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Parenteral Drug Delivery: A Review

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 Recent Patents on Drug Delivery & Formulation 2011, 5, 133-145 133

Parenteral Drug Delivery: A Review

Neha Gulati1 and Himanshu Gupta2*

1
Babu Banarasi Das National Institute of Technology and Management, Lucknow, U.P, India, 2Department of
Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India

Received: January 9, 2011; Accepted: February 21, 2011; Revised: March 8, 2011
Abstract: The parenteral route of administration is the most effective route for the delivery of the active pharmaceutical
substances with narrow therapeutic index, poor bioavailability especially for those drugs, prescribed to unconscious
patients. To maintain a therapeutic effective concentration of the drug, it requires frequent injections which ultimately
lead to patient discomfort. In parenteral drug delivery, major progress has been done in the field of formulation
technologies so as to provide a targeted and sustained release of drug in predictable manner. The present article reviews
recent patents and major advancements in parenteral drug delivery systems along with general introduction. This article
also deals with importance of novel systems in drug delivery to overcome the problems associated with conventional
parenteral drug delivery systems.
Keywords: in situ Depot forming systems, liposomes, nanodispersions, niosomes, parenteral drug delivery, polymeric
nanoparticles, solid lipid nanoparticles.

INTRODUCTION
The word parenteral was derived from the two words
‘‘para’’ and ‘‘enteron’’ means to avoid the intestine [1].
According to the USP 24/NF19 parenteral articles are
defined ‘‘as those preparations intended for injection through
the skin or other external boundary tissue, rather than
through the alimentary canal, so that the active substances
can be administered directly into a blood vessel, organ,
tissue, or lesion. In today’s health care scenario, the key
component of therapy for hospitalized patients is parenteral
products [2]. Parenteral route of administration i.e.
subcutaneous, intramuscular, intravenous, intradermal and
intraarterial etc. also possess good absorption characteristics
and provide good bioavailability of drugs [3]. The route has
plethora of advantages for patients who cannot take drug
orally and require rapid onset of action i.e. in case of
unconscious patients [4]. Hospitalized and bed ridden
patients are totally dependent on parenteral nutrition like
fluids, electrolytes, or nutrients through parenteral route [1].
Now a day’s novel parenteral drug delivery systems like
biodegradable implants, transdermal patches, colloidal drug
carriers like liposomes, nanoparticles, intramuscular depot
injections, are playing a major role. Novel preparations
provide sustained, targeted and controlled drug delivery to
the patients with less dosing frequency [2, 4, 5]. Despite so
many benefits parenteral formulations are more expensive
and costly than conventional formulations. It requires
specialized equipments, devices and techniques to prepare
and administer parenteral formulations [6].
Despite all these problems, parenteral formulations hold
a top place for the treatment of hospitalized patients. Since
parenteral products are meant to be introduced directly into
*
Address correspondence to this author at the Department of Pharmaceutics,
Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India;
Tel: 91-11-23824848; Fax: 919868918282; E-mail: dr.hgupta@yahoo.com
the blood for which they should be properly sterile and free
from pyrogens [1].
CONVENTIONAL PARENTERAL FORMULATIONS
Conventional parenteral formulations that have been used
for a long time mainly include solutions, suspensions and
emulsions [7, 8].
Solutions
The simplest and most convenient form of presentation
of an injectable product is an isotonic aqueous solution,
which has pH close to that of blood and body tissues (pH
7.4). Parenteral solutions include large volume parenterals
(LVP), small volume parenterals (SVP) and irrigation solu-
tions. Infusion fluids are aqueous solutions given in larger
volumes than those normally administered by intravenous
injection [6-8]. Infusions generally include preparations used
for basic nutrition, restoration of electrolyte balance, fluid
replacement etc. The formulation aspect of solutions
includes vehicles and added substances. There are three
types of vehicles used for the preparation of injectable solu-
tions. One is aqueous vehicles which are officially recog-
nized to which drug is added at the time of administration
i.e. sodium chloride injection, ringer’s injection, dextrose
injection, lactated ringer’s injection etc. Second one is water
miscible vehicles that are used to partially dissolve the drug
in combination with water i.e. cardiac glycosides solutions
are prepared in ethyl alcohol and glycols are used for
dissolving barbiturates but these preparations are given
intramuscularly. Third and last category involves non-
aqueous vehicles which are fixed oils. According to USP
specifications fixed oils should be of vegetable origin so that
they can be metabolized easily in the body i.e. cottonseed
oil, corn oil. Added substances in parenteral solutions may
involve antimicrobial agents, buffers, chelating agents etc [2,
6]. There are many USP approved marketed formulations

1872-2113/11 $100.00+.00 © 2011 Bentham Science Publishers Ltd.

134 Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2
used widely for electrolyte replacement as mentioned in
Table 1.
Table 1. List of Marketed Formulations of Parenteral
Solutions
Parenteral Solutions Marketed Formulation
LVPs 0.9% sodium chloride injection, USP
5% sodium chloride injection
5% dextrose injection, USP
10% dextrose injection, USP
Lactated ringers and 5% Ringers injection
Irrigation solutions 0.9% sodium chloride irrigation
Tis- u- sol® solution pentalyte irrigation
1.5% glycine irrigation, USP
Many drugs which have narrow therapeutic index and
stable aqueous pharmaceutical compositions are formulated
as parenteral solutions i.e. bis-indole alkaloid, preferably
vincristine, vinblastine or 5'-Nor-dihydrovinblastine [9].
Suspensions
Parenteral suspensions are useful dosage form for
administering insoluble or poorly soluble drugs [5]. Drug is
dispersed in the aqueous/oily solution for aqueous/oily
suspensions respectively. The main property, a suspension
should possess for parenteral delivery is that it should not
produce tissue irritation on injection. The larger surface area
of disperse drug ensures higher solubility which helps in
providing a high degree of availability for absorption of
drug. Parenteral suspension provides more prolonged release
as compared to solution from the injection site. This system
is used through subcutaneous and intramuscular route.
Suspensions are better than solutions as they provide
increase resistance to hydrolysis and oxidation as drug is
present in solid form [7, 8]. Despite of all these benefits
many problems are associated with suspensions like
difficulty in formulation, stabilization of suspensions for the
period between manufacture and use and chances of non-
uniformity of dose at the time of administration [10,11] etc.
Some of the official parenteral suspensions includes sterile
ampicillin suspension USP’2009, sterile aurothiglucose
suspension USP’2009 - vegetable oil suspension, tetanus
toxoid adsorbed USP’2009, IP’96, betamethasone acetate
suspension USP’2009 aq. suspension, Insulin inc suspension
USP’2009, IP’96 aq. suspension and procaine penicillin
suspension IP’96 etc. The formulation aspect of suspension
involves drug and added agents like wetting agent (parti-
cularly surfactant of 7-9 HLB values), buffers, viscosity
increasing agents (natural gums like tragacanth, acacia),
preservatives [6] etc. US has approved many suspensions to
be given parenterally Table 2.
Suspensions provide the drug release in sustained
manner. Chang et al. prepared the aqueous suspension of
butorphanol by free base and oil suspension of tartarate salt.
The in vivo studies were carried out in dogs and results
Gulati and Gupta
Table 2. Marketed Preparation of Suspensions (US)
Drug Brand Name Manufacturer
Aurothioglucose Solganl® Schering
Betamethasone sodium phosphate Celestor® Schering
and Betamethasone acetate
Penicillin G Procaine Bicillin ® CR Wyeth
®
Medroxyprogesterone acetate DepoMedrol Upjohn
indicate a sustained release drug profile with the plasma drug
concentration maintained within the desirable therapeutic
range over a period of 24 hours [12]. Some workers prepared
a pharmaceutical aqueous suspension formulation for paren-
teral administration having substantially stabilized pH,
comprising a steroidal compound with an effective concen-
tration of L-Methionine (pH controlling agent) [13].
Emulsions
An emulsion is a two phase system prepared by
combining two immiscible liquids, one of which is dispersed
uniformly throughout the other and consists of globules that
have diameters equal to or greater than those of large
colloidal particles [14, 15]. Emulsions are generally used in
administration of total parenteral nutrition (TPN). TPN is the
practice of feeding patients who are unable to get their
nutrition through eating, mainly for the coma patients and
etc. It is normally used during surgical recoveries [15].
Emulsions generally fall into two categories i.e. a hetero-
genous system comprised of a drop of organic liquid
immersed/surrounded in an aqueous solution that is known
as oil in water emulsion (o/w type) and a heterogenous
system comprised of a drop of water immersed/surrounded
in organic solutions that is known as water in oil emulsion
(w/o type) [16]. The formulation view of emulsion includes
pharmaceutical oils (as mentioned in non aqueous vehicles in
solutions), pharmaceutical emulsifiers (surface active agents,
natural polymers, finely divide solids), preservatives and
antioxidants.
Steps in emulsion formulation depends upon the type of
formulation, whether an o/w emulsion or w/o emulsion,
internal phase is selected in which drug is mixed. In the
external phase, pharmaceutical emulsifier is added so as to
stabilize the droplets that form during emulsification.
Mixture of drug and internal phase is poured in mixture of
emulsifier and external phase with a high pressure
homogenization, so as to break the internal phase droplets.
Emulsifier covers the whole surface so as to stabilize the
droplet of internal phase [15]. The procedure is simplified in
the Fig. (1). The major problem associated with emulsions is
that these are thermodynamically unstable because of
increase in surface free energy of the system, that depends on
the total surface area and interfacial tension which increases
by increasing surface area of system during emulsification
[17].
Parenteral emulsions are administered through subcu-
taneous and intramuscular routes. Commercially available
Parenteral Drug Delivery
Drug + Internal Phase
High pressure emulsification
External Phase + Emulsifier
Emulsion
Filtration
Fig. (1). Flow chart explaining steps involved in emulsion
formation.
oily emulsions are intralipid® 10%, lipofundin®, lipofundin®,
and liposyn®. The major focus on recent literature has been
in area of parenteral drug delivery like subcutaneous,
intramuscular, intraperitoneal delivery etc. Park et al.
evaluated the potential of flurbiprofen microemulsions in
parenteral delivery. The pharmacokinetic studies yield a 1.5
to 2 fold increase in half life, area under curve and mean
residence time of flurbiprofen from microemulsions [18].
Drugs in emulsion form provide sustained release i.e. bupre-
norphine emulsions. An oil-in-water buprenorphine formu-
lation including buprenorphine and a surfactant that
emulsifies the buprenorphine in oil, wherein oil concen-
tration control the drug release. A buprenorphine oil
formulation including a buprenorphine salt suspended in
pharmaceutically acceptable oil [19].
NOVEL PARENTERAL FORMULATIONS
Parenteral drug therapy has been used in emergency
situations but certainly there are lots of problems associated
with these conventional parenteral formulations like drug
solubility, product stability (particularly with biopharma-
ceuticals), drug delivery (sustained/controlled-release
formulations after intramuscular or subcutaneous injection)
and manufacturability [20]. In present scenario, a number of
technological advances have been made in the field of
parenteral drug delivery leading to development of systems
that allow drug targeting along with sustained or controlled
release of pharmaceutically active ingredient [21]. Novel
parenteral formulation includes colloidal drug delivery via
parenteral route like nanoparticles, niosomes, liposomes,
polymeric micelles, in situ forming parenteral drug delivery
system [22, 23]. Donelly et al. reviewed the potential of
novel parenteral formulations as mucoadhesive drug delivery
systems like hydrogels, nanoparticulates for various
parenteral routes of drug administration [24].
Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 135
Micro and Nanoparticulates
Recently, the nano and microparticle approach has
become popular [22]. A decrease in particle size results in
increased surface area, resulting in faster dissolution and
absorption. This also increases the bioavailability of many
drugs. According to Ostwald and Freundlich, the solubility
of drug depends upon its particle size. They postulate that as
the particle size decreases the solubility of drug increases
[25].
Lipid Micro and Nanoparticles
Conventional lipid systems for parenteral drug delivery
comprise of oil solutions, suspensions as well as emulsions
for subcutaneous or intramuscular injection. Liver and spleen
cleared the particles from the circulation by uptaking them
which minimize the risk of clotting and aggregating, that
lead to embolism [26]. The incorporation of a lipophillic
drug in these systems is quite easy and the release of the
drug from these systems is mainly controlled by the partition
of the dissolved drug from the oily vehicle to the aqueous
environment at the injection site. Whereas, the incorporation
of hydrophilic drug is quite cumbersome in these lipid
systems [23]. Advanced lipid micro- and nanoparticulate
systems have been developed for parenteral sustained release
of water soluble and insoluble drugs. In addition to
subcutaneous and intramuscular injection, lipid particulate
systems in nano size can be given intravenously [27]. SLN
(solid lipid nanoparticles), NLC (nanostructured lipid
carrier), LDC (lipid drug conjugate) and polymeric nano-
particles are particles in nanometer range with a solid lipid
matrix and natural/synthetic polymers respectively. The
particle dispersions contain surfactants as stabilizers in
addition to lipid, polymer and drug. SLN are the nano-
particles made up of solid lipids (i.e. lipids solid at room
temperature and also at body temperature) which is
stabilized by surfactants [28]. The main features of SLN
which makes them suitable for parenteral delivery of drug
are excellent physical stability, protection of incorporated
labile drugs from degradation, controlled drug release and
site specific targeting. Inspite of benefits, there are two
foremost problems associated with SLNs like insufficient
loading capacity, drug expulsion especially after poly-
morphic transition during storage [27, 28]. Many drugs have
been entrapped in solid lipid matrix such as AZT-P and
derivatives [29- 31], Camptothecin [32, 33], Clobetasol
propionate [34], Cortisone [35], Diazepam [36], Doxorubicin
[37-40].
NLC is nanoparticulate lipid carrier with a certain
nanostructure so as to increase the loading efficiency and
prevent drug expulsion from the particles. It mainly uses
liquid lipids in conjunction with solid lipid which then
reduces the chances of polymorphic transformation [41, 42].
The basic difference between the structures of SLN and NLC
are shown in Fig. 2. NLC have only been exploited for the
topical delivery, however their advantages over conventional
SLN are also of interest for parenteral application routes
[43].
LDC comprises of an insoluble drug-lipid conjugate,
hydrophilic drugs which are not so potent are used. LDC is
prepared either by salt formation (e.g. with a fatty acid) or by
136 Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2
(A)
(B)
Fig. (2). (A) Structure of Solid lipid nanoparticles (SLN) (B) Structure of nanostructured lipid carrier (NLC).
covalent linking (e.g. to esters or ethers) [44]. In the
literature, surface-modified diminazenestearate and oleate
LDC were used to carry out cytotoxicity studies, its plasma
protein absorption (2-DE) and antitrypanosomiasis activity
via brain targeting have been performed [45-47].
There are many methods reported for the preparation of
solid lipid nanoparticles like solvent emulsification tech-
nique [48], solvent injection method [49, 50], solvent
emulsification diffusion technique [51], high pressure homo-
genization (hot and cold) [52], micro emulsion technique
[53], homogenization followed by sonication [53, 54].
Cavalli et al. formulated tripalmitin SLN loaded with
paclitaxel as an alternative tool for parenteral administration
and reported sustained release of drug [55]. Yang et al.
compared the pharmacokinetics and body distribution of
camptothecin after i.v. injection of drug solution and SLN in
mice. They reported that the SLN give much higher
Gulati and Gupta
AUC/dose and mean residence times (MRT) especially in
brain, heart and reticuloendothelial cells containing organs as
compared to drug solution [56].
Nanoemulsions
Nanoemulsions are transparent or translucent oil-in-water
(o/w) or water-in-oil systems with a mean droplet diameter
in the range between 100 and 500nm. They are synony-
mously known as mini-emulsions or sub micron emulsions
[57]. These are thermodynamically stable system in which
two immiscible phases are stabilized with the help of
emulsifiers to form a single phase.
The system is regarded as ‘single phase’ because studies
carried out on nanoemulsion formation by phase inversion
temperature method have shown a relationship between
minimum droplet size and complete solubilization of oil in
emulsion. As the size of droplet of dispersed phase decreases
Parenteral Drug Delivery
to nano level, the system tends to become clear and
solubilized, which is considered as single phase as compared
to microemulsions. The system is devoid of problems like
creaming, flocculation, coalescence and sedimentation which
are the main problems associated with macroemulsions [58].
Methods to produce nanoemulsions may be classified on the
basis of energy involved. High energy method includes high
pressure homogenization, microfluidization, ultrasonification
while the low energy methods include spontaneous emul-
sification, solvent diffusion method, and phase inversion
temperature (PIT) [59]. The components of nanoemulsion
systems includes oils like castor oil, coconut oil, soybean oil,
wheatgerm oil, linseed oil, olive oil, peanut oil, PEG-
vegetable oil; emulsifiers like natural lecithins from plant
and animal sources, poloxamers, polysorbates, steraylamine,
oleylamine and additives like antioxidants (tocopherol),
tonicity modifiers (glycerol, sorbitol), preservatives, pH
adjustment agents [60]. Many commercial nanoemulsion
formulations are enlisted in Table 3.
Table 3. Commercial Nanoemulsion Formulations.
DRUG BRAND INDICATION
Propofol Diprivan® Anesthetic
Dexamethasone Limethason ®
Steroid
Flurbiprofen axetil Ropion® Nonsteroidal analgesic
® nanosuspensions [64]. Muthu et al. formulated resperidone
Vitamin A, D, E & K Vitalipid Parenteral nutrition
Amani et al. formulated the budesonide based nano-
emulsion for the respiratory delivery when nebulized using a
jet and a vibrating mesh nebulizer. The in vitro studies of the
nanoemulsions were compared with the commercially
available suspension of budesonide (Pulmicort Respules®). A
smaller mass median aerodynamic performance (MMAD)
with increased aerosol output was observed in the nano-
emulsion formulations in comparison with the corresponding
suspension formulations which indicate an improved in vitro
performance for the nanoemulsion-based formulations [61].
Shakeel et al. formulated the celecoxib nanoemulsions for its
enhanced bioavailability. The results of skin permeation and
pharmacokinetic studies shown that the nanoemulsions can
enhance the bioavailability of poorly soluble drugs with
improved skin permeability [62].
Nanosuspensions
Nanosuspensions are submicron colloidal dispersion of
solid active pharmaceutical ingredient (API) particles in
aqueous phase which is stabilized by surfactants [63].
Nanosuspensions can be administered by oral, topical,
parenteral and pulmonary administration. The particle size
distribution of the drug in nanosuspensions is usually less
than one micron with an average particle size ranging
between 200 and 600nm [64]. Nanosuspensions have many
positive points that make them amenable to numerous
applications. This system increases the saturation solubility
as well as dissolution velocity of the drug which leads to
enhanced bioavailability of the poorly soluble/hydrophobic
drug [65]. Unlike suspensions, nanosuspensions are less
Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 137
prone to ostwald ripening therefore stable for long time.
Ostwald ripening is the term used for the growth of large
particles at the expense of smaller ones because of difference
in solubility rates of different size particles. Regarding the
formulation aspect of nanosuspensions, many methods had
been reported, which are more cost effective and technically
more simple particularly for hydrophobic drugs [64, 66].
Nanosuspension formulation techniques currently used are
precipitation, high pressure homogenization (disso cubes),
emulsion and media milling techniques. DissocubesTM are
crystalline nanoparticles of active substance obtained by a
liquid state high energy process using a high pressure piston
gap homogenizer, to reduce the drug particle size in presence
of surface modifiers that associate at freshly generated drug
interface. Out of these, media milling and high pressure
homogenization are patented technologies. High speed
homogenization i.e. Dissocubes technology was developed
by Muller. The patent rights (patent application number
US5858410) of disso cubes were initially owned by DDS
(Drug Delivery Services) GmbH, Germany but currently
they are owned by Skye Pharma PLC, England and Wales.
While media milling (patent application number US51-
45684) i.e. nanocrystals is also patent protected technology
which was developed by Liversidge in 1992. Formerly the
technique was owned by company Nanosystems, Dublin
Ireland but recently it has been acquired by Elan Drug
Delivery, Dublin Ireland. Stabilizers, co-surfactants are the
main additives that determine the stability of the
nanosuspension using Pluronic® F-68 or Pluronic® F-127 as
polymeric stabilizer. Nanosuspension contains resperidone
loaded poly (D, L-Lactide) nanospheres, formulated by
nanoprecipitation technique. The in vitro release studies
indicated that this formulation approach can be used to
improve the therapeutic efficacy of drug. The controlled drug
release from the suspensions indicates that the frequency of
administration could be reduced, if administered via
parenteral (i.v) route [67]. Salem et al. formulated a
sustained release form of natural progesterone using stearic
acid as surface stabilizer. Firstly, progesterone loaded
nanoparticles were prepared by solvent precipitation method
which was then formulated into nanosuspension dispersed in
thermosensitive gel matrix. The formulation was meant to be
given as i.m injection. The in vivo studies were carried out in
rats that indicate that the natural progesterone which was
loaded in nanoparticles and then formulated in thermo-
sensitive gel significantly sustained the action of natural
progesterone. This reduces the dosing frequency of natural
progesterone to be injected every 36 hrs instead of every day
[68]. Method for formulating a stable nanosuspension was
patented for delivery of vitamin B-12. A nanofluidizable
mixture containing vitamin B-12 is initially formed and
processed via a nanofluidization process to form the stable
nanosuspension, which may be administered via the trans-
mucosal membranes or other suitable routes of adminis-
tration [69].
Liposomes
Liposomes are discovered in mid 1960s [70]. Liposomes
are vesicles having concentric phospholipid bilayers as
shown in Fig. (3). The water soluble drugs are present in
inner aqueous core while lipid soluble drugs and amphiphilic
138 Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 Gulati and Gupta

drugs insert themselves in phospholipid bilayers [71]. Lipo- Table 4. Liposomes Preparation Methods.
somes are formed as a result of self assembly of phos-
pholipid molecules in an aqueous environment [72, 73]. Liposome Type Method of Preparation Ref.
Liposomes are suitable for the delivery into the veins. They
are preferentially taken up by phagocytic cells of the Multilamellar Hydration method [76]
mononuclear phagocyte system (MPS) mainly in the liver large vesicles Solvent spherule method [77]
and spleen. The liposomes containing drugs can also be
administrated by other parenteral routes like inhalation, French pressure method [76]
topical application [74, 75]. Small unilamellar Sonication method [76]
Liposomes are classified as Multilamellar large vesicles vesicles
(MLV 0.1-6m), Small unilamellar vesicles (SUV 0.02- Reverse phase evaporation method [78]
0.05m), Large unilamellar vesicles (LUV
0.06m), Giant
liposomes (10,000- 1,00,000nm) [76]. Depending upon the Large unilamellar Modified reverse phase evaporation [79]
type of vesicle obtained, various preparation methods of vesicles method [80]
liposomes have been discussed in Table 4 [76-82]. Freeze thaw method [81]
Liposomes being amphoteric in nature offer a unique Microfluidization method [82]
ability to entrap both hydrophilic and hydrophobic drugs. Extrusion through polycarbonate
Research in liposomal drugs has led to commercialization of filters under nitrogen
several anticancer drugs such as Doxil®, Myocet® (two
Giant liposomes Detergent dialysis method [76]
liposome-based anticancer drugs containing doxorubicin);
and an antifungal drug formulation, AmBisome®, which is a
liposomal formulation of amphotericin B used for systemic
targeting which involves attaching ligands on the surface of
therapy [83]. Applications of the liposomes are in the
liposomes that directs it to the specific target only because
treatment of immunity related disorders, dermatology, as a
ligand recognizes specific receptor sites. The ligand recog-
vaccine adjuvant, ophthalmic disorders, targeting to specific
nizes specific receptor sites and, thus, causes the liposomes
organs like brain, infective diseases and in tumor therapy
to concentrate at target sites only. Liposomes also used to
[84]. In case of intravenous administration the drug enters
correct gene-associated disorders or for vaccine therapy [85].
the blood stream and available to every organ which require
A quantitative entrapment of DNA can be achieved with the
drug or not, which may lead to adverse effects. Liposomes
help of the preparation of placebo liposomes with cationic
had been used in drug targeting via use of ligands (e.g.
lipids followed by mixing with DNA of interest. Because of
antibodies, sugar residues, apoproteins or hormones), which
its convenience and excellent efficacy, cationic lipid
are tagged on the lipid vesicles. This is known as active
mediated gene delivery technology is a promising system for

Fig. (3). Basic Structure of liposomes.

Parenteral Drug Delivery
in vivo gene therapy. With drug targeting it is possible to
deliver a drug to a tissue or cell region not normally
accessible to the free or untargeted drug with less wastage
[86].
In Situ Depot Forming Systems
Biodegradable injectable in situ depot forming systems
represent an attractive alternative to implants for the delivery
of drugs [87, 88]. These systems are made up of a bio-
degradable carrier dissolved or dispersed in a solvent/
cosolvent system, whereas the drug is either dispersed or
dissolved in the liquid phase of the system [89, 90].
Following subcutaneous or intramuscular injection, a solid
depot is formed at the site of injection. The controlled
release of bioactive macromolecules via in situ forming
systems has a number of advantages, such as ease of
administration, less complicated formulation techniques, less
stressful manufacturing conditions for sensitive drug
molecules [91]. Other benefits of these systems include
reduced dose and dosing frequency, enhancement of patient
compliance and the most important is ‘infusion-like’ plasma
level time profiles [92]. According to the mechanism of
depot formation, these systems are classified as follows
thermoplastic pastes, in situ crosslinked polymer systems,
in situ polymer precipitation, thermally induced gelation and
in situ solidifying organogels [93, 94]. For various types of
in situ systems, different parameters are shown in Table 5.
In situ cross-linked systems can be produced by causing
polymer precipitation from solution and the method is
known as Atrigel technology (QLT, Vancouver, Canada),
which is used as a vehicle for Eligard. ELIGARD® is a
sterile polymeric matrix formulation of leuprolide acetate. It
is prefilled and supplied in two separate sterile syringes, one
syringe contains the ATRIGEL® delivery system and the
other contains leuprolide acetate. A lipophillic biodegradable
polymer is solubilized in a biocompatible organic solvent
and drug is added to polymeric solution which forms a
solution/suspension upon mixing. On injecting this formu-
lation into the body, the solvent diffuses away and water
penetrates into the organic phase which leads to phase
separation and polymer precipitation lead to formation of a
depot at the injection site [95, 96]. Kranz et al. studied the
in vivo release of bupivacaine hydrochloride from an
injectable in situ forming microparticulate system (ISM).
Table 5. In situ forming Parenteral Drug Delivery Systems [94].
Thermoplastic Paste
Injection Semi solid paste
Depot Formation Solidification
Polymer POE
Drug Burst Low
Drug Loading Dry powder
Injection Pain Low
Release Surface erosion
{POE: poly (ortho esters); A: PLA (poly lactic acid), B: PEG (polyethylene glycol); PLGA: poly- lactic-glycolides)
Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 139
The in vivo drug release studies indicates the prolonged
analgesic effect of bupivacaine HCl, when compared to an
injection of drug solution and concluded ISM as an attractive
alternative for parenteral drug delivery system [97]. Jain and
his co-worker developed the novel injectable compositions.
The aims of this invention was to form a depot upon
administration in vivo and are in the form of an in situ
gelling composition or an implant composition which
provides a prolonged release of tamsulosin or letrozole for
extended periods of time [98].
Niosomes
Niosomes are vesicular systems made up of non-ionic
surfactant obtained by hydration of synthetic nonionic
surfactants, with or without incorporation of cholesterol or
other lipids [99]. Nonionic surfactants, such as sorbitan esters
(span series), polysorbates (tween series) are used for the
preparation of niosomes [100, 101, 102] Table 6.
Niosomes are osmotically active and are stable on their
own [103]. Inspite of this, the drug entrapped have increased
stability within the niosomes. These can be administered by
parenteral as well as topical routes and reach the site of
action. The surfactants used are biodegradable, biocom-
patible and non-immunogenic. The most advantageous
reason for administering the niosomes for drug targeting via
parenteral route is it delay clearance from the circulation,
protecting the drug from biological environment and
restricting effects to target cells. Niosomes are prepared by
the methods used for liposomes formulation i.e. film hy-
dration method, sonication, ether injection method, micro-
fluidization, reverse phase evaporation and bubble method.
Niosomes are extensively used for the parenteral adminis-
tration of a number of drug moieties Table 7 [104-113].
Desai et al reported the delivery of niosomal all-trans-
retinoic acid (ATRA) by aerosolization. ATRA is a
hydrophobic anticancer drug. Various nonionic surfactants
were used and the best formulations were obtained with
combinations of (Span 20 + Tween 80) and (Span 60 +
Tween 80) using an ATRA concentration of 1 mg/ml which
have optimum encapsulation and nebulization efficiencies.
The route proved to be advantageous since it offered an
effective way to deliver high levels of drug to the lung
without apparent side effects [114].
Thermogelling System Polymer Precipitation
Aqueous solution Organic solution
Sol to gel transition Phase separation
ABA & BAB PLGA
Medium High
Aqueous solution Organic solution
Low High
Pore diffusion/bulk erosion Pore diffusion/bulk erosion
140 Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 Gulati and Gupta

Polymeric Particulates reconstituted for parenteral use [118]. Various marketed

Polymeric nanoparticles prepared from biodegradable
polymers are another innovative parenteral carrier system.
Many of the parenteral sustained-release products are
polymeric microsphere formulations that can be injected
subcutaneously or intramuscularly for systemic therapy or
injected into a specific body site for localized treatment
[115]. Polymers used are generally biodegradable and
biocompatible in nature. The manufacturing processes of
micro and nanoparticles are not easy and usually involve the
use of technical equipment. The use of organic solvents can
make the process more complex and costly because of the
requirement of the solvent removal [116]. Mansour et al.
exhaustively reviewed and explained the potential of
biodegradable materials for the pharmaceutical dosage forms
that provide better therapy and disease state management for
patients through controlled release [117]. One of the
patented technologies involves formulation of microparticles
containing biologically active substance. The manufacturing
process involves the preparation of an aqueous solution of
the said substance which is then mixed with an aqueous
solution of PEG so as to form a concentrated and/or soli-
dified mixture. The mixture is mixed with an aqueous
solution of starch and polymer which forms an emulsion of
starch droplets. The starch droplets are solidified into
microparticles, and the microparticles are dried and can be
polymeric sustained release preaparations for parenteral drug
delivery are given in Table 8.
Different Polymers Used
Lactides/ glycolides The PLGA copolymers are highly
hydrophobic in nature. Hence, the copolymers are dissolved
in organic solvents like dichloromethane, chloroform,
acetone, ethylacetate etc. Single emulsion or double emul-
sion technique can be used for the particles formulation
depending upon the nature of drug whether it is hydrophobic
or hydrophilic [117]. A single emulsion method is applied
when the drug is dissolved or dispersed in an organic solvent
solution of the copolymer, this results in matrix systems in
which drug is uniformly distributed in microspheres. If the
drug is dissolved in an aqueous solution, it can be encap-
sulated via a double emulsion method (water/oil/water). The
removal of the organic solvent can be achieved either by
solvent evaporation or solvent extraction [115, 119, 120].
Muthu et al. formulated extended release PLGA nano-
particles of resperidone by nanoprecipitation technique and a
thermoresponsive in situ gel containing resperidone
nanoparticles for parenteral (subcutaneous) delivery. In vivo
studies showed a significantly prolonged antipsychotic effect
for upto 72 hours as compared to resperidone solution with
fewer extrapyramidal side effects [121].

Table 6. List of some Non-Ionic Surfactant used in the Preparation of Niosomes.

Class Composition Examples Ref. No.

Glycerol and glyceryl esters Fatty acid esters of glycol and glycerol Glyceryl monostearate, Glyceryl monopalmitate [100]

Sorbitan esters Esters of sorbitol and its mono and di-anhydrides Sorbitan monopalmitate, Sorbitan monostearate [101]

Polysorbates Polyoxyethylene derivatives of Sorbitan esters Tween 20, Tween 40 [102]

Table 7. Therapeutic Applications of Niosomes with their Method of Preparation.

Drug Method of Preparation Applications Ref. No.

Sumatriptan succinate Film hydration Migraine [104]

Vasoactive intestinal peptide Shaking followed by Sonication Anti-inflammatory, immunomodulatory, neuroprotective [105]

DNA vaccines Reverse phase evaporation Hepatitis B [106]

Minoxidil Dehydration-rehydration Alopecia [107]

Tretinoin Film hydration Psoriasis, acne, epidermotropic T-cell lymphomas or epithelial [108]
skin cancer

5-Fluorouracil Film hydration Skin cancer [109]

Piroxicam Film hydration Anti inflammatory [110]

Camptothecin Sonication Antitumor [111]

Finasteride Film hydration Androgenetic alopecia [112, 113]

Parenteral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 141

Table 8. Approved Parenteral Sustained Release Products.

Delivery system Product Application Trade name Company

Polymeric microparticulate Risperidone Schizophrenia Risperdal Consta® Johnson & Johnson

®
system Triptorelin pamoate Advanced prostate cancer Trelstar LA Debio RP
®
Lipid system Morphine sulfate Postoperation pain DepoDur SkyePharma
management

In situ depot-forming Leuprolide acetate Advanced prostate cancer Eligard® QLT (formally Atrix)
system

Implantable system Leuprolide acetate Advanced prostate cancer Viadur® Alza Corp.

Table 9. List of Various Patents on Parenteral Delivery.

Patent No. Contents Ref. No.

US20100098735 (2010) Injectable depot compositions and its process of preparation [98]

US20100272639 (2010) Polysaccharide nanoparticles useful in drug delivery, tissue specific targeting, for medical imaging and diagnosis [127]

US20090156670 (2009) Non aqueous liquid parenteral aceclofenac formulation [128]

US20100323977 (2010) Mucoadhesive nanoparticles for cancer treatment [129]

US20090181101 (2009) Nanoparticles comprising anti bacterial ligands using antibiotics for aerosol delivery [130]

US20090233951 (2009) Parenteral solutions containing metolazone [131]

US20090275660 (2009) Stable parenteral formulations of tigecycline [132]

US20090304665 (2009) Super fast-acting insulin compositions [133]

US007638558 (2009) Polymeric micelles for drug delivery [134]

US200800885263 (2008) Liquid depot formulations [135]

US20080119408 (2008) PTH formulations for intranasal delivery [136]

US20080213177 (2008) Nanoparticles comprising RNA ligands to impart targeting characteristics for delivery of RNA for targeting cells [137]
and imaging purposes

US20070265190 (2007) Opoid depot formulations [138]

US20070173447 (2007) Method for treating osteoporosis by intranasal delivery of teriparatide with an antiresorptive agent [139]

US7125909 (2006) Sterile parenteral nutrition compositions comprising oil-in-water emulsions [140]

US006685940 (2004) Stable lyophilized protein formulation for subcutaneous delivery [141]

US20030078266 (2003) Reconstituable parenteral composition [142]

US20020081336 (2002) Parenterally administered microparticles [118]

US20020110587 (2002) Liposomal compositions and methods of using liposomal compositions to treat dislipidemias [143]

US6495534 (2002) Stabilized aqueous suspensions for parenteral use [13]

US005556637 (1996) Aqueous liposome system which contains atleast one phospholipid and selectively a non toxic organic solvent [144]

US5397784 (1995) Stable parenteral compositions of vinblastine or vincristine [9]

US4927571 (1990) Preparation of injectable doxorubicin/liposome suspension [145]

US4029782 (1977) Cefazoline suspension for parenteral administration [146]

142 Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2
Polycaprolactones
Poly--caprolactone (PCL) is semicrystalline biode-
gradable polyester and exhibits slow degradation. It is
suitable for sustained release extending to a period of more
than 1 year. The encapsulation of many active drug subs-
tances like antigens, antihypertensive drugs and chemo-
therapeutic agents in PCL microspheres for effective
delivery has been extensively reviewed [122]. Insulin loaded
PCL microspheres were formulated and evaluated and
results explain that it maintain constant plasma drug
concentrations over a prolonged period of time for effective
control of blood sugar levels in rats [121]. Jagadeesh et al
formulated the tamoxifen loaded poly (
caprolactone) based
injectable microspheres using solvent evaporation technique
for the treatment of breast cancer. The in vitro studies
concluded that the injectable polymeric microspheres
therapy for breast cancer will be less toxic and valuable for
the preoperative treatment [123].
Polyorthoesters
The POEs are thermoplastic polymers. These can be
easily formulated into microparticles using an extrusion
method followed by cryogenic milling. With the use of
spinning disk technology, a spray congealing process was
developed for the formulation of bupivacaine loaded POE
microspheres that showed prolonged local anaesthetic effect
[124]. POEs are soluble in commonly used organic solvents
so microspheres can be prepared by an emulsion-solvent
evaporation method. The POE polymer matrix drug release
pattern is controlled by the polymer‘s surface erosion [125].
Nguyen et al. formulated the POE microspheres by blending
it with polyethylenediamine using modified double emulsion
technique for the enhancement of DNA vaccine delivery.
The microspheres enhanced delivery of DNA vaccines to the
targeted cells [126].
Patents
There are many conventional and novel parenteral
preparations which had been patented till date and still going
on. The list of some patents has been given in the Table 9
[127-146].
CURRENT & FUTURE DEVELOPMENTS
Continuous advances in biotechnology and product deve-
lopment will produce more pharmaceutically active dosage
forms, which will be quite difficult to administer by
conventional route of administration. Extended release
parenteral products are complex dosage forms but emerged
as a very attractive approach for controlled release of
bioactive molecules. Major progresses in development of
parenteral sustained release systems have been made in
recent years as evidenced by regulatory approval and market
launch of several new products. Aforementioned drug deli-
very systems have greater potential for many applications
like anti cancer therapy, radio imaging, gene therapy, AIDS
therapy etc. As each delivery system has its own pros and
cons, the novel parenteral drug delivery systems may
improve the bioavailability of drugs. These systems also find
application for the acid and enzyme sensitive drugs as
compared to conventional dosage forms.
Gulati and Gupta
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
None.
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