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

used widely for electrolyte replacement as mentioned in Table 2. Marketed Preparation of Suspensions (US)
Table 1.
Table 1. List of Marketed Formulations of Parenteral Drug Brand Name Manufacturer
Solutions
Aurothioglucose Solganl® Schering

Parenteral Solutions Marketed Formulation Betamethasone sodium phosphate Celestor® Schering


and Betamethasone acetate
LVPs 0.9% sodium chloride injection, USP
Penicillin G Procaine Bicillin ® CR Wyeth
5% sodium chloride injection
®
5% dextrose injection, USP Medroxyprogesterone acetate DepoMedrol Upjohn

10% dextrose injection, USP


Lactated ringers and 5% Ringers injection indicate a sustained release drug profile with the plasma drug
concentration maintained within the desirable therapeutic
Irrigation solutions 0.9% sodium chloride irrigation
range over a period of 24 hours [12]. Some workers prepared
Tis- u- sol® solution pentalyte irrigation a pharmaceutical aqueous suspension formulation for paren-
1.5% glycine irrigation, USP teral administration having substantially stabilized pH,
comprising a steroidal compound with an effective concen-
tration of L-Methionine (pH controlling agent) [13].
Many drugs which have narrow therapeutic index and
Emulsions
stable aqueous pharmaceutical compositions are formulated
as parenteral solutions i.e. bis-indole alkaloid, preferably An emulsion is a two phase system prepared by
vincristine, vinblastine or 5'-Nor-dihydrovinblastine [9]. combining two immiscible liquids, one of which is dispersed
uniformly throughout the other and consists of globules that
Suspensions have diameters equal to or greater than those of large
colloidal particles [14, 15]. Emulsions are generally used in
Parenteral suspensions are useful dosage form for administration of total parenteral nutrition (TPN). TPN is the
administering insoluble or poorly soluble drugs [5]. Drug is practice of feeding patients who are unable to get their
dispersed in the aqueous/oily solution for aqueous/oily nutrition through eating, mainly for the coma patients and
suspensions respectively. The main property, a suspension etc. It is normally used during surgical recoveries [15].
should possess for parenteral delivery is that it should not
Emulsions generally fall into two categories i.e. a hetero-
produce tissue irritation on injection. The larger surface area
genous system comprised of a drop of organic liquid
of disperse drug ensures higher solubility which helps in immersed/surrounded in an aqueous solution that is known
providing a high degree of availability for absorption of as oil in water emulsion (o/w type) and a heterogenous
drug. Parenteral suspension provides more prolonged release system comprised of a drop of water immersed/surrounded
as compared to solution from the injection site. This system in organic solutions that is known as water in oil emulsion
is used through subcutaneous and intramuscular route.
(w/o type) [16]. The formulation view of emulsion includes
Suspensions are better than solutions as they provide
pharmaceutical oils (as mentioned in non aqueous vehicles in
increase resistance to hydrolysis and oxidation as drug is solutions), pharmaceutical emulsifiers (surface active agents,
present in solid form [7, 8]. Despite of all these benefits natural polymers, finely divide solids), preservatives and
many problems are associated with suspensions like antioxidants.
difficulty in formulation, stabilization of suspensions for the
period between manufacture and use and chances of non- Steps in emulsion formulation depends upon the type of
uniformity of dose at the time of administration [10,11] etc. formulation, whether an o/w emulsion or w/o emulsion,
Some of the official parenteral suspensions includes sterile internal phase is selected in which drug is mixed. In the
ampicillin suspension USP’2009, sterile aurothiglucose external phase, pharmaceutical emulsifier is added so as to
suspension USP’2009 - vegetable oil suspension, tetanus stabilize the droplets that form during emulsification.
toxoid adsorbed USP’2009, IP’96, betamethasone acetate Mixture of drug and internal phase is poured in mixture of
suspension USP’2009 aq. suspension, Insulin inc suspension emulsifier and external phase with a high pressure
USP’2009, IP’96 aq. suspension and procaine penicillin homogenization, so as to break the internal phase droplets.
suspension IP’96 etc. The formulation aspect of suspension Emulsifier covers the whole surface so as to stabilize the
involves drug and added agents like wetting agent (parti- droplet of internal phase [15]. The procedure is simplified in
cularly surfactant of 7-9 HLB values), buffers, viscosity the Fig. (1). The major problem associated with emulsions is
increasing agents (natural gums like tragacanth, acacia), that these are thermodynamically unstable because of
preservatives [6] etc. US has approved many suspensions to increase in surface free energy of the system, that depends on
be given parenterally Table 2. the total surface area and interfacial tension which increases
by increasing surface area of system during emulsification
Suspensions provide the drug release in sustained [17].
manner. Chang et al. prepared the aqueous suspension of
butorphanol by free base and oil suspension of tartarate salt. Parenteral emulsions are administered through subcu-
The in vivo studies were carried out in dogs and results taneous and intramuscular routes. Commercially available
Parenteral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 135

Micro and Nanoparticulates


Recently, the nano and microparticle approach has
Drug + Internal Phase 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
High pressure emulsification 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
External Phase + Emulsifier [25].
Lipid Micro and Nanoparticles
Conventional lipid systems for parenteral drug delivery
comprise of oil solutions, suspensions as well as emulsions
Emulsion 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
Filtration 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
Fig. (1). Flow chart explaining steps involved in emulsion of hydrophilic drug is quite cumbersome in these lipid
formation. systems [23]. Advanced lipid micro- and nanoparticulate
systems have been developed for parenteral sustained release
oily emulsions are intralipid® 10%, lipofundin®, lipofundin®, of water soluble and insoluble drugs. In addition to
and liposyn®. The major focus on recent literature has been subcutaneous and intramuscular injection, lipid particulate
in area of parenteral drug delivery like subcutaneous, systems in nano size can be given intravenously [27]. SLN
intramuscular, intraperitoneal delivery etc. Park et al. (solid lipid nanoparticles), NLC (nanostructured lipid
evaluated the potential of flurbiprofen microemulsions in carrier), LDC (lipid drug conjugate) and polymeric nano-
parenteral delivery. The pharmacokinetic studies yield a 1.5 particles are particles in nanometer range with a solid lipid
to 2 fold increase in half life, area under curve and mean matrix and natural/synthetic polymers respectively. The
residence time of flurbiprofen from microemulsions [18]. particle dispersions contain surfactants as stabilizers in
Drugs in emulsion form provide sustained release i.e. bupre- addition to lipid, polymer and drug. SLN are the nano-
norphine emulsions. An oil-in-water buprenorphine formu- particles made up of solid lipids (i.e. lipids solid at room
lation including buprenorphine and a surfactant that temperature and also at body temperature) which is
emulsifies the buprenorphine in oil, wherein oil concen- stabilized by surfactants [28]. The main features of SLN
tration control the drug release. A buprenorphine oil which makes them suitable for parenteral delivery of drug
formulation including a buprenorphine salt suspended in are excellent physical stability, protection of incorporated
pharmaceutically acceptable oil [19]. labile drugs from degradation, controlled drug release and
site specific targeting. Inspite of benefits, there are two
NOVEL PARENTERAL FORMULATIONS foremost problems associated with SLNs like insufficient
loading capacity, drug expulsion especially after poly-
Parenteral drug therapy has been used in emergency
morphic transition during storage [27, 28]. Many drugs have
situations but certainly there are lots of problems associated
been entrapped in solid lipid matrix such as AZT-P and
with these conventional parenteral formulations like drug
derivatives [29- 31], Camptothecin [32, 33], Clobetasol
solubility, product stability (particularly with biopharma-
propionate [34], Cortisone [35], Diazepam [36], Doxorubicin
ceuticals), drug delivery (sustained/controlled-release
[37-40].
formulations after intramuscular or subcutaneous injection)
and manufacturability [20]. In present scenario, a number of NLC is nanoparticulate lipid carrier with a certain
technological advances have been made in the field of nanostructure so as to increase the loading efficiency and
parenteral drug delivery leading to development of systems prevent drug expulsion from the particles. It mainly uses
that allow drug targeting along with sustained or controlled liquid lipids in conjunction with solid lipid which then
release of pharmaceutically active ingredient [21]. Novel reduces the chances of polymorphic transformation [41, 42].
parenteral formulation includes colloidal drug delivery via The basic difference between the structures of SLN and NLC
parenteral route like nanoparticles, niosomes, liposomes, are shown in Fig. 2. NLC have only been exploited for the
polymeric micelles, in situ forming parenteral drug delivery topical delivery, however their advantages over conventional
system [22, 23]. Donelly et al. reviewed the potential of SLN are also of interest for parenteral application routes
novel parenteral formulations as mucoadhesive drug delivery [43].
systems like hydrogels, nanoparticulates for various LDC comprises of an insoluble drug-lipid conjugate,
parenteral routes of drug administration [24]. 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 Gulati and Gupta

(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 AUC/dose and mean residence times (MRT) especially in
literature, surface-modified diminazenestearate and oleate brain, heart and reticuloendothelial cells containing organs as
LDC were used to carry out cytotoxicity studies, its plasma compared to drug solution [56].
protein absorption (2-DE) and antitrypanosomiasis activity
Nanoemulsions
via brain targeting have been performed [45-47].
Nanoemulsions are transparent or translucent oil-in-water
There are many methods reported for the preparation of
(o/w) or water-in-oil systems with a mean droplet diameter
solid lipid nanoparticles like solvent emulsification tech-
nique [48], solvent injection method [49, 50], solvent in the range between 100 and 500nm. They are synony-
mously known as mini-emulsions or sub micron emulsions
emulsification diffusion technique [51], high pressure homo-
[57]. These are thermodynamically stable system in which
genization (hot and cold) [52], micro emulsion technique
two immiscible phases are stabilized with the help of
[53], homogenization followed by sonication [53, 54].
emulsifiers to form a single phase.
Cavalli et al. formulated tripalmitin SLN loaded with
paclitaxel as an alternative tool for parenteral administration The system is regarded as ‘single phase’ because studies
and reported sustained release of drug [55]. Yang et al. carried out on nanoemulsion formation by phase inversion
compared the pharmacokinetics and body distribution of temperature method have shown a relationship between
camptothecin after i.v. injection of drug solution and SLN in minimum droplet size and complete solubilization of oil in
mice. They reported that the SLN give much higher emulsion. As the size of droplet of dispersed phase decreases
Parenteral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 137

to nano level, the system tends to become clear and prone to ostwald ripening therefore stable for long time.
solubilized, which is considered as single phase as compared Ostwald ripening is the term used for the growth of large
to microemulsions. The system is devoid of problems like particles at the expense of smaller ones because of difference
creaming, flocculation, coalescence and sedimentation which in solubility rates of different size particles. Regarding the
are the main problems associated with macroemulsions [58]. formulation aspect of nanosuspensions, many methods had
Methods to produce nanoemulsions may be classified on the been reported, which are more cost effective and technically
basis of energy involved. High energy method includes high more simple particularly for hydrophobic drugs [64, 66].
pressure homogenization, microfluidization, ultrasonification Nanosuspension formulation techniques currently used are
while the low energy methods include spontaneous emul- precipitation, high pressure homogenization (disso cubes),
sification, solvent diffusion method, and phase inversion emulsion and media milling techniques. DissocubesTM are
temperature (PIT) [59]. The components of nanoemulsion crystalline nanoparticles of active substance obtained by a
systems includes oils like castor oil, coconut oil, soybean oil, liquid state high energy process using a high pressure piston
wheatgerm oil, linseed oil, olive oil, peanut oil, PEG- gap homogenizer, to reduce the drug particle size in presence
vegetable oil; emulsifiers like natural lecithins from plant of surface modifiers that associate at freshly generated drug
and animal sources, poloxamers, polysorbates, steraylamine, interface. Out of these, media milling and high pressure
oleylamine and additives like antioxidants (tocopherol), homogenization are patented technologies. High speed
tonicity modifiers (glycerol, sorbitol), preservatives, pH homogenization i.e. Dissocubes technology was developed
adjustment agents [60]. Many commercial nanoemulsion by Muller. The patent rights (patent application number
formulations are enlisted in Table 3. US5858410) of disso cubes were initially owned by DDS
Table 3. Commercial Nanoemulsion Formulations.
(Drug Delivery Services) GmbH, Germany but currently
they are owned by Skye Pharma PLC, England and Wales.
While media milling (patent application number US51-
DRUG BRAND INDICATION 45684) i.e. nanocrystals is also patent protected technology
which was developed by Liversidge in 1992. Formerly the
Propofol Diprivan® Anesthetic
technique was owned by company Nanosystems, Dublin
Dexamethasone Limethason ®
Steroid Ireland but recently it has been acquired by Elan Drug
Delivery, Dublin Ireland. Stabilizers, co-surfactants are the
Flurbiprofen axetil Ropion® Nonsteroidal analgesic main additives that determine the stability of the
® nanosuspensions [64]. Muthu et al. formulated resperidone
Vitamin A, D, E & K Vitalipid Parenteral nutrition
nanosuspension using Pluronic® F-68 or Pluronic® F-127 as
polymeric stabilizer. Nanosuspension contains resperidone
Amani et al. formulated the budesonide based nano- loaded poly (D, L-Lactide) nanospheres, formulated by
emulsion for the respiratory delivery when nebulized using a nanoprecipitation technique. The in vitro release studies
jet and a vibrating mesh nebulizer. The in vitro studies of the indicated that this formulation approach can be used to
nanoemulsions were compared with the commercially improve the therapeutic efficacy of drug. The controlled drug
available suspension of budesonide (Pulmicort Respules®). A release from the suspensions indicates that the frequency of
smaller mass median aerodynamic performance (MMAD) administration could be reduced, if administered via
with increased aerosol output was observed in the nano- parenteral (i.v) route [67]. Salem et al. formulated a
emulsion formulations in comparison with the corresponding sustained release form of natural progesterone using stearic
suspension formulations which indicate an improved in vitro acid as surface stabilizer. Firstly, progesterone loaded
performance for the nanoemulsion-based formulations [61]. nanoparticles were prepared by solvent precipitation method
Shakeel et al. formulated the celecoxib nanoemulsions for its which was then formulated into nanosuspension dispersed in
enhanced bioavailability. The results of skin permeation and thermosensitive gel matrix. The formulation was meant to be
pharmacokinetic studies shown that the nanoemulsions can given as i.m injection. The in vivo studies were carried out in
enhance the bioavailability of poorly soluble drugs with rats that indicate that the natural progesterone which was
improved skin permeability [62]. loaded in nanoparticles and then formulated in thermo-
sensitive gel significantly sustained the action of natural
Nanosuspensions progesterone. This reduces the dosing frequency of natural
Nanosuspensions are submicron colloidal dispersion of progesterone to be injected every 36 hrs instead of every day
solid active pharmaceutical ingredient (API) particles in [68]. Method for formulating a stable nanosuspension was
aqueous phase which is stabilized by surfactants [63]. patented for delivery of vitamin B-12. A nanofluidizable
Nanosuspensions can be administered by oral, topical, mixture containing vitamin B-12 is initially formed and
parenteral and pulmonary administration. The particle size processed via a nanofluidization process to form the stable
distribution of the drug in nanosuspensions is usually less nanosuspension, which may be administered via the trans-
than one micron with an average particle size ranging mucosal membranes or other suitable routes of adminis-
between 200 and 600nm [64]. Nanosuspensions have many tration [69].
positive points that make them amenable to numerous Liposomes
applications. This system increases the saturation solubility
as well as dissolution velocity of the drug which leads to Liposomes are discovered in mid 1960s [70]. Liposomes
enhanced bioavailability of the poorly soluble/hydrophobic are vesicles having concentric phospholipid bilayers as
drug [65]. Unlike suspensions, nanosuspensions are less 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 Recent Patents on Drug Delivery & Formulation, 2011, Vol. 5, No. 2 139

in vivo gene therapy. With drug targeting it is possible to The in vivo drug release studies indicates the prolonged
deliver a drug to a tissue or cell region not normally analgesic effect of bupivacaine HCl, when compared to an
accessible to the free or untargeted drug with less wastage injection of drug solution and concluded ISM as an attractive
[86]. alternative for parenteral drug delivery system [97]. Jain and
In Situ Depot Forming Systems his co-worker developed the novel injectable compositions.
The aims of this invention was to form a depot upon
Biodegradable injectable in situ depot forming systems administration in vivo and are in the form of an in situ
represent an attractive alternative to implants for the delivery gelling composition or an implant composition which
of drugs [87, 88]. These systems are made up of a bio- provides a prolonged release of tamsulosin or letrozole for
degradable carrier dissolved or dispersed in a solvent/ extended periods of time [98].
cosolvent system, whereas the drug is either dispersed or Niosomes
dissolved in the liquid phase of the system [89, 90].
Following subcutaneous or intramuscular injection, a solid Niosomes are vesicular systems made up of non-ionic
depot is formed at the site of injection. The controlled surfactant obtained by hydration of synthetic nonionic
release of bioactive macromolecules via in situ forming surfactants, with or without incorporation of cholesterol or
systems has a number of advantages, such as ease of other lipids [99]. Nonionic surfactants, such as sorbitan esters
administration, less complicated formulation techniques, less (span series), polysorbates (tween series) are used for the
stressful manufacturing conditions for sensitive drug preparation of niosomes [100, 101, 102] Table 6.
molecules [91]. Other benefits of these systems include
Niosomes are osmotically active and are stable on their
reduced dose and dosing frequency, enhancement of patient
own [103]. Inspite of this, the drug entrapped have increased
compliance and the most important is ‘infusion-like’ plasma
stability within the niosomes. These can be administered by
level time profiles [92]. According to the mechanism of
parenteral as well as topical routes and reach the site of
depot formation, these systems are classified as follows action. The surfactants used are biodegradable, biocom-
thermoplastic pastes, in situ crosslinked polymer systems,
patible and non-immunogenic. The most advantageous
in situ polymer precipitation, thermally induced gelation and
reason for administering the niosomes for drug targeting via
in situ solidifying organogels [93, 94]. For various types of
parenteral route is it delay clearance from the circulation,
in situ systems, different parameters are shown in Table 5.
protecting the drug from biological environment and
In situ cross-linked systems can be produced by causing restricting effects to target cells. Niosomes are prepared by
polymer precipitation from solution and the method is the methods used for liposomes formulation i.e. film hy-
known as Atrigel technology (QLT, Vancouver, Canada), dration method, sonication, ether injection method, micro-
which is used as a vehicle for Eligard. ELIGARD® is a fluidization, reverse phase evaporation and bubble method.
sterile polymeric matrix formulation of leuprolide acetate. It Niosomes are extensively used for the parenteral adminis-
is prefilled and supplied in two separate sterile syringes, one tration of a number of drug moieties Table 7 [104-113].
syringe contains the ATRIGEL® delivery system and the Desai et al reported the delivery of niosomal all-trans-
other contains leuprolide acetate. A lipophillic biodegradable
retinoic acid (ATRA) by aerosolization. ATRA is a
polymer is solubilized in a biocompatible organic solvent
hydrophobic anticancer drug. Various nonionic surfactants
and drug is added to polymeric solution which forms a
were used and the best formulations were obtained with
solution/suspension upon mixing. On injecting this formu-
combinations of (Span 20 + Tween 80) and (Span 60 +
lation into the body, the solvent diffuses away and water
Tween 80) using an ATRA concentration of 1 mg/ml which
penetrates into the organic phase which leads to phase have optimum encapsulation and nebulization efficiencies.
separation and polymer precipitation lead to formation of a
The route proved to be advantageous since it offered an
depot at the injection site [95, 96]. Kranz et al. studied the
effective way to deliver high levels of drug to the lung
in vivo release of bupivacaine hydrochloride from an
without apparent side effects [114].
injectable in situ forming microparticulate system (ISM).

Table 5. In situ forming Parenteral Drug Delivery Systems [94].

Thermoplastic Paste Thermogelling System Polymer Precipitation

Injection Semi solid paste Aqueous solution Organic solution

Depot Formation Solidification Sol to gel transition Phase separation

Polymer POE ABA & BAB PLGA

Drug Burst Low Medium High

Drug Loading Dry powder Aqueous solution Organic solution

Injection Pain Low Low High

Release Surface erosion Pore diffusion/bulk erosion Pore diffusion/bulk erosion


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

Polycaprolactones CONFLICT OF INTEREST


Poly--caprolactone (PCL) is semicrystalline biode- The authors declare no conflict of interest.
gradable polyester and exhibits slow degradation. It is
suitable for sustained release extending to a period of more ACKNOWLEDGEMENTS
than 1 year. The encapsulation of many active drug subs-
tances like antigens, antihypertensive drugs and chemo- None.
therapeutic agents in PCL microspheres for effective
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