Single Emulsion-Solvent Evaporation Technique and Modifications For The Preparation of Pharmaceutical Polymeric Nanoparticles

Recent Patents on Drug Delivery & Formulation 2012, 6, 209-223 209
Single Emulsion-Solvent Evaporation Technique and Modifications for the

Preparation of Pharmaceutical Polymeric Nanoparticles
María G. Nava-Arzaluza*, Elizabeth Piñón-Segundob, Adriana Ganem-Ronderoa and David

Lechuga-Ballesterosc
a
Laboratorio de Investigación y Posgrado en Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán,
Universidad Nacional Autónoma de México. Av 1º de Mayo s/n, Col. Santa María las Torres, Cuautitlán Izcalli, Estado
de México, 54740, México; bLaboratorio de Sistemas de Liberación Modificada, L-13 UIM, Facultad de Estudios Supe-
riores Cuautitlán, Universidad Nacional Autónoma de México. Km 2.5 Carretera Cuautitlán–Teoloyucan, San
Sebastián Xhala, Cuautitlán Izcalli, Estado de México, 54714, México cPearl Therapeutics, Inc., 200 Saginaw Drive,
Redwood City, California, 94063, USA
Received: January 14, 2012; Revised: May 22, 2012; Accepted: May 28, 2012
Abstract: In recent years, there has been an increased interest in using nanoparticles for drug delivery and pharmaceutical
development. Nanoparticles can offer significant advantages over the conventional drug delivery systems in terms of high
drug loading, stability and specificity, controlled release capability, and the ability to deliver both hydrophilic and hydro-
phobic drug molecules through various routes of administration. This review article focuses on the use of the single emul-
sion solvent evaporation method, the first method proposed for the preparation of polymeric nanoparticles, and modifica-
tions that have been developed over the years to improve the results obtained with this technique.
Keywords: Drug delivery, hydrophilic drugs, polymeric nanoparticles, preformed polymers, poorly soluble drugs, single emul-
sion, solvent evaporation, surface modifications.
INTRODUCTION in which the drug is localized within the inner cavity; the
system consists of a liquid core surrounded by a polymeric
Over the past decades, polymer nanoparticles (PNPs) membrane. The drug is usually dissolved in the inner core,
have been widely investigated in the pharmaceutical area as
but can also be adsorbed to the surface of the capsule [4].
drug delivery systems, as they offer several advantages over
conventional drug release dosage forms, such as increased One of the most significant characteristics of nanoparti-
bioavailability, improved efficacy, reduced toxicity, im- cles is their size, which facilitates the entry and improves
proved stability both during storage and in vivo (labile mole- their interaction with biological substrates. Conventionally,
cules are better preserved from enzymatic degradation in PNPs have been prepared by methods either involving the
biological medium), high pharmacological target specificity, in situ polymerization of monomers or using dispersions of
high drug-carrying capacity, ability to control drug release, preformed polymers.
and to release both hydrophilic and hydrophobic drugs Size control of nanoparticulate systems is achieved by
through various routes of administration [1]. PNPs made out optimizing the experimental variables of the method of
of biodegradable and biocompatible polymers have been preparation. Methods utilizing preformed polymers are pre-
shown to enable drug delivery applications such as con- ferred because the latter avoid the presence of toxic residues
trolled release, tissue targeting in cancer therapy, and carrier as compared with methods based on polymerization reac-
for the delivery of oligonucleotides, peptides, and proteins tions, which can possess unreacted monomers and free radi-
[1-3]. cals. The choice of method for the preparation of PNPs is
Pharmaceutical nanoparticles within the content of this highly dependent on the physicochemical properties of both
review article are defined as solid submicron sized colloidal the polymer and the drug compound. The emulsification-
particles loaded with a biologically active agent. The term evaporation method, in which a polymer is dissolved in a
nanoparticle is the collective name assigned to both nano- volatile water-immiscible organic solvent, was originally
spheres and nanocapsules. Nanospheres are matrix-type, and developed by Vanderhoff et al. [5] and was quickly adopted
the drug can be adsorbed onto the outer surface or encapsu- for pharmaceutical use [6]. This review will focus on the
lated within the particle. Nanocapsules are vesicular systems preparation of the PNPs by the single emulsion-solvent
evaporation using preformed polymers.
*Address correspondence to this author at the Laboratorio de Investigación
y Posgrado en Tecnología Farmacéutica, Facultad de Estudios Superiores SINGLE EMULSION-SOLVENT EVAPORATION
Cuautitlán, Universidad Nacional Autónoma de México. Av 1º de Mayo s/n, METHOD
Col. Santa María las Torres, Cuautitlán Izcalli, Estado de México, 54740,
México; Tel: +52 55 56232065; Fax: +52 55 56232043; The single emulsion-evaporation method (SESEM) in-
E-mail: gpearz@hotmail.com volves two basic steps. The first one consists of the dissolu-
2212-4039/12 $100.00+.00 © 2012 Bentham Science Publishers

210 Recent Patents on Drug Delivery & Formulation, 2012, Vol. 6, No. 3 Nava-Arzaluz et al.
tion of the polymer and the drug in a volatile organic solvent. Commonly used polymers to produce PNPs by the SE-
In the past, dichloromethane and chloroform were frequently SEM include poly(lactic acid) (PLA), poly(glycolic acid)
used, but these have now been replaced by ethyl acetate to (PGA), poly(lactic-co-glycolic acid) (PLGA), ethylcellulose
address residual solvent toxicity concerns. The emulsion is (EC), cellulose acetate phthalate (CAP), poly(-caprolac-
prepared by adding water and a stabilizer to the polymer tone) (PCL), and poly(-hydroxybutyrate) (PHB) [1].
organic solution (oil phase) to form the oil-in-water emulsion
The size and shape of nanoparticles are influenced by the
(o/w). In many cases, the formation of “nano-drops” by the
presence and concentration of surfactants whose main func-
polymer is induced by either ultrasonication or homogeniza-
tion is to stabilize the emulsion in order to reduce clotting.
tion. In the second step, the organic solvent is evaporated
Stabilizers are usually incorporated in the aqueous phase and
either by continuous stirring at room temperature or under
they are hydrophilic polymers, anionic or cationic surfac-
reduced pressure. Evaporation of the organic solvent is fol- tants. Commonly used stabilizers include poly(vinyl alcohol)
lowed by precipitation of the polymer as nanospheres of a
(PVA), poloxamer 127, poloxamer 188 and polysorbate 80
few hundred nanometers in diameter. The nanoparticles are
among others.
generally recovered by ultracentrifugation and washed with
distilled water to remove the excess of stabilizer and free The solvent used to prepare the organic phase must be
drug. Water is subsequently removed by lyophilized to en- immiscible with water and its boiling point must be less than
hance shelf life during storage. An alternative method for the that of water (volatile organic solvents) to ensure complete
solvent removal in the SESEM is lyophilization. For exam- evaporation from the finished product due to their potential
ple, this process has been describe to prepare submicron- to pose a health risk. Removal of residual solvents to very
sized particles of a pharmacologically active compound by low concentrations is also important to ensure a stable
forming a crude dispersion in a water-immiscible solvent and nanoparticulate product. Residual solvents in pharmaceutical
a surfactant, subjecting the crude dispersion to sonication in products are divided into three main classes: class 1, solvents
order to form a fine dispersion, freezing the fine dispersion, known to cause unacceptable toxicities and that should be
and lyophilizing the frozen dispersion to obtain particles avoided in the production of pharmaceutical products; class
with a diameter of <500 nm [7]. A schematic representation 2, solvents associated with less severe toxicities and that
of the SESEM is shown in Fig. (1). A number of patents em- should be limited in use, and class 3, less toxic solvents. The
ploying SESEM to produce PNPs for various applications most common solvents currently used in the SESEM are
are listed in Table 1. dichloromethane (DCM) and ethyl acetate, which belong to
class2. Other more toxic solvents used are chloroform and
Factors that influence the nanoencapsulation process and
acetonitrile. When the drug is not completely soluble in a
the final nanoparticles obtained include: a) nature and solu-
single organic solvent, a mixture is required, the most com-
bility of the drug; b) polymer concentration, molecular
monly used solvent mixture is DCM-ethanol.
weight, and type; c) the drug/polymer proportion; d) the or-
ganic solvent utilized; e) concentration and type of stabilizer SESEM has been successfully employed to encapsulate a
utilized; f) stirring speed and temperature of the emulsifica- variety of hydrophobic drugs and the availability of pharma-
tion process; and g) the volume and viscosities of the dis- ceutically acceptable solvents for the SESEM, its high yield,
persed and continuous phases. Manipulation of these vari- good reproducibility, and ease of scaling up have all contrib-
ables has been shown possible to optimized nanoparticles uted to its continued use. The major SESEM disadvantage is
size and maximized efficiency of encapsulation. its poor efficiency in the incorporation of hydrophilic drugs
such a peptides, proteins and genetic material [1, 2, 4, 16].
Fig. (1). Schematic representation of the PNPs preparation by single emulsion-solvent evaporation method.
Preparation of Pharmaceutical Colloids by the Emulsion Solvent Evaporation Recent Patents on Drug Delivery & Formulation, 2012, Vol. 6, No. 3 211
Table 1. Patents that used single emulsion-solvent evaporation method to prepare nanoparticles for different pharmaceutical ap-
plications.
Application Scope of the invention Reference(s)
Topical drug delivery Polymeric nanoparticles for topical administration of antibiotics for the treatments of wounds [8]
Drug delivery to prevent cardiovas- PLGA nanoparticles loaded with paclitaxel in order to coat an implant and delivery the drug to [9]
cular restenosis vascular smooth muscle cells.
a) Local drug delivery by PNPs, b) local drug delivery by PNPs during percutaneous transluminal
coronary angioplasty and c) pulmonary drug delivery by PNPs to prevent restenosis.
Parenteral drug delivery to treatment PLGA/vitamin E TPGS nanoparticles as emulsifier agent with Nordihydroguaiaretic acid [10]
of tumors (NDGA)
Time release depot for local delivery Bupivicane biodegradable polymer particle based on polymers, such as polyester amide (PEA) [11]
Contrast agents for NIR/MR bimodal PLGA nanoparticles loaded with iron oxide and rhodamine, showing near infrared (NIR) fluores- [12]
imaging cent properties and magnetic properties simultaneously
Pulmonary delivery to cancer ther- PLGA nanoparticles loaded with nordihydroguaiaretic acid (NDGA) [13]
apy
Treatment of cancer by increasing Combination of resveratrol and TETRAC nanoparticles [14]

the pro-apototic action
Photodynamic therapy for athero- texaphyrin, porhyrin, benzochlorin or chlorophil -loaded nanoparticles into the diseased vascular [15]
sclerotic plaque tissue
Usually hydrophilic drugs are retained in the aqueous phase solvent diffusion, and ionic interaction. The authors found
during the emulsion formation process. The use of organic that the encapsulated efficiency of rifampicin was higher
solvents, like methylene chloride or ethyl acetate, may also with the SESEM. They observed a decrease in particle size
affect the secondary structure of proteins resulting in loss of and polydispersity index on increasing PVA concentration.
activity. The need for high shear mixing to obtain small In addition, higher encapsulation efficiency was found by
emulsion droplets can produce energy which may affects increasing the drug:polymer ratio. The in vitro drug-release
thermally sensitive drugs and necessitating the use of a stabi- profile was biphasic. These authors utilized dichloromethane
lizer to form a stable emulsion prior to removing the solvent. as solvent, PVA (3%, w/v) as stabilizer, formed emulsion by
means of 20 min of ultrasonication, and evaporated the sol-
The formation mechanism of nanoparticles by the emul-
vent at room temperature for 12 h under magnetic stirring.
sification-evaporation method has been studied by Des-
Afterwards, the nanoparticles were recovered by ultracentri-
gouilles et al. [17]. Nanoparticles can be produced from sin-
gle or multiple coalesced droplets present in the emulsion. fugation at 35,000 rpm.
The emulsion droplets are stabilized by surfactant, and these Some researchers have found that increasing the concen-
are stable during solvent evaporation. The mechanism is tration of the stabilizer (PVA) in the preparation of PLGA
depicted in Fig. (2). Desgouilles et al. also found that this nanoparticles by the SESEM using dichloromethane as sol-
mechanism is dependent on the polymer type utilized. When vent, leads to a marked decrease in particle size, while the
EC was used, emulsion droplet coalescence occurred prior to homogenization speed and evaporation rate exert little influ-
obtaining stable and solvent-free nanoparticles during evapo- ence [19].
ration and nanoparticles were generated from several drop-
Gonsalves et al. [8] developed PNPs for topical admini-
lets. In contrast, when PLA was employed, limited or no
stration of antibiotics in the treatments of wounds, which
coalescence occurred; therefore, a nanoparticle was formed
could replace systemic therapy and improve the antibiotic’s
from a single droplet. Differences were attributed to the sur-
efficacy in preventing soft-tissue infection and osteomyelitis
face activity properties of the polymers; EC is surface active caused by Staphylococcus aureus which is frequently
whereas PLA has no interfacial adsorption.
chronic and highly resistant to antibiotic therapy. In this
As previously mentioned, the SESEM is one of the most case, PNPs could facilitate the movement of antibiotics
frequently used techniques because of its simplicity and across the osteoblast cell membrane. The therapeutic treat-
straightforward scale up. Development of PNPs via SESEM ment included two types of PNPs: a fast-release type, to tar-
with desired properties has been achieved with the use of get extracellular microbes present on tissue surfaces, and a
different polymers and copolymers, various solvents and slow-release type to target intracellular microbes. PLGA
stabilizers. nanoparticles loaded with nafcillin were prepared by SE-
SEM, using PVA as stabilizer and released drug within 35-
For example, Tripathi et al. [18] prepared PLGA nano-
40 days. Examples describing the synthesis of different
particles loaded with rifampicin (an antibiotic use to treat
polyanhydrides for the preparation of fast and slow release
tuberculosis) by single- and double-evaporation method,
Fig. (2). Schematic representation of formation mechanisms of nanoparticles by single emulsion-solvent evaporation method proposed by
Desgouilles et al. (A) using EC in ethyl acetate and (B) using PLA in ethyl acetate.
nanoparticles through the SESEM loaded with vancomycin, were centrifuged and washed twice at 11,000 rpm to remove
tobramycin, and piperacillin-tazobactam. The biodegradable the non- encapsulated LEV. The standard method produced
delivery vehicle comprised PLA, PLGA, polyanhydride nanoparticles with low encapsulated efficiency (<16.0%).
(PAH), and poly(1,3-bis-(carboxyphenoxypropane) (poly Addition of lecithin (1.0% w/v) to the PVA aqueous phase
(CPP):sebacic acid (poly[CPP:SA]). during PLGA nanoparticle preparation resulted in two-fold
improvements in the percentage of encapsulation efficiency
Cardiovascular disease is one of the leading causes of
and in decreasing LEV release rate [21].
death worldwide; 10-50% of patients experience restenosis
(re-obstruction of the coronary arteries) after surgical treat- The WO 2004112696 A2 invention prepared PLGA/
ment [20]. Si-Shen [9] prepared PLGA PNPs loaded with TPGS nanoparticles as emulsifier agent with Nordihy-
paclitaxel by the SESEM, using d-alpha Tocopheryl poly- droguaiaretic acid (NDGA) compounds by modified oil-in-
ethylene glycol 1000- succinate (TPGS) as stabilizer, in or- water single emulsion-solvent evaporation. TPGS was used
der to coat an implant, obtaining nanospheres with a size of instead of PVA in order to avoid limitations of this stabilizer
685 ± 39 nm and 100% encapsulation efficiency. The im- (difficulty to removed excess after emulsification). The
plant may be used in a cardiovascular drug-eluting stent, polymer and the NDGA compounds are added to the di-
which is utilized in brachytherapy to lower the incidence of chloromethane. The organic-phase solution is then slowly
restenosis. poured in the stirred aqueous solution with or without emul-
sifier and sonicated simultaneously. The o/w emulsion
Levofloxacin (LEV)-loaded PLGA nanoparticles have
formed can be gently stirred at room temperature by a mag-
been prepared using the SESEM by Cheow and Hadinoto
netic stirrer overnight to evaporate the organic solvent [10].
[21]. PLGA and LEV were dissolved in dichloromethane
and then this organic phase was added into the PVA aqueous The SESEM has also been used to prepare nanoparticles
solution (1.0% w/v) under ultrasonication to form an oil-in- based on cyclodextrin, Lemos-Senna et al. [22] prepared
water nanoemulsion. The dichloromethane was then slowly loaded progesterone nanospheres from an amphiphilic, 2,3-
evaporated overnight at room temperature. The nanoparticles di-O-hexanoyl--Cyclodextin (CDC6). This was achieved
by emulsifying dichloromethane with cyclodextrin and a tan sesquioleate in triethylcitrate was added. Nanoparticles
drug in an aqueous phase containing Pluronic F68 as stabi- with a mean size of 198 nm were obtained and proposed for
lizer, utilizing a high-speed homogenizer at 20,500 rpm for 2 intravascular administration in cancer therapy [27].
min. Thereafter, the dichloromethane is evaporated by stir-
Jaiswal et al. prepared biodegradable Cyclosporine (CsA)
ring for 12 h at room temperature and the aqueous suspen- nanoparticles by a modified single emulsion/evaporation
sion is concentrated in a low pressure system. Cyclodextrin
method. The polymer (PLGA or poly(ethylene glycol)
nanospheres had a mean diameter ranging from 50-200 nm.
(PEG)-PLGA) and the drug were dissolved in dichloro-
The drug content found in the nanospheres ranged from 4-
methane by magnetic stirring. The organic phase was dis-
5% (w/w) of the carrier [22].
persed in PVA aqueous solution (2%) utilizing a high-speed
homogenizer at 13,000 rpm. This emulsion was passed
OPTIMIZATION AND ADAPTATIONS OF THE SIN- through a high-pressure homogenizer four times at 500 bars
GLE EMULSION-SOLVENT EVAPORATION and the solvent was removed from the nanosuspension over-
METHOD night using a magnetic stirrer. The nanoparticles obtained
The nanometric size of the emulsion droplet is controlled were 152-223 nm, with low polydispersity index (0.14),
by applying high shear forces usually by high speed stirring and possessed high encapsulation efficiency (82–92%) de-
or ultrasonication. Another way to obtain very-small-size pending on the polymer type [23].
oily globules is by means of a high-pressure homogenizer. In Desai et al. described a drug delivery system for pacli-
general, the high-pressure emulsification and solvent evapo- taxel, a water-insoluble drug in a modified composition that
ration method consists of forming a crude emulsion with the does not cause allergic reactions due to the presence of
polymer and the drug in an organic solvent and an aqueous added emulsifiers and solubilizing agents, such as those cur-
solution with a stabilizer agent; this emulsion is transferred rently employed in drug delivery systems such as emulsions.
into a high-pressure homogenizer and the emulsification is They prepared nanoparticles (< 200 nm in diameter) by
performed at high pressure by recycling the emulsion by means of a solvent evaporation technique from an oil-in-
several cycles. The organic solvent is removed by either water emulsion, produced under high shear forces (e.g.,
slow evaporation at ambient temperature and normal pres- high-pressure homogenization), employing proteins as stabi-
sure under stirring, or by quick evaporation at reduced pres- lizing agents (e.g., human serum albumin). One part of the
sure and the formed the nanodroplets solidify in the aqueous drug is bound to the albumin, and the remaining portion of
system [23-24]. the drug is contained within the protein-coated nanoparticle.
High-pressure emulsification has been employed to pre- The nanoparticles were sterile filtered through a 0.22-micron
pare pharmaceutical nanoemulsions; in US Patent No. filter; this is particularly important because formulations that
6120778, a nanoemulsion was prepared based on silicone contain a significant amount of any protein cannot be steril-
surfactants utilizing a high-pressure homogenizer at 1,500 ized by conventional methods. The dispersion was further
bars and upon seven passes, nanodroplets were formed with lyophilized for 48 h without the addition of a cryoprotectant.
a mean size of <100 nm [25]. The resulting cake could be easily reconstituted to the origi-
nal dispersion by the addition of sterile water or saline solu-
Kreuter et al. applied high-pressure emulsification and tion. The particle size of the reconstituted cake was the same
solvent evaporation method to prepare a drug targeting as prior to lyophilization [28, 29].
system for administering a drug to the Central Nervous
System (CNS) that can cross the blood brain barrier. The In another invention nanoparticles were prepared loaded
invention discloses a drug targeting system that comprises with a poorly water-soluble drug, a poorly aqueous-soluble
Pluronic 188-coated nanoparticles made of PLA or PLGA. non-ionizable cellulosic polymer, and TPGS in order to form
The doxorubicin- loaded nanoparticles were prepared by a a blend that produces nanoparticles with improved perform-
high-pressure homogenization-solvent evaporation method, ance and stability. In this case, the non-ionizable cellulosic
using dichloromethane as the organic solvent and PVA polymer is chosen so that a portion of the drug will be solu-
(0.5%) as stabilizer agent. The emulsification process was ble in the polymer. This prevents or reduces the drug’s crys-
carried out at 400 bars and the organic solvent was eva- tallization rate in the nanoparticle. TPGS provides nanoparti-
porated under reduced pressure. The particle size of these cles with suspension stability by reducing or eliminating
nanoparticles was 140-220 nm and entrapment efficiency nanoparticle agglomeration in aqueous suspension. The use
was 40% when the oil phase was formed by PLA and of these two different materials (polymer and TPGS) pro-
cholesteryl sulfate potassium in chloroform and the aqueous vided a synergistic effect, resulting in improved nanoparticle
phase by doxorubicin hydrochloride, using PVA (1%) as stability and resuspendability. In general, the nanoparticles
stabilizer. The resulting primary emulsion was passed four were prepared by the modified single- emulsion solvent
times through a high-pressure homogenizer at 600 bars and evaporation technique. The drug (Valdecoxib or Celecoxib)
the solvent was removed under reduced pressure generating and ethyl cellulose were dissolved in ethyl acetate to form an
500-600 nm nanoparticles, having doxurubicin loading of organic solution. This organic solution was poured into wa-
89% [26]. ter-containing TPGS and emulsified for 4 min using a ro-
tor/stator at 10,000 rpm to form a pre-emulsion. In order to
U.S.Patent application No. 2005129777A1 describes the reduce the droplet size, the pre-emulsion was subjected to
production of nanoparticles that contain methotrexate pre- high-pressure homogenization in a microfluidizer, with an
pared from a water-in-oil emulsion employing high-pressure inlet pressure of 80 psi, for 6 min. Ethyl acetate was re-
homogenization. Briefly, the drug was dissolved in an am- moved from the emulsion with a rotary evaporator, resulting
monium-hydroxide aqueous solution and a mixture of sorbi-
in aqueous suspension of nanoparticles with an average di- PLA nanoparticles loaded with bovine serum albumin
ameter of < 200 nm and low polydispersity index [30]. (BSA) using membrane emulsification have been prepared
by Wei et al. [33]. The membrane pore size was 1.4 m and
MEMBRANE EMULSIFICATION-SOLVENT a pressure of 1,000 kPa was used. Ethyl acetate was used as
EVAPORATION METHOD the organic solvent, and the nanosuspension was stirred
overnight to evaporate the organic solvent. The mean
Control of nanoparticle size distribution by the SESEM nanoparticle size was about 321 nm and this size tends to
has been a subject of study. In general ultrasonication as well increase when the volume ratio of aqueous phase increases;
as high speed or pressure homogenization are high energy encapsulation efficiency was 32.3%.
processes which could affect the stability of certain drugs.
To overcome these disadvantages, a novel method that com- Kanakubo et al. prepared PLGA and surface-modified
bined emulsification by low energy conventional process and PLGA particles by using block polymer (PEG)-assisted
premix membrane emulsification has been proposed. The membrane emulsification. The polymers (PLGA and block
coarse emulsion obtained by low-speed stator homogeniza- polymer) were dissolved in a mixture of dichloromethane-
tion is extruded through membrane under high pressure to toluene. To form the emulsion, the organic phase was added
form uniform-size nanodroplets. During the process of pre- to the dispersion tank of the membrane (pore size, 300-nm)
mix membrane emulsification for nanoparticle preparation, and the emulsification apparatus was wet with PVA aqueous
the size of the coarse emulsions was reduced to nanoscale solution (2.0%, w/v). The dispersion tank was connected to
due to high transmembrane pressure due to droplet disrup- nitrogen gas. The nitrogen flowing into the tank forced the
tion. The most commonly used membranes for oil- in-water organic phase through the membrane containing the PVA
emulsions are hydrophilic Shirasu porous glass (SPG) mem- solution. After membrane emulsification, the organic solvent
branes and for water-in-oil emulsions polytetrafluoroethyl- was removed by stirring the emulsion at 300 rpm for 18 h
ene (PTFE) membranes. The solvent present in the nanoe- and the resulting nanoparticles were washed with water. The
mulsion is removed either by prolonged stirring or evaporat- average size of the nanoparticles increased as the amount of
ing under vacuum conditions. The solvent commonly used is added block copolymer increased; PLGA nanoparticles were
ethyl acetate due to its relatively high boiling point. SPG- 669 nm in size, while PLGA nanoparticles with high
membrane pore size is crucial to the preparation of uni- amounts of copolymer were 977 nm in size. These nanopar-
formly sized nanoparticles. Droplet size can be controlled by ticles loaded with gadolinium can be used as contrast agent
the membrane type, the cross-flow velocity and transmem- in Magnetic Resonance Imaging (MRI) [34].
brane pressure; with increased transmembranal pressure, Kazuki et al. patented a porous silica membrane by sol-
small-size particles with narrow-size distribution were ob- gel process, which includes surface chemical modification
tained. Advantages of this modification include narrow-size groups (SiO2 as main component) in a large amount and with
distribution and size control, high productivity, simplicity, pores suitable for membrane emulsification [35].
and suitability for synthetic and natural polymers [31-33].
Figure 3 shows a schematic representation of premix emulsi- Hideki et al. reported on the formation of a submicron
fication systems. emulsion with excellent uniformity by membrane emulsifica-
tion method. He also disclosed oil-in-water emulsion which
Fig. (3). Schematic representation of the preparation of nanoparticles by membrane emulsification.

contains water-soluble solid particles that are present in the possibility is to promote the liposolubility of drug. It has
oil droplets. The particles are prepared via the emulsion by been observed that the solubility of a specific protein freeze-
means of dehydration before the entire particle/oil suspen- dried in organic solvents can be modified by controlling the
sion is dispersed in an aqueous phase using the porous mem- pH of the aqueous protein solution prior to lyophilization.
brane emulsification process [36]. When recombinant human-Granulocyte colony-stimulating
factor (rhG-CSF) was lyophilized at pH 4, rhG-CSF was
The membrane emulsification has been used to produce
completely soluble in Dimethyl sulfoxide (DMSO); this sol-
microcapsules with controlled size by Biggs et al. Standard
vent was employed to co-dissolve PLGA and it lyophilized
homogenizer (rotor-stator type) and mixers were used to
rhG-CSF powder in a single organic phase. This organic
produce a coarse emulsion, then it was processed through
phase was dispersed into Pluronic F-127 aqueous solution
cross-membrane or rotating membrane to obtain small drop-
lets with more uniform size distribution that those prepared (1% w/v) and then homogenized at 4,000 rpm. The sus-
pended solution was dialyzed in de-ionized water to remove
by homogenization. They obtained microcapsules where
residual DMSO. rhG-CSF-loaded PLGA nanoparticles ex-
their mean size was controlled by membrane emulsification
hibited a sustained release profile [43].
[37].
Tewes et al. evaluated the efficiency of encapsulation of
NANOPARTICLES LOADED WITH HYDROPHILIC Doxorubicin (DOX) in PLGA (50:50) nanoparticles obtained
DRUGS PREPARED BY THE SINGLE EMULSION- by the single emulsion-evaporation method and compared
SOLVENT EVAPORATION METHOD with the double- emulsion method. To form the nanoparti-
cles by the single-emulsion method, they used a drug solu-
For many new biotechnologically obtained drugs such as tion in dichloromethane by partition from buffer pH 8.6 to
proteins, peptides, and oligonucleotides to be clinically ef- control DOX protonation and polarity (the neutral form of
fective requires the development of proper delivery systems. DOX can be extracted from the aqueous to organic phase
Biodegradable nanoparticle delivery systems provide an at- with a proper pH); this was combined with the polymer and
tractive alternative for drug delivery. It is well known that was then emulsified in an aqueous poly(vinyl alcohol) solu-
the SESEM to prepare nanoparticles results in poor encapsu- tion at 3% (w/v) by sonication to obtain an o/w emulsion.
lation efficiencies of hydrophilic drugs and macromolecules The solvent was removed by evaporation under vacuum
such as proteins, oligonucleotides, etc., due to their limited conditions at 40°C and the nanoparticles were washed with
solubility in organic solvents. Thus, these molecules have de-ionized water by centrifugation at 20,000 rpm for 20 min.
been generally prepared by the double-emulsion method; They obtained PLGA nanoparticles with a particle size of
however, they exhibited low protein- loading efficiency and about 280 nm that exhibited better entrapment efficiency
high burst release. Formulation of hydrophilic peptides and than those formulated by means of double emulsion [44].
proteins involving these carriers continues to remain a chal-
lenge. In addition, the biodegradable polymers used, such as Generally, the double emulsion (w/o/w)-solvent evapora-
PLA, PGA, and PLGA, are not water-soluble, rendering it tion method is utilized to entrap hydrophilic drugs. However,
more difficult to efficiently encapsulate hydrophilic drugs when the particle size is reduced to nanometer range, the
into these polymers. hydrophilic-drug loading capacity of the carriers is reduced
due to rapid partitioning to the external aqueous phase. This
A number of patents that used a modified SESEM to pre- has been observed with Mitomycin C (MC) in PLA nanopar-
pare nanoparticles of hydrophilic drugs are listed in Table 2. ticles. In order to overcome this disadvantage, Hou et al.
To overcome the aforementioned drawbacks, several re- [45] developed a new method by emulsion-solvent evapora-
searchers have modified the single-emulsion method. One tion where Soybean phosphatidylcholine (SPC) was em-
Table 2. Patents that used modified single emulsion-solvent evaporation method to prepare nanoparticles.
Modification Applied Scope of the invention Reference(s)
High-pressure homogenization The doxorubicin- loaded nanoparticles [26]
High-pressure homogenization Methotrexate nanoparticles prepared from a water-in-oil emulsion [27]
High-pressure homogenization Nanoparticles containing paclitaxel coated with human serum albumin [28, 29]
High-pressure homogenization Valdecoxib or Celecoxib nanoparticles with non-ionizable cellulosic polymer, and Tocopheryl [30]
polyethylene glycol succinate
High-pressure homogenization Protein stabilized nanoparticle formulations containing liposomal-digitalis glycosides [38]
High-pressure homogenization Docetaxel nanoparticles stabilized by human serum albumin. [39]
Formation of polymer blend Nanoparticles from a PLGA-poloxamer blend to immobilize somatotropin [40]
Oil-in-oil emulsion Everolimus nanoparticles from Cellulose Acetate Phthalate [41]
Oil-in oil-emulsion PEA-Insulin.sub.z conjugate nanoparticles [42]

ployed to improve the hydrophilic drug’s liposolubility by eliminate DMSO. The resulting Somatotropin immobiliza-
formation of the drug-SPC complex. To prepare the com- tion efficiency was 90% [40].
plex, the drug and SPC are dissolved in an anhydrous solvent
Another modification of the SESEM to encapsulate hy-
such as DMSO by gentle agitation. The solution is then
drophilic drugs consists in the formation of oil- in- oil (o/o)
freeze-dried and the complex is formed after removal of the emulsion, where the continuous phase is formed by an or-
solvent. With this complex, the nanoparticles are then pre-
ganic liquid such as mineral oil, in order to achieve the en-
pared by the single emulsion-solvent evaporation method.
capsulation of hydrophilic drugs. In this case, a water-
An organic solution of polymer (PLA in dichloromethane) is
miscible solvent or a mixture of organic solvents (acetone,
added to the drug-SPC complex by agitation until a solution
acetone-ethanol, acetonitrile-dichloromethane, DMF-aceto-
is obtained. This organic phase is then emulsified with PVA
nitrile) is used to solubilize the drug in which polymers such
aqueous solution (0.25% w/v), then sonicated to form a sta- as PLGA or PLA are also soluble. This solution is then dis-
ble o/w emulsion. The solvent was removed by gentle stir-
persed into oil, such as a light mineral oil or paraffin, in the
ring under atmospheric pressure for 24 h, the complex and
presence of an oil- soluble surfactant (such as sorbitan
the polymer gradually co-precipitated; thus, the drug-SPC-
monooleate (SPAN 80)) by mechanical stirring to yield the
polymer is obtained. Hou et al. prepared PLA nanoparticles
o/o emulsion. The nanoparticles are finally obtained by
loaded with MC by means of this method and found that
evaporation or extraction of the organic solvent and are
drug entrapment efficiency was 94.8% when the MC-SPC washed with organic solvent (n-hexane) to remove the paraf-
complex is used, while when prepared by the classical
fin. Mahdavi et al. studied the effect of process parameters
method under the same conditions, entrapment efficiency is
and found that stirring speed, polymer concentration, impel-
only 34.5%. The nanoparticles obtained showed uniform size
ler type, and dropping size had a significant effect on particle
and narrow size distribution (594 nm) with a longer sus-
size. The polydispersity index of particles exhibited a strong
tained drug release [45]. Using this same approach, Cui et al.
relationship with surfactant concentration, impeller type, and
[46] formulated insulin into polymer nanoparticles. Briefly, a droplet size [47].
polymer (PLA or PLGA) organic solution in ethyl acetate or
dichloromethane was added to insulin-SPC complex, fol- The o/o method was initially develop for the preparation
lowed by gentle agitation until a clear micellar solution was of microparticles; for example, Zhu et al. prepared PLA mi-
obtained. This organic solution was emulsified with PVA croparticles loaded with 5-Fluorouracil (5-FU) and Kim
(2%, w/v) aqueous solution by sonicatation to form a stable et al. prepared microspheres using acrylate methacrylate
o/w emulsion. The solvent was eliminated by stirring for 6 h copolymers to encapsulate the anti-hypertension drug
and the complex and polymer progressively co-precipitated, felodipine. Additionally, the oil-in-oil emulsion evaporation
yielding nanoparticles loaded with insulin-SPC complex. method was reported to succeed in encapsulating the BSA
Nanoparticles with small size (~200 nm) and high entrap- into PLG microspheres. It is reported that drug leakage was
ment efficiency (~90%) were obtained [46]. restricted and macromolecule drug stability during encapsu-
lation was maintained [48-49].
Another way to improve the efficiency of the encapsula-
tion of hydrophilic drugs into nanoparticles prepared by the Asmatulu et al. synthesized a drug-carrying magnetic
single emulsion-solvent evaporation method is to form a nanocomposite using magnetite nanoparticles and PLGA for
polymer blend. Grandfils et al. [40] patented the modifica- the purpose of magnetic targeted drug delivery in order to
tion of emulsion solvent evaporation method by the forma- improve the therapeutic efficiency of the drug by reducing
tion of a polymer blend prior to the preparation of the emul- collateral toxic side effects on healthy cells. The polymer
sion. The polymer blend is formed by a biocompatible poly- was embedded with magnetic nanoparticles (MNP) and a
mer to form nanoparticles and other biocompatible interact- drug via the oil-in-oil emulsion-solvent evaporation tech-
ing agents (polymer containing alcohol-, ether-, or ester- nique. Briefly, two dissimilar oil phases were prepared and
constitutive units such as polyethylene glycol or poloxamer) mixed to form an oil-in-oil emulsion; the first oil phase was
for rendering the polymeric blend compatible with the drug. constituted by PLGA (50:50) in acetonitrile until dissolution
The polymer is melted or dissolved in the organic solvent was obtained, after which the MNP and the drug were added.
together with or prior to the addition of the interacting agent; The second oil phase comprised 1% v/v of SPAN 80 as sur-
in this step, the drug can be added in such a manner that the factant in heavy liquid paraffin. The mixture of two oil
mixture of the polymer, the interacting agent, and the drug phases was placed in a mixer operated at 7,000 rpm (the im-
form a homogenous mixture. The mixture can be formed peller shape and size are important for achieving smaller
from the emulsion when it comes into contact with the aque- sized spheres). The mixer was allowed to run for 1.5 h to
ous phase utilizing an appropriate surfactant. For example, evaporate acetonitrile and to form nanocomposite spheres.
they prepared nanoparticles from a PLGA-poloxamer blend The nanoparticles were collected by centrifugation and
to immobilize somatotropin. PLGA copolymer and Pluronic washed several times with n-hexane to remove the heavy
F68 (1:1) were dissolved in dichloromethane at room tem- paraffin liquid. They obtained nanocomposite spheres with
perature for 15 min. The organic solvent was allowed to several diameter sizes (ranging from 200 nm to 1.1 m) with
evaporate under nitrogen at room temperature and then at superparamagnetic properties [50].
40°C. Cholesterol 3-sulfate was added to the polymer blend Recently, Arjmand et al. [51] prepared PLGA nanoparti-
followed by DMSO. Somatotropin was added to the organic cles loaded with Alpha 1-antitrypsin (AAT), a potential
solution and the organic phase was dispersed in water with therapeutic agent for the protection of lung tissue against
rotor-stator equipment at 24,000 rpm. The suspension ob- free proteolytic activity. The nanoparticles were prepared by
tained was diluted and then purified by ultrafiltration to the oil-in-oil emulsification-solvent evaporation method. The
polymer was dissolved in acetonitrile; the protein, in 250 l roto-evaporation. The insulin nanoparticles can then be
of water, was incorporated into the polymer solution. The stored in solution or further lyophilized.
resulting mixture was added to viscous liquid paraffin con-
In the o/o emulsion solvent evaporation method, PEA-
taining SPAN 80 and stirred at 5,500 rpm for two h to ensure
Insulin.sub.z conjugate is dissolved with PEA or PEUR in
complete evaporation of the solvent. The nanospheres were warm HFIP/ tetrafluoroethylene (TFE). The polymer-
collected by ultracentrifugation and washed with n-hexane to
biologic mixture is emulsified in cottonseed oil containing
remove the mineral oil. The ATT protein was encapsulated
sorbitan monooleate. The energy of emulsification is pro-
in the PLGA nanoparticles of an average size of 550 nm with
vided by mixing at high rpm, and phase separation occurs at
significant efficiency (~50%).
the o/o interface so that the polymer wraps the inner polar
EP 2347776A1describes the preparation nanoparticles by organic phase, containing the insulin, into particles. The
the single (o/o) emulsion method followed by the evapora- HFIP/TFE was then removed by roto-evaporation in a water
tion of solvent from Cellulose Acetate Phthalate (CAP). The bath at a temperature of 40˚C and the oil organic phase is
drug (everolimus: 40-O-[2-hydroxyethyl]-rapamycin) can be removed by washing in hexane and filtering this solution
dispersed in the CAP organic solution to form a drug- through a 0.45 micron PTFE filter. The product were re-
polymer dispersion. In a second step, liquid paraffin was moved from the surface of the filter and lyophilized. These
combined with a sorbitan oleate as surfactant; this was then particles can be re-dispersed in water containing a surfactant
blended and vigorously stirred, both solutions were com- and this new dispersion can be re-lyophilized to a powder of
bined and the solvent was allowed to evaporate for 24 h at polymer particles containing crystalline Zn-insulin and
30°C, and the nanoparticles formed were collected, and bound water, in order to stabilize the protein promoting in-
washed with ether. These nanoparticles can be coated with or teraction between protein and polymer [42].
deposited on a medical device (e.g., a drug delivery or stent
coating) by a stereolithography technique and released upon SURFACE MODIFIED NANOPARTICLES OB-
implantation of the medical device to treat, prevent, or ame- TAINED BY THE SINGLE EMULSION-SOLVENT
liorate vascular medical conditions [41]. EVAPORATION METHOD
Formation of macromolecular-polymer conjugate and its Surface properties of nanoparticles can be modified by
encapsulation in polymer nanoparticles has been described utilizing polymer blends (coating nanoparticles surface with
by Turnell et al. [42] based on polymers, such as polyester polymeric surfactant such as poloxamers, poloxamines and
amide (PEA), polyester urethane (PEUR), and polyester urea PEG or chemically modified polymers (biodegradable co-
(PEU). The three-dimensional structure of the active macro- polymers containing a hydrophilic moiety). This modifica-
molecular can be protected by conjugate formation and its tion change nanoparticle zeta potential, as well as their hy-
encapsulation within polymer particle such as nanoparticles drophobicity [52]. Modification of the PNPs surface proper-
using an emulsion solvent evaporation method either oil in ties has several objectives such as: i) surface modification
water emulsion or oil in oil emulsion. The single, double and can stabilize nanoparticles against agglomeration; ii) to ren-
triple emulsion techniques are all applicable for this purpose. der PNPs compatible with another phase; iii) enable PNPs
SESEM can be used to encapsulate some macromolecu- self-organization; iv) PNPs with specific recognition ligands
lar biologics, such as Zn-insulin, which are stable in strong bound to the surface have a good potential for drug targeting
organic solvents like dichloromethane. Based on this premise (site-selective delivery), and offer higher drug carrier capac-
the, nano-crystals of Zn-insulin are mixed with a PEA poly- ity; and v) PNPs surface coverage by amphiphilic polymeric
mer, in dichloromethane containing surfactant-A to form a surfactants such as poloxamers, poloxamines and poly (eth-
liquid-solid slurry. This liquid-solid slurry is emulsified in ylene glycol) (PEG) derivatives over the nanoparticles in-
water containing surfactant-B. The energy of emulsification creases the blood circulation time [53-54].
is provided by vortexing followed by sonication. The volatile A drug delivery system based on montmorillonite
organic phase is removed by rotary evaporation. The particle (MMT)/Poly(D,L-lactide-co-glycolide) (PLGA) nanopar-
aggregate so formed can be re-dispersed in water containing ticles loaded with paclitaxel may be utilized for delivering a
surfactant-C. This dispersion of particles can be lyophilized. drug across a mucosal membrane. The idea is to use the
Briefly; The PEA polymer and dioleoylphosphotidylchloline mucoadhesive property and therapeutic effects of medical
(DOPC) were co-dissolved in dichloromethane to obtain a clays such as MMT to make a novel type of nanoparticle to
polymer solution. Then PEA-Insulun.sub.z conjugate (to deliver paclitaxel across a mucosal membrane, such as the
prepared PEA-Insulin.sub.z conjugate, the polymer PEA-H gastrointestinal barrier. The nanoparticles were prepared by
and free insulin were dissolved in hexafluoroisopropanol the single emulsion-solvent evaporation method. Paclitaxel
(HFIP)/Dioxane with a different coating polymer (PEA, and PLGA were dissolved in dichloromethane; this organic
PEUR or PEU) and the solution was stirred until both poly- phase was emulsified en PVA aqueous solution (2% w/v)
mers were completely dissolved. This solution was then in with different amounts of MMT and then sonicated to form
dioxane, frozen, and lyophilized to obtain an amorphous an emulsion. The organic solvent was allowed to evaporate
material having the polymer-insulin conjugate (PEA- overnight at room temperature. The suspension of the
Insulin.sub.z) conjugate) dispersed in DCM was mixed with nanoparticles was centrifuged, washed, and freeze-dried. The
the polymer solution by vortexing. This solution was emulsi- mucoadhesive property of the MMTpermits the uptake of the
fied in water containing additional surfactant like PVA by nanoparticles into the cells and the MMT can control and/or
ultrasonication, and then the organic solvent was removed by reduce side effects of the paclitaxel. Nanoparticle size was
around 310 nm with polydispersity of < 0.150 and 50%
encapsulation efficiency. Nanoparticles with an increased nizer at 5,000 rpm for 2 min. The particles were hardened by
amount of MMT showed more negative surface charge. The allowing dichloromethane to evaporate at room temperature
nanoparticle cellular association with Caco-2 and HT-29 cell while stirring for 2 h [58].
line was increased due to the incorporation of MMT [55].
The patent WO2008091465 (A2) disclosed surface modi-
Chorny et al. patented the formation of magnetic fied nanoparticles containing paclitaxel as a model drug by a
nanoparticles for gene delivery. Biodegradable polymer modified emulsion solvent evaporation method referred to as
(polylactide), Pluronic F-68, and Poly(ethylenimine) (PEI) interfacial activity assisted surface functionalization
were incorporated into the iron oxide suspension in the or- (IAASF). These nanoparticles are useful in treating tumors,
ganic solvent (chloroform); subsequently, this organic phase imaging the particles in tissues, and in targeting therapeutic
was emulsified in water pre-cooled to 0°C through sonica- agents to specific tissues and locations in the body.
tion. Chloroform was removed by rotoevaporation at 30°C.
Panyam et al. [59] prepared oil–in-water emulsion by
The size of the nanoparticles was found to be 302 nm and
introducing a diblock copolymer poly(lactide)-poly(ethylene
remained stable for 1 week. Iron encapsulation efficiency
glycol) conjugated to folic acid (PLA-PEG-folic acid) and/or
was 74%. They did studies for the transfection of cells in
PLA-PEG-biotin. The emulsion was stirred for 18 h at ambi-
culture from complex nanoparticles with green fluorescent
ent conditions to eliminate the organic solvent. Nanoparticles
protein (GFP)-encoding deoxyribonucleic acid (DNA) plas- thus formed were recovered by ultracentrifugation to sepa-
mid and found that magnetically responsive formulations
rate unentrapped paclitaxel, washed to remove PVA and then
resulted in high levels of gene product as opposed to non-
lyophilized to obtain a dry powder. The introduction of PLA-
magnetic nanoparticles in correlation with their cellular up-
PEG and PLA-PEG-ligand conjugate during the emulsifica-
take [56].
tion step results in nanoparticles with PEG and PEG- ligand
The single emulsion-solvent evaporation method can be on nanoparticle surface due to the partitioning of hydropho-
applied to nanoparticles prepared with amphiphilic copoly- bic PLA into the oil phase and hydrophilic PEG into the
mers such as PEG-PLA, PEG-PLGA, PEG-PCL, PEG- aqueous phase. This method allows the incorporation of mul-
PACA and polysaccharide-PCL, with the advantage that in tiple functional groups and tumor-targeting ligands on drug-
these cases, there is no need to add a surfactant in order to loaded nanoparticles in a single step. These nanoparticles
perform the emulsion. were used to evaluate the effect of folic acid and biotin con-
Hildgen et al. [57] prepared stealthy polymeric biode- jugation on the in vitro cytotoxicity of paclitaxel in breast
cancer cell line MCF-7. Conjugation of biotin and paclitaxel
gradable nanospheres to avoid phagocytic uptake, having
on nanoparticles increased the cytotoxicity of nanoparticle-
increased water solubility, reduced renal clearance, and de-
encapsulated paclitaxel. The main advantages of IAASF are
creased toxicity, based on a novel polyester-polyethylene
that it depends only on the interfacial activity of the block
multiblock copolymer (ABA-type polyester-polyethylene
copolymer and the presence of an emulsion and allow the
multiblock copolymer). This method comprises poly(lactic
acid) and Polyethylene oxide (PEO), and with poly(lactic incorporation of multiple ligands on nanoparticle surface in a
single step.
acid) (PLA-PEG-PLA) to produce rigid nanospheres by the
single-emulsion process. Polymer conjugations are used to improve the biophar-
maceutical properties of the drug. Several water-soluble
A mixture comprising an organic solvent (chloroform),
polymers have been shown to modify biodistribution, im-
the fluorescent compound (Rhodamine B), and the copoly-
mer (PLA and PLA-PEG-PLA) was prepared by dissolution prove the mode of cellular uptake, change the permeability
through physiological barriers, and modify the rate of clear-
at room temperature [57]. The polymeric solution of the drug
ance through the body. Representative compositions of the
was slowly injected into the chamber (containing the sonica-
present invention include thyroid hormone or analogs thereof
tion micro tip) to prepare the emulsion. The aqueous phase
conjugated to polymers such as polyvinyl alcohol, PEG,
containing 0.5% PVA was pumped continuously into the
polyesters, polyanhydrides, polysaccharides, and polyamino
chamber. The emulsification was achieved by ultrasonica-
tion. The solvent was evaporated by magnetically stirred acids. The ester linkage to the polymer may undergo hy-
drolysis
under low vacuum conditions for 2 h and the nanoparticles
in vivo to release the active thyroid hormone analog. In this
were recovered by centrifugation or dialysis. These nano-
invention [60], nanoparticles prepared by means of the sin-
spheres may be employed for the long term non-toxic release
gle-emulsion method with different compositions, such as
of Rhodamine B into the blood stream or in the tissues of a
the thyroid hormone or analog, Tetraiodothyroacetic acid
mammal may be controlled. The nanoparticles thus obtained
have a size of less < 800 nm. Rhodamine B release from the (TETRAC)-loaded nanoparticles of PLGA coated with
Tween 80,were prepared using acetone as solvent and PVA
PNPs showed sustained release over a 29-day period with a
in aqueous solution (1%) as stabilizer. The nanoparticles
biphasic pattern [57].
were purified by dialysis. The nanoparticles may incorporate
Invention (WO 2011084458 A2) relates to therapeutic a chemotherapeutic agent; the thyroid hormone analog is
compounds encapsulated within polyether-anhydride poly- immobilized on the surface of the nanoparticles [60].
mers. Biodegradable particles made from these polymers
Hanes and Fu provided a novel functionalized poly(ether-
have a hydrophobic polyanhydride core and a hydrophilic
anhydride) block copolymer, which can be suitable for the
PEG shell. Paclitaxel and PEG- poly(sebacic acid) (PSA)
administration of therapeutic and biologically active agents,
were dissolved in dichloromethane and emulsified into a 1%
including sustained release administration, through a wide
w/w polyvinyl alcohol aqueous solution using a homoge-
variety of routes. The copolymer is made up of Biotin, which
can be attached to a hydroxy- W:amine PEG, and this Bio- be added to the organic solution to favor partitioning of the
tin-PEG-OH can be attached to a variety of groups, in this hydrophilic drug into the organic phase. For example, a fatty
case with the Sebacic acid (SA) prepolymer to form the Bio- acid salt (sodium palmitate) an anionic agent which forms a
tin-PEG-PSA block copolymer, which can be used to form complex with a cationic drug, to force the drug (ibutilide)
nanoparticles with modified surface. The authors prepare into the organic phase. Other agents which favor partitioning
nanoparticles from modified polymer (Biotin-PEG-PSA) by into the organic phase include agents that affect the pH of
the single emulsion-solvent method. The polymer (Biotin- the aqueous phase.
PEG-PSA) was dissolved in dichloromethane; this organic
PLGA nanoparticles containing ciprostene, a hydropho-
phase was emulsified with PVA aqueous solution (5% w/v),
bic prostaglandin antagonist were made in accordance with
sonicated for 3 minutes and maintained under stirring condi-
the single emulsion solvent evaporation method for hydro-
tions for 3 h in order for the dichloromethane to be evapo- phobic agents, but using a co-solvent system comprising a
rated. Nanoparticles were collected by centrifugation and
polar and semipolar organic solvent. PLGA was dissolved in
washed in distilled water [61].
a mixture methylene chloride-acetone and ciprostene was
US 2010/0015051 A1 discloses the use of transferring- dissolved in dimethyl acetamide. These two organic phases
conjugated PLGA nanoparticles containing paclitaxel (as a was joined and emulsified in aqueous stabilizer solution. The
model antineoplastic agent in breast and prostate cancer) for emulsion was adjusted to pH 4.5 in order to favor partition-
increased intracellular retention and efficacy of the therapeu- ing of the drug into the organic phase to improve entrapment
tic agent. The inventors prepared PLGA nanoparticles loaded efficiency. The ciprostene-loaded nanoparticles had a small
with paclitaxel, using chloroform and PVA (5%). They used mean particle size (97.4 ± 38 nm) and 21.6% w/w drug load-
ultrasonication in order to form the emulsion and removed ing.
the solvent by stirring. To determine intracellular retention
A fatty acid solution is formed by dissolving palmitic
of the drug, nanoparticles containing tritium- or fluorescent- acid sodium salt in a co-solvent system (dimethyl acetamide
labeled paclitaxel were prepared using the same procedure as
- methylene chloride). The fatty acid solution was warmed (<
above. The incorporated dye acts as a probe for nanoparti-
40˚C) until a clear solution was formed, PLGA and ibutilide
cles, and offers a sensitive method to determine intracellular
are added to fatty acid solution and was stirred. While still
nanoparticle uptake. Transferrin was conjugated to PLGA
warm, the fatty acid solution was added to PVA (2% w/v) in
nanoparticles loaded with paclitaxel or with dye by two
borate buffer (pH 9.0) saturated with methylene chloride.
steps: first nanoparticles were active by epoxy compound The mixture was sonicated to form oil in water emulsion.
(tetrafluoroborate hydrate (catalyst) was added to the
The emulsion was stirred for 18 hours. Nanoparticles are
nanoparticle suspension followed by a solution of multifunc-
recovered by ultracentrifugation. The fatty acid forms a
tional epoxy compound DENACOL®) and second activated
complex with the cationic drug, ibutilide, due to ionic inter-
nanoparticles were conjugated to transferring. The nanopar-
action. The complex is hydrophobic and therefore, partitions
ticles obtaining have a mean diameter of 216-220 nm with
into the organic phase. The ratio of semipolar to nonpolar
low polydispersity index. Conjugation with transferring solvents in the co-solvent system depends upon the solubility
slightly increased the diameter of particles and their zeta
of the drug and the polymer. The nanoparticles obtaining
potential was slightly more negative than unconjugated
were surface modify by several methods: a) Adsorption of
nanoparticles. It was found that the transferring-conjugate
surface modifying agent; in this case the surface modifying
nanoparticles provided greater antitumor activity of the
agent (didodecyldimethyl ammonium bromide; DMAB) is
therapeutic agent [62]
dissolved in a solvent to form a solution and the pre-formed
EP 0805678 B1 relates to surface-modified biodegrad- nanoparticles are suspended in the solution. b) Incorporation
able nanoparticles for targeted delivery of drugs. Surface of the surface modifying agent into the polymer matrix; the
modifying agents include, various synthetic polymers, bio- surface modifying agent was added into the polymer solution
polymers, low molecular weight oligomers, natural products, during formulation. The surface modifiers are palmitic acid
and surfactants. The inventors used the typical single emul- (PA), beeswax (Wax), isobutyl cyanocrylate (IBCNA) and
sion-solvent evaporation method to incorporate hydrophobic dioleoylphosphatidylethanolamine (DOPE). c) Covalent at-
drugs into PLGA nanoparticles with some modification; a) tachment of surface modifying agent by Epoxy. Surface
PLGA-lipid nanoparticles loaded with model drug U86, us- modification of nanoparticles with DMAB improves reten-
ing L--dioleoylphosphatidylethanolamine as lipid, which tion to tissue. Nanoparticles modified with DMAB were re-
functions both as a partitioning agent and a surface modify- tained in higher amounts than unmodified nanoparticles. The
ing agent. b) PLGA nanoparticles loaded with dexametha- increased binding demonstrates the tissue specific increase in
sone, using mixture alcohol-acetone in order to dissolve the affinity for the surface modified nanoparticles [63].
drug. For hydrophilic drugs, the inventor developed a tech-
The European Patent EP 0520888 Al discloses nanoparti-
nique using a co-solvent system. The polymer is dissolved in
cles made of a poly(lactic acid) and a poly(alkylene oxide)
a non-polar organic solvent (such as methylene chloride,
block copolymer. A high-molecular-weight poly(lactic acid)
chloroform, ethyl acetate, tetrahydrofuran). The hydrophilic
is used and a surfactant is employed in preparing a colloidal
drug is dissolved in a semipolar organic solvent (such as
suspension of the nanoparticles. In this patent, nanoparticles
dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO), are prepared by dissolving the block copolymer and a drug in
dimethyl formamide (DMF), dioxane and acetone). When
an organic solvent, emulsifying the organic solution in water
combined, the result is an organic phase incorporating both
by high pressure homogenization, and evaporating the or-
polymer and drug. The organic phase is emulsified in an
ganic solvent to precipitate the nanoparticles containing the
aqueous solution of an emulsifying agent. Also, an agent can
Table 3. Patents that used single emulsion-solvent evaporation method to prepare surface modified nanoparticles for different
pharmaceutical applications.
Application Scope of the invention Reference(s)
High cellular uptake Magnetic nanoparticles for gene delivery [56]
Long blood circulation time Rhodamine B stealthy biodegradable nanospheres from PLA-PEG-PLA copolymer. Rhodamine [57]
B loaded into nanoparticles displayed a controlled release.
Sustained drug delivery effective for Paclitaxel encapsulated within polyether-anhydride polymers [58]
treatment peritoneal disorders.
Drug tumor-targeting and sustained Paclitaxel as a model drug by a modified emulsion solvent evaporation method referred to as [59]
cytotoxicity interfacial activity assisted surface functionalization (IAASF). Nanoparticles from polylactide-
polyethylene glycol conjugated to folic acid (PLA-PEG-folic acid) and/or PLA-PEG-biotin
Improved cellular uptake of thyroid Thyroid hormone or analogs thereof conjugated to polymers such as polyvinyl alcohol, PEG, [60]
hormone or analogs to promote or polyesters, polyanhydrides, polysaccharides, and polyamino acids
inhibit angiogenesis
Sustained release administration Nanoaparticles from modified polymer (Biotin-PEG-PSA) [61]
Greater antitumor activity Transferring-conjugated PLGA nanoparticles containing paclitaxel [62]
Local intravascular administration of PLGA nanoparticles with some modification: [63]

smooth muscle inhibitors and anti- PLGA-lipid nanoparticles loaded with model drug U86
thrombogenic agents
PLGA nanoparticles loaded with dexamethasone, using mixture alcohol-acetone
Developed a technique using co-solvent system
Long blood circulation time Nanoparticles are composed of an ethylene and/or propylene polyoxide polylactic copolymer. [64]
Long blood circulation time Nanoparticles contain poly(alkylene glycol) and a biodegradable polymer, poly(lactic acid) [65]
Inhibition of angiogenesis Tetraiodothyroacetic acid (TETRAC) nanoparticles, PLGA nanoparticles coated with Tween 80 [66]
Treatment of heart tissue PGG-PLGA nanoparticles comprise an elastin stabilization agent as glutaraldehyde [67]
Foil impregnated with PNPs to be Dexamethasone nanoparticles made of poly(D,L-lactic acid co-trimethylenecarbonate) [68]
later incorporated in prosthesis (vas-
cular stent)
Local drug delivery Poly(stearic acid carbonate-co--caprolactone) nanoparticles loaded with paclitaxel [69]
Drug targeting toward HepG2 cells Paclitaxel loaded nanoparticles composed of poly(-glutamic acid)-poly(lactide) block copoly- [70]
mers conjugate with galactosamine for delivering to a target liver tumor.
Hepatic drug targeting Placlitaxel loaded nanoparticles of hepatic targeting based on glycyrrhetinic acid- [71]
ethylenediamine-PLGA
Anticancer drug delivery and Long PLA Nanoparticles containing natural anticancer drugs and sterically stabilized with polysaccha- [72]
blood circulation time rides of kelp (PK) as polymer to improve the anticancer therapeutic efficacy. Also, PK has the
function of increasing immunity.
Brain drug targeting Polymeric nanoparticles containing doxorubicin coated with Tween 80 (polysorbate) for the [73]
transportation of drug directly to the brain by crossing the blood brain barrier
drug. The resulting nanoparticles are fine particles with a the biodegradable moieties of the copolymer are localized
mean size of 145 nm that possess both hydrophilic and hy- within the core of the nanoparticle or microparticle and the
drophobic components and that are unable to form clear, poly(alkylene glycol) moieties are localized on the surface of
stable aqueous liquids and this PNPs have an extended the nanoparticle or microparticle in an amount sufficiently
plasma circulation time before capture by the reticulo- effective to decrease uptake of the nanoparticle or micropar-
endothelial system [64]. ticle by the reticulo-endothelial system. Thus, nanoparticles
or microparticles are designed to circulate for prolonged pe-
U.S. Patent No. 5543158 discloses nanoparticles or mi-
croparticles formed from a block copolymer consisting es- riods within the blood fluids. In this patent, the molecular
weight of the block copolymer is too high to be water-
sentially of poly(alkylene glycol) and a biodegradable poly-
soluble, and a nanoparticle can only be prepared by first dis-
mer, poly(lactic acid). In the nanoparticle or microparticle,
solving the block copolymer and a drug in an organic sol- DNA = Deoxyribonucleic acid
vent, forming an o/w emulsion by sonication or stirring and
DOPC = Dioleoylphosphotidylchloline
subsequently collecting the precipitated nanoparticles con-
taining the drug (lidocaine as model drug) when evaporated DOPE = Dioleoylphosphatidylethanolamine
solvent, slow evaporation of the organic solvent allows a CDC6 = 2,3-di-O-hexanoyl--Cyclodextin
reorganization of the polymer chains inside and on the sur-
face of the droplets. The poly(alkylene glycol), which is not DOX = Doxorubicin
soluble in organic solvent, tends to migrate to the aqueous EC = Ethylcellulose
phase, while, the other unit of the copolymer, which is not
soluble in water, remains inside the droplets and forms the 5-FU = 5-Fluorouracil
core of the nanospheres after the completion of solvent GFP = Green fluorescent protein
evaporation. The particles have a biodegradable solid core
containing a biologically active material and poly(alkylene HFIP = Hexafluoroisopropanol
glycol) moieties on the surface. The terminal hydroxyl group IAASF = Interfacial activity assisted surface
of the poly(alkylene glycol) can be used to covalently attach functionalization
onto the surface of the injectable particles biologically active
IBCNA = Isobutyl cyanoacrylate
molecules, including antibodies targeted to specific cells or
organs, or molecules affecting the charge, lipophilicity or LEV = Levofloxacin
hydrophilicity of the particle [65]. Table 3 contains some
MC = Mitomycin C
patents that used single emulsion-solvent evaporation
method to prepare surface modified nanoparticles. MMT = Montmorillonite
MNP = Magnetic nanoparticles
CURRENT & FUTURE DEVELOPMENTS
MRI = Magnetic Resonance Imaging
The simplicity of the SESEM and the fact that it relies on
the use of pharmaceutically acceptable solvents, biocompati- NDGA = Nordihydroguaiaretic acid
ble polymers and common surfactants, rationalizes its con- PA = Palmitic acid
tinued use. The versatility of the SESEM has also been dem-
PAH = Polyanhydride
onstrated by allowing the use of modified polymers to enable
the production of surface modified PNPs with various func- PCL = Poly(-caprolactone)
tionalities. Future research on SESEM should be focused on PEA = Polyester amide
a better understanding of the factors that control particle size
and surface modification which are important to the applica- PEG = Poly(ethylene glycol)
tions of these particles. Reports on the scale up and produc- PEI = Poly(ethylenimine)
tion of large batches of PNPs in a reproducible way using
SESEM is expected to increase. PEO = Polyethylene oxide
PEU = Polyester urea
CONFLICT OF INTEREST
PEUR = Polyester urethane
The authors confirm that this article content has no conflicts of
PGA = Poly(glycolic acid)
interest.
PHB = Poly(-hydroxybutyrate)
ACKNOWLEDGEMENT PLA = Poly(lactic acid)
None declared. PLGA = Poly(lactic-co-glycolic acid)
ABBREVIATIONS PNPs = Polymer nanoparticles

Poly[CPP:SA] = Poly(1,3-bis-(carboxyphenoxy-
AAT = Alpha 1-antitrypsin
propane) (poly(CPP):sebacic acid
BSA = Bovine serum albumin
PSA = Poly(sebacic acid)
CAP = Cellulose acetate phthalate
PTFE = Polytetrafluoroethylene
CNS = Central Nervous System
PVA = Poly(vinyl alcohol)
CsA = Cyclosporine
rhG-CSF = Recombinant human-Granulocyte
DCM = Dichloromethane colony-stimulating factor
DMAB = Didodecyldimethyl ammonium bro- SA = Sebacic acid
mide
SESEM = Single emulsion-evaporation method
DMAC = Dimethyl acetamide
SPAN 80 = Sorbitan momooleate
DMF = Dimethyl formamide
SPC = Soybean phosphatidylcholine
DMSO = Dimethyl sulfoxide
SPG = Shirasu porous glass
TETRAC = Tetraiodothyroacetic acid methods. Colloids and Surfaces A: Physicochem. Eng. Aspects
2010; 370: 79-86.
TFE = Tetrafluoroethylene [22] Lemos-Senna E, Wouessidjewe D, Lesieur S, Duchêne D. Prepara-
tion of amphiphilic cyclodextrin nanospheres using the emulsifica-
TPGS = d-alpha Tocopheryl polyethylene gly- tion solvent evaporation method. Influence of the surfactant on
col 1000- succinate preparation and hydrophobic drug loading. Int J Pharm 1998; 170:
119-28.
Wax = Beeswax [23] Jaiswal J, Gupta SK, Kreuter J. Preparation of biodegradable cy-
closporine nanoparticles by high-pressure emulsification-solvent
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Single Emulsion-Solvent Evaporation Technique and Modifications For The Preparation of Pharmaceutical Polymeric Nanoparticles

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Recent Patents on Drug Delivery & Formulation 2012, 6, 209-223 209

Single Emulsion-Solvent Evaporation Technique and Modifications for the

María G. Nava-Arzaluza*, Elizabeth Piñón-Segundob, Adriana Ganem-Ronderoa and David

2212-4039/12 $100.00+.00 © 2012 Bentham Science Publishers

Application Scope of the invention Reference(s)

Treatment of cancer by increasing Combination of resveratrol and TETRAC nanoparticles [14]

Fig. (3). Schematic representation of the preparation of nanoparticles by membrane emulsification.

Modification Applied Scope of the invention Reference(s)

High-pressure homogenization The doxorubicin- loaded nanoparticles [26]

High-pressure homogenization Methotrexate nanoparticles prepared from a water-in-oil emulsion [27]

High-pressure homogenization Docetaxel nanoparticles stabilized by human serum albumin. [39]

Oil-in-oil emulsion Everolimus nanoparticles from Cellulose Acetate Phthalate [41]

Oil-in oil-emulsion PEA-Insulin.sub.z conjugate nanoparticles [42]

Application Scope of the invention Reference(s)

High cellular uptake Magnetic nanoparticles for gene delivery [56]

Sustained release administration Nanoaparticles from modified polymer (Biotin-PEG-PSA) [61]

Greater antitumor activity Transferring-conjugated PLGA nanoparticles containing paclitaxel [62]

Local intravascular administration of PLGA nanoparticles with some modification: [63]

ABBREVIATIONS PNPs = Polymer nanoparticles

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