparticles

composed of chitosan/poly-gamma-
Sung H.-W. US20077265090 Chitosan and poly-gamma- Nanoparticles for paracellular glutamic acid characterized with a
et al. [45] glutamic acid (gamma-PGA) drug delivery positive surface charge and their
enhanced permeability through Caco-2
cells for paracellular drug delivery.

The invention discloses nanoparticles of

chitosan, poly-glutamic acid, and at least
Sung, H.-W. US20070116772A1 Chitosan and poly-gamma- Nanoparticles for protein drug one bioactive agent characterized with a
et al. [46] glutamic acid (gamma-PGA) delivery positive surface charge and their
enhanced permeability through Caco-2
cells for paracellular drug delivery.
46 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

(Table 1) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

One polymerizable hydrocarbon monomer

(acrylic monomer, a vinyl monomer, an acrylic This invention relates to polymeric
resin, or a vinyl resin) and an acrylic or vinyl nanoparticles obtained by
monomer (acrylonitrile, acrylic acid, maleic microemulsion polymerization
US20070190160 acid, methyl acrylate, ethyl acrylate, butyl techniques. The drug/target substance is
Turos, E. Nanoparticles for
acrylate, butyl methacrylate, 2-ethylhexyl covalently bonded to the novel
et al. [47] drug-delivery
acrylate, methoxyethyl acrylate, polymeric nanoparticles to secure them
dimethylamino acrylate, methacrylic acid, from outer intervention in vivo or cell
isobutyl methacrylate, 2-ethyl hexyl culture in vitro until they are exposed at
methacrylate, lauryl methacrylate, stearic the target site within the cell.
methacrylate, dimethyl amino methacrylate)

US20036645721
US20046812334
US20046818753
US20046828432 The invention provides methods of
detecting a nucleic acid. The methods
US20056861221
comprise contacting the nucleic acid
US20056878814 Nanoparticles having
with one or more types of particles
Mirkin, oligonucleotides
US20056902895 - having oligonucleotides attached thereto.
CA. et al. attached thereto and
US20056903207 The oligonucleotides are attached to
uses therefor
gold nanoparticles and have sequences
US20056969761
complementary to portions of the
US20066986989 sequence of the nucleic acid.
US20067098320
US20077259252
[48]

Polyacrylates, Polymethacrylates
Polycyanoacrylates, Polyarylamides
US20030152636A1 Nanoparticles used as a tool to deliver
Sabel, Polylactates, Polyglycolates, Polyanhydrates Method of treating
Polyorthoesters, gelatin, Polysaccharides drugs to a specific target within or on a
BA. et al. [49] cancer
albumin, Polystyrenes, Polyvinyls mamalian body.

Polyacrolein and Polyglutaraldehydes

The inventive nanoparticles comprise

WO04112758 hyaluronic acid in salt form, a
Alonso, Hialuronic acid
Hialuronic acid + Chitosan/Gelatin/Collagen positively-charged polymer (chitosan), a
M.J. et al. [50] nanoparticles
polyanionic salt and at least one active
ingredient.

Polymeric nanoparticles useful in drug

Poly(acrylamide), Poly(2-hydroxyethyl
delivery, as well as for imaging and
US20050196343A1 methacrylate), Poly(glycerol
diagnosis. The polymeric nanoparticles
Reddy, monomethacrylate), Poly(acrylic acid) Degradable
WO05089106 comprise cross-linkers that, when
GR. et al. Poly((aminoalkyl)methacrylamides) nanoparticles
[51] degraded, leave simple linear polymeric
Poly(sodium acrylate), Poly(vinyl pyrrolidone)
molecules that can be excreted by the
and mixtures thereof
body.

The microemulsion precursors for solid

nanoparticles consist of either alcohol-
Emulsifying wax, Polyoxyethylene sorbitan
in-fluorocarbon, liquid hydrocarbon-in-
US7153525 fatty acid esters, Polyoxyethylene alkyl ethers, Microemulsions as
Mumper, fluorocarbon, or liquid hydrocarbon-in-
Polyoxyethylene stearates, Phospholipids, precursors to solid
RJ. et al. [52] water microemulsions. The
fatty acids or fatty alcohols or their nanoparticles
nanoparticles can be made to entrap
derivatives, or combinations thereof
various materials including drugs,
magnets, and sensors.
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 47

(Table 1) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

Nanoparticles for the The invention relates to nanoparticles used for

administration of active the administration of active ingredients, the
Alonso, MJ. US2006134785 ingredients, method of method of producing said nanoparticles with
Chitosan + glucomannan
et al. [53] producing said particles chitosan, glucomannan, at least one active
and composition ingredient and, if necessary, an anionic salt,
containing same preferably in sodium tripolyphosphate form.

System comprising nanoparticles for the

WO06128937 release of biologically-active molecules, in
Alonso, MJ. Nanoparticles comprising
Chitosan + cyclodextrin which the nanoparticles contain at least 40%
et al. [54] chitosan and cyclodextrin
chitosan and less than 60% cyclodextrin,
whereby both components (a and b) are mixed.

Nanoparticles of chitosan
and polyethyleneglycol as Systems for the release of biologically-active
Alonso, MJ. WO06097558 a system for the molecules comprising chitosan modified
PEGilated chitosan
et al. [55] administration of chemically with polyethyleneglycol and cross-
biologically-active linked with a cross-linking agent.
molecules

Poly-gamma-glutamic acid-
WO06041613 For targeting liver cancer cells, galactosamine
Sung, HW. Poly lactic acid block Nanoparticles for targeting
was conjugated on the prepared nanoparticles
et al. [56] copolymers conjugated with hepatoma cells
as a targeting moiety.
Galactosamine

Methacrylic acid copolymer

hydroxypropyl
Methylcellulose phthalate
hydroxypropyl
Methylcellulose acetate Nanoparticle compositions The invention relates to orally administrable
succinate, cellulose acetate of water-soluble drugs for nanoparticles having enhanced entrapping rate
Pai, C.-M. US20070154559A1
Phthalate, Shellac, Chitosan oral administration and of water-soluble drugs within nanoparticles
et al. [57] hydroxypropyl preparation methods composed of lipids and polymers, and being
Methylcellulose thereof stable against lipases.
Ethylcellulose
Methylcellulose
Polyvinylalcohol, Sodium
alginate and Carbomer

The invention discloses nanoparticles of

chitosan, poly-glutamic acid, and at least one
Sung, HW. US20070116772 Chitosan and poly-gamma- Nanoparticles for protein bioactive agent characterized with a positive
et al. [58] glutamic acid (gamma-PGA) drug delivery surface charge and their enhanced
permeability through CACO2 cells for
paracellular drug delivery.

The nanoparticles have a core including the

anticancer drug and polymer chains that are
soluble at the pH of the cancer cell. The core is
surrounded by a layer of polymer chains that
WO07001356 PEG, PEO, PDMA, PVA Nanoparticles for are insoluble at the pH of healthy tissue but
Radosz, M.
(polyvinyl alcohol), or co- cytoplasmic drug delivery soluble at the pH of the cancer interstitium. An
et al. [59] polymers thereof to cancer cells outside layer is made of water-soluble polymer
chains to shield the nanoparticle from RES
recognition and give the nanoparticle a long
circulation time in the bloodstream of the
subject.
48 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

(Table 1) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

Biodegradable or non-biodegradable
Polymers derivatized with PEG and
coated with mucoadhesive polymers Coated controlled release
The composition includes a polymer
WO07001448 like chitosan, Poly(Lysine) polymer particles as
core encapsulating the active agent and a
Jon, S. et al. Poly(Ethylene imine), lecithin, lectin efficient oral delivery
[60] mucoadhesive coating disposed about
Polycarboxylic acids, Poly(Acrylic vehicles for
the core.
acids), Polysaccharides, Hydrogels biopharmaceuticals
monosaccharides, Oligosaccharides
oligopeptides, Polypeptides

Nanoparticulate systems comprising

Vila Pena, WO07042572 Chitosan and heparin ionically cross-linked chitosan, heparin
Chitosan
AI. et al. [61] nanoparticles and optionally a polyoxyethylenated
derivative.

way comprising successive Michael-type addition reactions and the shell that are reactive with each other rather than
between methylacrylate and ethylenediamine, rendering the with themselves [79]. These materials were denomined
polyamidoamines (PAMAM) [62,63]. The kind of core and tectodendrimers. Other noteworthy work is the design of a
number of synthetic cycles determines the generation of the product (Vivagel®) based on a pharmacologically active
dendrimeric molecule (nomenclature) and also the associated dendrimer for prophylaxis or treatment of sexually trans-
molecular weight, the number of superficial moieties and mitted diseases and actually investigated as contraceptive
their nature. [80]. Hubbell et al. patented a group of polyethylene glycol/
poly(lysine) (PEG/PLL) tissue coatings showing preventing
These highly functionalized materials enable drug incor-
cell-cell contact and inhibiting post-surgical tissue adhesions,
poration into the core of the molecule and drug complexation
and conjugation on the surface [64-67], being the ability of metastasis of tumors and restenosis in damaged blood
vessels [81]. A synopsis of patents focused on dendrimer-
the molecules to enter the ramified 3D structure fully related
based approaches is presented in Table 2 [77-95].
to the size of the dendrimer. Thus, it is assumed that due to
sterical hindrance, PAMAMs larger than generation 4 (G4) 4. POLYMERIC MICELLES
are only capable of superficial complexation or conjugation
and drugs cannot access the inner domains of the molecule. Polymeric micelles are nano-structures formed by the
Cytocompatibility investigations suggested the concentra- self-assembly of amphiphiles in water, above a minimal
tion-dependent toxicity of -NH2-terminated derivatives. The concentration called the critical micelle concentration or
main mechanism is apparently related to the cationization of CMC [96]. Polymeric micelles are composed by internal and
the molecule and later membrane damage [68]. A similar external zones named core and shell, respectively. Due to the
effect was observed in contact with red blood cells. In high molecular weight of the amphiphiles, they display
contrast, dendrimers with a carboxylic or hydroxyl surface higher stability (slower dissociation upon dilution) than
are, in general, less toxic. Regardless some compositional micelles formed by regular surfactants (e.g., polyethoxylated
drawbacks of NH2-terminated PAMAMs, this rationale was castor oil or Cremophor® EL, polysorbate 80 or Tween® 80),
capitalized to the design of modifications that led to more even at concentrations below the CMC, extending their
compatible materials. For example, poly(ethylene glycol)- circulation times in blood [97]. These materials are also safer
containing materials were synthesized by modifying the for parenteral administration [98,99] and display larger cores
terminals with PEG chains [69,70] and pro-adhesive peptides and hence, result in higher solubilization capacity. The
like RGD for tissue engineering and drug delivery appli- hydrophobic character of the core enables the inclusion of
cations [71]. Similar findings were observed by D´Emanuele hydrophobic drugs by physical means or chemical conju-
and collaborators by modifying the surface with lauroyl and gation and their dispersion at the molecular level, resulting in
PEG chains [72]. Also, PEG-diamine was used as the initia- enhanced water-solubility [100]. Also, the isolating effect
tor to generate novel molecular structures and larger cores (from the environment) of the polymeric entity can protect
[73,74]. Inspired in this technology, other interesting appro- molecules sensitive to chemical or biological triggers from
aches like dendrimer-shape DNA structures were developed degradation and metabolism [101]. Based on the core-drug
[75]. In terms of intellectual property, Dow Chemical Co. interactions through chemical and physical forces, drugs
and Dendritech Inc. have made a tremendous contribution display different release profiles. Also, polymeric micelles
along the last 21 years. From the first reported PAMAMs containing poly(ethylene oxide) as the hydrophilic compo-
(the first patent was published in 1986 [76]) to more nent evade opsonization and uptake by the macrophages of
innovative and biocompatible modifications to fine tune the the reticuloendothelial system (RES), prolonging circulation
properties and applications [77,78] a long way has been times in blood [102,103]. Another aspect of relevance is the
transited. For example, in 2003 Tomalia et al. patented inhibition of efflux transporters like PGP [104].
dendrimers displaying different reactive moieties in the core
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 49

Table 2. Patents Describing the Development of Dendrimers for the Improvement of Technological Aspects of Drugs (Refs 77-95)

Patents No.
Inventors Polymers Title Observations
[Ref.]

US20067078461 The present invention relates to compositions and

Tomalia, Poly(propylene imine) (POPAM) and Biocompatible
methods involving biocompatible dendrimers for
DA. et al. [77] Poly(amidoamine) (PAMAM) dendrimers
use in transfection and imaging applications.

The antineoplastic agents conjugated to the dendritic

polymer may be administered intravenously, orally,
US20067005124 Dendritic-
Malik, N. Polyamidoamine (PAMAM) and parentally, subcutaneously, intramuscularly,
antineoplastic drug
et al. [78] Polypropylamine intraarterially or topically to an animal in an amount
delivery system
which is effective to inhibit growth of the malignant
tumor.

Core-shell tecto (dendrimers) useful in biomedicine,

Tomalia, US20036635720 Core-shell pharmaceuticals, personal care products, and in
Polyamidoamine (PAMAM)
DA. et al. [79] tectodendrimers other ways analogous to the known uses for
dendrimers.

Use of a polylysine, polyamidoamine or

Agent for the
US20050008611 polypropylenimine dendrimer having naphthyl
Matthews, Poly(lysine), polyamidoamine prevention and
disulphonate terminal groups as a topically applied
BR. et al. [80] (PAMAM) and polypropylenimine treatment of sexually
agent in prophylaxis or treatment of sexually
transmitted diseases-I
transmitted diseases.

The systems are useful in inhibiting formation of

US20060122290 Multifunctional post-surgical adhesions, protecting damaged blood
Hubbell, JA. Polyethylene glycol/poly(lysine)
polymeric tissue vessels from thrombosis and restenosis, and
et al. [81] (PEG/PLL)
coatings decreasing the extent of metastasis of attachment-
dependent tumor cells.

Polyamidoamine (PAMAM) Anionic or cationic

US20030129158 dendrimers, PAMAM (EDA) dendrimer A dendrimer to inhibit, prophylactically or
Matthews,
dendrimers, Poly(Propyleneimine) antimicrobial or therapeutically, a bacterial, yeast, fungal, or
BR. et al. [82]
(PPI) dendrimers and Polylysine antiparasitic parasitic agent in a patient.
dendrimers compositions

US20030096280 Targeted transfection

Weber, M. of cells using a The present invention relates to processes for the
US7192744 Polyamidoamine (PAMAM)
et al. biotinylated targeted transfection of cells.
[83] dendrimer

Method of treating The dendritic polymer platinates may be

US20046790437 cancerous tumors administered intravenously, orally, parentally,
Malik, N. Polyamidoamine (PAMAM) and
with a dendritic- subcutaneously or topically to an animal in an
et al. [84] Polypropylamine
platinate drug amount which is effective to inhibit growth of the
delivery system malignant tumor.

Dendrimers and a biologically active

molecule bonded to the dendrimer
WO04009666 through a disulfide linkage, an ether Dendrimers as
Goodman, Transport molecules consisting of dendrimers with
linkage, or a thioether linkage, molecular
M. et al. [85] bonded active molecules.
wherein the dendrimer comprises at translocators
least one guanidine, Amidine, Ureido,
or Thioureido groups

US20056878374 Poly(ethylene imine), Poly(propylene Biodegradable polymers containing acetal recurring

Biodegradable
Yu, L. et al. imine) (PPI), Poly(lysine) and units for using them in polynucleotide delivery
[86] polyacetals
Polyamidoamine (PAMAM) applications.
50 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

(Table 2) Contd….

Patents No.
Inventors Polymers Title Observations
[Ref.]

Hydrophilic coating for a medical device comprises a

mixture of colloidal aliphatic polyurethane, an aqueous
Highly lubricious
US20050175669 dilution of PVP and specific dendrimers to enhance the
Jiménez, O. hydrophilic
Polyamidoamine (PAMAM) physical integrity of the coating, to improve adhesion
et al. [87] coating utilizing
and to covalently bind or load one of an
dendrimers
antithrombolitic drug or an antibiotic drug within the
dendrimer.

Methods for Small dendrimer-based MRI contrast agents are

US20056852842 functional kidney disclosed to accumulate in renal tubules. The
Brechbiel, Diaminobutane (DAB) and
imaging using accumulation enables visualization of renal structure
MW. et al. [88] Polyamidoamine (PAMAM)
small dendrimer and function, permitting assessment of structural and
contrast agents functional damage to the kidneys.

Polymers: Poly(alkylene oxides), star

Poly(alkylene oxides)
US20067097856 polysaccharides, poly(amino acids)
and Poly(hydroxystyrene)
The present invention provides a family of dendrimers
Synthetic organic polymer
Dendrimeric that are useful as supports, vectors, carriers or delivery
Frechet, JJ. Poly(vinylphenol) support or carrier vehicles for the delivery of drugs, genetic material,
et al. Poly(hydroxymethacrylate), poly(N- macromolecule imaging components or other functional molecule to
2-hydroxypropylmethacrylamide) which they can be conjugated.
Poly(diallylamine), Poly(lactic acid)
[89] and
Poly(hydroxymethylcaprolactone)
Poly(4-hydroxyethylcaprolactone)

Methods for tumor The dendrimer conjugate comprises an effective

Kobayashi, US20060204443 Diaminobutane (DAB), poly(lysine) treatment using amount of an anti-tumor agent. The anti-tumor agent is
H. et al. [90] and polyamidoamine (PAMAM) dendrimer selectively concentrated in the lymphatic system to
conjugates treat metastatic disease.

Relates to dendrimers multivalently substituted with

Dendrimers
WO06135233 active groups such as peptides, carbohydrates and drug
Liskamp, multivalently
Amino acid based dendrimers molecules, and processes for the preparation thereof
RMJ. et al. [91] substituted with
based on microwave assisted reactions, and to the use
active groups
of such multivalent dendrimers.

PAMAM dendrimers, PEHAM

dendrimers, polylysine dendrimers
New Janus dendrimers where at least two dendrons are
dendrigraft dendrimers, Random
WO06105043 attached at the core, and where at least two of the
Tomalia, hyperbranched dendrimers Janus dendrimers
dendrons have different functionality. Specific
DA. et al. [92] hyperbranched dendrimers and other and dendrons
targeting entities for diagnostic and therapeutic
dendritic polymers. Preferably at least
applications can be attached to the dendrimer.
one of the dendrons in the Janus
dendrimer is a PEHAM dendrimer

Multifunctional
Diaminobutane poly(propylene dendrimers and Synthesis of multifunctional dendrimeric and
Paleos, C. US2006204472 imino) dendrimer (DAB) or other hyperbranched hyperbranched polymers for application as drug
et al. [93] dendrimeric molecules of similar polymers as drug delivery systems of bioactive pharmaceutical
structure, e.g. PAMAM dendrimers and gene delivery compounds and as gene delivery systems.
systems
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 51

(Table 2) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

The present invention is directed to

Dendrimer based
dendrimer based compositions and
US20070041934 Polyamideamine (PAMAM) and compositions and
William, B. et al. systems for use in disease diagnosis and
[94] Polypropylamine (POPAM) methods of using
therapy (e.g., cancer diagnosis and
the same
therapy).

Polyamidoamine, Polypropylene Compositions and

A composition exhibiting anti-
Polyethyleneimine, Carbohydrate based complexes
inflammatory activity comprising of a
dendrimer, peptide based dendrimer containing a
monodisperse macromolecular polymers
Chauhan, AS. US20070014757 Glycopeptide dendrimer, Poly aryl amine macromolecular
such as dendrimer having a plurality of
et al. [95] polyamide, Poly (alkyl amine), Polyamido compound as
terminal groups or such molecules
alcohol, Polyether, Polythioether potential anti-
bound/complexed to drug moieties
Polysiloxane, Dendritic aryl ester inflammatory
having anti-inflammatory activity.
Perchlorinated dendrimer agents

The most broadly studied amphiphiles are derivatives of 5. POLYMERSOMES

poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO-
PEO) block copolymers [105-107]. However, the bio-stabi- Polymersomes, defined as polymeric vesicles made of
lity of these derivates and relatively high CMC values moti- amphiphilic block copolymers that self-assemble in aqueous
vated the design and development of counterparts displaying medium forming a bilayer that surrounds a liquid aqueous
enhanced features. Among them, it is worth mentioning the core, were described in recent years [142]. The formation of
replacement of PPO by more hydrophobic polymeric these structures is constrained to a very narrow hydrophilic/
segments based on, styrene oxide and butylene oxide and hydrophobic ratio [143]. For example, polystyrene-poly-
conjugates of hydrophilic poly(ethylene glycol) segments acrylic acid block copolymers are among those displaying
with hydrophobic blocks of phospholipids [108], poly(L- polymersome-forming tendency [144]. Since these deri-
amino acid)s [109-112] and polyesters [113, 114]. In the last vatives are not biodegradable, molecules combining PEG
years, these strong investigative efforts gave place to a and polyesters like PLA and PCL were designed. Thus, lipo-
profuse number of amphiphilic polymers based on these philic drugs can accommodate across the membrane and
block combinations. water-soluble ones within the core. Discher et al. combined
two anticancer drugs with different solubility: doxorubicin
Rapoport and co-workers registered polymeric micelles (core) and taxol (membrane) in order to attain improved acti-
made of a variety of acrylamide derivatives, acrylic and vity against solid tumors [145]. Due to the relatively short
methacrylic acid [132] and other materials [133] for the way these entities have gone, a limited number of patents is
encapsulation of antitumoral drugs like paclitaxel and doxo- available (Table 4) [146-151], most of them by Discher et al.
rubicin. These systems incorporated an innovative feature,
ultrasound, that resulted in micellar disruption and increased 6. CURRENT AND FUTURE DEVELOPMENTS
delivery. This phenomenon reverts as the radiation is turned The present work has reviewed the most recent intellec-
off, and the substance is re-encapsulated. Kwon et al. have tual property on polymer-based nanotechnolgical strategies
developed a vast platform of thermo-responsive amphiphiles for the design of optimal drug delivery devices. This is an
belonging to all the described families for drug solubili- effervescing area, with large investment volumes being
zation, stabilization and delivery [134-138]. Another group poured by both public and private sectors [152]. Most of the
with a tradition in the design of this kind of carriers is the novelties still remain as experimental enterprises and are
one led by J-C Leroux at the University of Montreal. Mate- dealing with regulatory agencies to get approval. A few have
rials display pH-dependency and associate or dissociate reached clinical studies or were approved (see Table 5) [12,
depending on the pH of the medium [139]. Heller and 153-160].
collaborators introduced the versatile poly(orthoesters) that
allow degradation rates from a few hours to several months. A key feature is to understand and internalize that due to
In this context, fine tuning of the compositions (e.g., the multidisciplinary nature of this area a convergence of
incorporation of PEG) rendered novel micelle-forming different professionals is demanded to bring a product to the
materials [140]. Regardless the higher stability upon dilution, market [152]. Dr. Robert Langer, a renowned and pioneering
a gradual de-assembly of the micelles takes place at concen- figure, scientific leader and mentor in emerging disciplines
tration below the CMC. Thus, several scientists developed like biomaterials, Tissue Engineering, bio and nanotech-
stable core or shell-crosslinked micelles. For example, nology recently expressed that "the intersection of materials
Bronich and Kabanov patented a diversity of core-stabilized science and biotechnology is in my mind one of the most
micelles for the delivery of drugs, proteins and DNA [141]. interesting, dynamic emerging fields today. Broadening our
Table 3 concentrates the main patents relying on this ability to predict and engineer nanotechnology and nanoscale
technology [115-141]. materials at that interface is a critical next step" [161].
Following this vision, the best is probably still to come.
52 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

Table 3. Patents Describing the Development of Polymeric Micelles for the Improvement of Technological Aspects of Drugs (Refs
115-141)

Inventors Patents No. [Ref.] Polymers Title Observations

Poly([poly(ethylene glycol)] Loaded drugs can be physically retained in the

Methacrylate)-block-poly(ethyl micelles when the pH of the surrounding medium
Unimolecular
US20026780428 methacrylate-co-tert-butyl favors interactions with the core. Upon a change
Ranger, M. polymeric micelles
methacrylate) and Star- in pH, modification in the ionization state of the
et al. [115] with an ionizable
Poly([poly(ethylene glycol)] core will decrease the interactions between the
inner core
methacrylate)-block-poly(ethyl drug and the inner core and facilitate the release
methacrylate-co-methacrylic acid) of the micellar contents.

Poly(ethylene glycol), Poly(ethylene Polymers with novel block structures, containing

oxide), Poly(ethylene oxide)-co- spatially separated hydrophobic and hydrophilic
Poly(propylene oxide), Poly(N-vinyl parts. These features allow the preparation of
US20030059906 Block copolymers
pyrrolidone), Poly(ethyloxazoline) carriers for bioactive lipo- or water-soluble
Hubbell, JA. for multifunctional
US20067132475 Poly(acrylic acid), Poly(ethylene-co- materials having the benefits of incorporation into
et al. self-assembled
[116] vinyl alcohol), Poly(acrylamide), such structures, including enhanced cellular
systems
Poly(N-alkyl or N,N- targeting because of the presence of antibodies or
dialkylacrylamides), Poly(acrylates) adhesion peptides on the surface.
Poly(peptides), and Poly(saccharides)

Polycaprolactone-
b-poly (ethylene
US20030176406 oxide) copolymer The drug delivery system (micelles) maintains the
Allen, C. Polycaprolactone-b-poly(ethylene
non-cross-linked release of the steroid compound in a patient
et al. [117] oxide) (PCL-b-PEO)
micelles as a having a deficient steroid level.
delivery vehicle
for steroid

Polyanhydrides, Polyglycolic acids,

US20040234472 Polybutrylactones, Micellar drug
A drug delivery system comprising a hydrophobic
Jackson, JK. Polyhydroxybutyrates, polylactic acids delivery systems
US20060189785 drug, a biocompatible micelle forming polymer,
et al. Polylacaprolactones, Polyethylene for hydrophobic
[118] and a biocompatible water-soluble polymer.
glycol (PEG) and drugs
Methoxypolyethylene glycol (MePEG)

Polymeric compositions capable of forming stable

Polylactides, Polyglycolides, micelles in an aqueous solution, comprising an
US20040253195 polydioxan-2-one, Polycaprolactone, Polymeric micelle amphiphilic block copolymer of a hydrophilic
Seo, M.-H.
Polylactic-co-glycolide, Polylactic-co- composition with block and a hydrophobic block, and a polylactic
et al. [119]
caprolactone, Polylactic-co-dioxan-2- improved stability acid derivative wherein one end of the polylactic
one acid is covalently bound to at least one carboxyl
group.

pH responsive
D,L-polylactic acid, a copolymer of biodegradable
Polylactic acid derivatives capable of forming
D,L-lactic acid and mandelic acid, a polylactic acid
micelles in an aqueous solution with a pH of 4 or
US20040247561 copolymer of D,L-lactic acid and derivatives
Seo, M.-H. above. The polylactic acid derivatives may be
glycolic acid, a copolymer of D,L- forming polymeric
et al. [120] applied as a drug delivery system in various forms
lactic acid and caprolactone, and a micelles and uses
since poor water soluble drugs can be entrapped
copolymer of D,L-lactic acid and 1,4- thereof for poorly
inside the micelles.
dioxane-2-one water soluble drug
delivery

Novel PEO-b-PCL micelles and micelles

Polymer based
containing cyclosporine A or analogs thereof are
WO05118672 nano-carriers for
Lavasanifar, Poly(ethylene oxide)-b-poly(
- provided as well as a novel method for making
the solubilization
A. et al. [121] caprolactone) (PEO-b-PCL) said micelles that reduces aggregation and
and delivery of
enhances delivery, the toxicity profile and
hydrophobic drugs
biodistribution of hydrophobic drugs.
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 53

(Table 3) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

Poly(ethylene glycol)-block-poly(2-(4-
vinylbenzyloxy)-N,N-
diethylnicotinamide), Poly(ethylene
glycol)-block-poly(2-(4-
vinylbenzyloxy)-N- Hydrotropic polymer micelles are formed in
picolylnicotinamide), poly(ethylene solution from copolymers that comprise a
glycol)-block-poly(2-(4- hydrophilic polymer and a hydrophobic polymer
vinylbenzyloxy)-nicotinamide) having pendant hydrotropic agents. A hydrophilic
Pharmaceutical
US20050158271 Poly(oligoethylene glycol chain comprises polyethyleneoxide (PEG) and a
Lee, SC. applications of
methacrylate-co-poly(2-(4- hydrophobic chain comprises hydrotropic
et al. [122] hydrotropic
Vinylbenzyloxy)-N,N- monomer units derived from nicotinamide. The
polymer micelles
Diethylnicotinamide) micelles are found to be much more effective in
Poly(oligoethylene glycol solubilizing poorly soluble drugs and exhibit an
Methacrylate-co-poly(2-(4- excellent long-term stability even at high loading
vinylbenzyloxy)-N- of drugs.
Picolylnicotinamide) and
Poly(oligoethylene glycol
Methacrylate-co-poly(2-(4-
vinylbenzyloxy)-nicotinamide).

Biodegradable
copolymer, and
US20050019303 The micelles possess good drug and bioactive
Tsai, B.-H. Polycaprolactone (PCL) and polymeric micelle
agent delivery characteristics and are suitable for
et al. [123] Polyethylene glycol (PEG) composition
use in drug delivery or cosmetic applications.
containing the
same

Monoacetoxypolyethylene glycol
Polyethylene glycol, polyethylene-co- Amphiphilic block The present invention relates to polymeric
Propylene glycol, polyvinyl copolymer and compositions capable of forming stable micelles
US20050201972 Pyrrolidone, polylactides, polymeric in an aqueous solution, comprising the
Seo, MH. et
Polyglycolides, polycaprolactone, composition amphiphilic block copolymer and a polylactic
al. [124]
Polydioxan-2-one, polylactic-co- comprising the acid derivative wherein one or more ends of the
Glycolide, polylactic-co-dioxan-2-one same for drug polylactic acid are covalently bound to at least
Polylactic-co-caprolactone and delivery one carboxyl group.
Polyglycolic-co-caprolactone

Micelle delivery A drug delivery system comprising a targeted

Torchilin, US20060216342 Polyethylene glycol and system loaded with form of a polyethyleneglycol (PEG)/lipid-
VP. et al. [125] phosphatidylethanolamine a pharmaceutical conjugated micelle, which is capable of stabilizing
agent poorly soluble pharmaceutical agents.

Polyethylene glycol
Monoalkoxypolyethylene glycol and A composition for the sustained delivery of a drug
Composition for
Monoacyloxypolyethylene glycol comprising an amphiphilic diblock copolymer.
sustained delivery
US7153520 Polylactides, polycaprolactone When administered into a particular body site, the
Seo, M.-H. of hydrophobic
Poly(lactide-co-glycolide) composition forms an implant containing the drug
et al. [126] drugs and process
Poly(lactide-co-caprolactone) and drug containing polymeric micelles, which
for the preparation
Poly(lactide-co-p-dioxanone) are slowly released from the implant for an
thereof
Polyorthoesters, polyanhydrides extended period of time.
Poly(amino acid) and polycarbonates

Propyne-aryl-poly(ethylene glycol)-b- The present invention relates to the field of

Breitenkamp US20060240092 Poly(aspartic acid)-b- Polymeric micelles polymer chemistry and more particularly to
K. et al. [127] [Poly(phenylalanine)-co- for drug delivery multiblock copolymers and micelles comprising
Poly(tyrosine)] the same.
54 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

(Table 3) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

siRNA-
Hydrophilic The present invention relates to conjugates
WO07021142 polymer between siRNA (small interfering RNA)
Kim, S-H. et Polyethylene glycol (PEG),
conjugates for molecules and hydrophilic polymers, which can
al. [128] Polyvinylpyrolidone or polyoxazolin.
intracellular effectively be used for gene therapy for treatment
delivery of siRNA of cancers and other infectious diseases.
and method thereof

Amphiphilic
The nanotube may have magnetic properties. A
nanotubes and
Polyoxypropylene (POP) or therapeutic agent may be incorporated in the
micelles
WO07042833 Polyoxyethylene (POE), micelle. The micelle may be coated to form a
Chowdhury, comprising same
Polyoxyethelyne glycol (PEG), capsule and can be introduced to the human or
DFH. [129] for use in the
Lecithin, Phosphatidylethanolamine animal body for treatment of tumors or targeted
delivery of
(PE) and poloxamers. drug delivery when a magnetic field or near-IR
biologically active
radiation is applied.
agents

Amphiphilic star- The present invention provides polymeric

Uhrich, KE. US20077262221 Poly(ethylene glycol) (PEG) and like compounds that can form micelles in solutions.
et al. [130] Poly(ethylene imine) (PEI) macromolecules These compounds have a hydrophobic, core that
for drug delivery is coupled to a plurality of hydrophilic moieties.

Conjugate for gene

transfer comprising
Polyethylene glycol, oligonucleotide
Polyvinylpyrrolidone and and hydrophilic
A conjugate for gene transfer, which is capable of
US20070041932 Polyoxazoline. Polyethylenimine, polymer,
Jeong, JH. et being used for treatment of incurable diseases,
Polyamidoamine, polylysine, polyelectrolyte
al. [131] comprising an oligonucleotide intended to be
Diethylaminoethyldextran and complex micelles
transferred into target cells.
Polydimethylaminoethyl formed from the
Methylacrylate conjugate, and
methods for
preparation thereof

The micelle comprises molecules of a block

N-isopropylacrylamide, N,N-
polymer having a hydrophobic block and a
Diethylacrylamide N,N- Stabilization and
hydrophilic block. A drug can be incorporated
US20036649702 Diethylmethacrylamide, N- acoustic activation
Rapoport, N. into the dense inner core of the micelles. When
Isopropylmethacrylamide, N-n- of polymeric
et al. [132] subjected to ultrasound, the micelles release the
Butylacrylamide, other mono- and di- micelles for drug
substance, and then reversibly revert to a stable
Alkyl substituted acrylamides, acrylic delivery
dense core and re-encapsulating the substance
acid and methacrylic acid
when the ultrasound is turned off.

A method for administering a drug to a selected

Poly(L-amino acid)-co-poly(ethylene Method of in vivo
site in a patient includes (a) administering a
oxide) diblock copolymer, drug targeting to
composition including a micellar drug carrier
US20050003008 Poly(ethylene oxide)-poly(propylene solid tumors via
having a hydrophobic core and an effective
Rapoport, N. oxide)-poly(ethylene oxide) triblock acoustically
[133] amount of the drug disposed in the hydrophobic
copolymer, PEGylated triggered drug
core; and (b) applying ultrasonic energy to the
Diacylphospholipid and mixtures delivery in
selected site such that the drug is released from
thereof. polymeric micelles
the hydrophobic core to the selected site.

Methods and Methods for formulating hydrophobic therapeutic

US20056939561 compositions for agents such as polyene antibiotics, especially
Kwon, GS. Poly (ethylene oxide) – block – poly
polyene antibiotics amphotericin B, such that toxicity is reduced. The
et al. [134] (N-hexyl stearate L-aspartamide).
with reduced antibiotic is incorporated within micellar
toxicity structures of block polymers.
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 55

(Table 3) Contd….

Inventors Patents No. [Ref.] Polymers Title Observations

Compositions for improving the solubility of

Methoxy poly(oxyethylene)-block- Polymeric micelle hydrophobic compounds, such as anticancer
US20040005351 Poly(epsilon-caprolactone) and formulations of drugs, polyene antibiotics, antilipidemic agents
Kwon, GS.
methoxy poly(oxyethylene)- hydrophobic for reducing the toxicity of Amphotericin B
et al. [135]
Poly(ethylene glycol)-block-poly(N- compounds and (AmB), and therapeutics such as paclitaxel,
hexyl-L-aspartamideacyl ester). methods tamoxifen, by incorporating these agents within
micelles.

Encapsulation and
deaggregation of The micelles can be reconstituted with the
US20040116360 polyene antibiotics Amphotericin B (or other hydrophobic
Monomethoxy poly(ethylene glycol)- using compound) in a deaggregated state and safely
Kwon, GS. WO04034992
phospholipid. poly(ethylene used in therapy for fungal infections of humans or
[136] glycol)- animals, especially for systemic fungal infections,
phospholipid or other desired application.
micelles

Novel PEO-b-PCL micelles and micelles

Polymer based
containing cyclosporine A or analogs thereof are
WO05118672 nano-carriers for
Lavasanifar, Poly(ethylene oxide)-b-poly(
- provided as well as a novel method for making
the solubilization
A. et al. [137] caprolactone) (PEO-b-PCL) said micelles that reduces aggregation and
and delivery of
enhances delivery, the toxicity profile and
hydrophobic drugs
biodistribution of hydrophobic drugs.

Micelles extend the time period the drug remains

in the micelles to improve drug circulation time.
Polyethylene glycol (PEG), and a Micelle Hydrophobic drugs for micelle encapsulation may
Kwon, GS. US20060251710 hydrophobic domain such as composition of include rapamycin, geldanamycin, and paclitaxel.
et al. [138] Poly(propylene glycol), Poly(L-amino polymer and Administration of these micelle compositions
acid), Poly(ester), and Phospholipids passenger drug does not require Cremophor EL or Tween 80,
avoiding serious side effects associated with these
products.

pH-sensitive block The supramolecular assemblies or micelles

Sant, V. US20067094810 Poly (ethylene oxide) - block - poly (n- copolymers for formed from said polymers associate or dissociate
et al. [139] butyl acrylate-co-methacrylic acid) pharmaceutical reversibly upon changes in the environmental pH.
compositions

PEG-POE, PEG-POE-PEG, and POE-PEG-POE

PEG-POE, PEG- block copolymers have both hydrophilic and
Ng, SY. US20030152630 Poly(ethylene glycol) (PEG) and POE-PEG, and hydrophobic blocks. They form micelles in
et al. [140] Poly(ortho ester) (POE) POE-PEG-POE aqueous solution, making them suitable for
block copolymers encapsulation or solubilization of hydrophobic or
water-insoluble materials.

Polymethylacrylic acid, Polyacrylic

acid, Poly(phosphate), Polyamino
acids, Polymalic acid, or Polylactic
The present invention provides polymer micelles
acid and Polyetherglycols,
with cross-linked ionic cores as delivery vehicles
US20040228823 Poly(ethylene oxide), copolymers of
Bronich, Cross-linked ionic for therapeutics, diagnostics, nucleic acids,
ethylene oxide and Propylene oxide
TK. et al. [141] core micelles proteins, small molecules and the like. The
Polysaccharides, Polyvinyl alcohol
present invention provides additionally methods
Polyvinyl pyrrolidone
of synthesis and uses for such micelles.
Polyvinyltriazole, N-oxide of
Polyvinylpyridine, HPMA, Polyortho
esters, Polyglycerols
56 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sosnik et al.

Table 4. Patents Describing the Development of Polymersomes for the Improvement of Technological Aspects of Drugs (Refs 146-
151)

Patents No.
Inventors Polymers Title Observations
[Ref.]

Polyethylene oxide (PEO) Biocompatible vesicles comprising semi-permeable, thin-walled

Polymersomes and
US20046835394 Poly(ethylethylene) (PEE) encapsulating membranes, and which comprise one or more
Discher, DE. related
Poly(butadiene) (PB or synthetic super-amphiphilic molecules can controlled the
et al. [146] encapsulating
PBD), Poly(styrene) (PS) and encapsulation or release of materials from the vesicle by
membranes
Poly(isoprene) (PI) modifying the composition of the membrane.

The present invention provides methods for preparing stable,

Polyethylene glycol (PEG)
purely synthetic, self-assembling, controlled release,
US20050003016 Polylactic acid (PLA), PEG-
Discher, DE. Controlled release polyethylene oxide (PEO)-based polymersome vesicles, and the
PLA, polycaprolactone
et al. [147] polymersomes resulting PEO-based polymersomes capable of such controlled
(PCL), PEG-PCL and
release, and methods of use therefor for the controlled transport
Polybutadiene
and delivery of encapsulatable active agents contained therein.

US20050048110 Polyethylene oxide (PEO)

Polymersomes and The vesicles cross-linking provides mechanical control and
Poly(ethylethylene) (PEE)
Discher, DE. US20070218123 related long-term stability, thereby also providing a means of
Poly(butadiene) (PB)
et al. US20077217427 encapsulating controlling the encapsulation or release of materials from the
Poly(styrene) (PS) and
membranes vesicle by modifying the composition of the membrane.
[148] Poly(isoprene) (PI)

Poly(ethylene oxide)-
Polyethylethylene The instant invention concerns compositions comprising
Poly(ethylene oxide)- Polymersomes polymersomes, visible or near infrared emissive agents, and
Hammer, US20050019265 Poly(butadiene) incorporating optionally a targeting moiety associated with a surface of the
DA. et al. [149] Poly(ethylene oxide)- highly emissive polymersome. The invention also relates to use of these
Poly(epsilon-caprolactone) probes compositions in the treatment of disease and in imaging
or Poly(ethylene oxide)- methodology.
Poly(lactic acid)

Poly(ethylene glycol)-
WO07038763 Polycaprolactone diblocks Self-assembled The invention concerns biodegradable polymersomes, more
Therien, MJ.
and copolymer of biodegradable particularly, polymersomes made of poly(ethyleneoxide)-b-
et al. [150]
Polyethyleneoxide and polymersomes polycaprolactone diblock copolymers.
Polycaprolactone

The thermo-responsive polymersomes display cold-controlled

Thermo- encapsulation near the physiological temperatures. Below the
WO07075502 Poly(ethylene oxide-O-N-
responsive block lower critical solution temperature (LCST), the thermo-
Qin, S. et al. isopropyl-acrylamide (PEO-
[151] co-polymers, and responsive block displays hydrophilic properties, such that the
6-PNIPAAm)
use thereof polymersome dissociates, providing fast release of an active
agent encapsulated therein.

Table 5. Marketed Products Utilizing Polymer-Based Nanotechnological Strategies for the Optimization of the Technological
Aspects of Drugs

System Trade name Company Application Ref.

These long-circulating ultrasmall superparamagnetic iron oxides (USPIO) have

Dextran- ® Advanced applications in angiography, including tumor angiogenesis imaging, and it was
Feridex [153]
nanoparticles Magnetics Inc. recently demonstrated that USPIO may be used for magnetic resonance
lymphograpy to detect cancer metastasis.

Silicone- Used in magnetic resonance imaging (MRI) to distinguish the loops of the
Lumirem® Guerbet S.A. [154,155]
nanoparticles bowel from other abdominal structures and physiology.

The FDA approved paclitaxel albumin-bound particles for injectable suspension for
Albumin- American
Abraxane® the treatment of metastatic breast cancer after failure of combination chemotherapy [156,157]
nanoparticles Bioscience, Inc.
or relapse within six months of adjuvant chemotherapy.
Polymeric Nanocarriers for Optimized Technological Aspects of Drugs Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 57

(Table 5) Contd….

System Trade name Company Application Ref.

Polyisohexylcyanoacryl Doxorubicin Transdrug® has been approved by the FDA for the multi-
Bio-Alliance
ate (PIHCA)- Transdrug® centre randomised Phase II/III clinical trial for the treatment of [158]
Pharma.
nanoparticles hepatocarcinoma.

VivaGelTM is a vaginal microbicide gel under development for the

TM
L-lysine dendrimer VivaGel Starpharma. prevention of sexually transmitted infections (STIs). The first clinical trial [159,160]
under this new dendrimer-based drug was completed in 2004.

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