APPROACHES FOR RATE CONTROLLED

&TARGETED DELIVERY BY PARENTERAL ROUTE

INTRODUCTION
Drug delivery is the method or process of administering a pharmaceutical compound
to achieve a therapeutic effect in humans or animals.
Drug delivery technologies modify drug release profile, absorption, distribution
&elimination for the benefit of improving product efficacy and safety, as well as
patient convenience and compliance.
Parenteral Administration
 Parenteral route delivers drugs via a needle into the skin layers, SC tissue,
muscles, or veins, with the needle angled at different degrees, depending on
the type of injection.
Limitations
 Much more invasive, invades the barrier of the skin.
 Aseptic technique must be strictly used.

Targeted Drug Delivery

Targeted drug delivery, which also refers to drug targeting or site specific drug
delivery, is to site-specifically deliver or activate the therapeutic compounds in the
site of action. Thus, the targeted drug delivery is expected to enhance drug efficacy
by increasing local active drug concentration in disease tissues, and to decrease side
effect by minimizing drug exposure in normal tissues.

 Site specific drug delivery using the novel targeting approaches improves the
therapeutic regime and also reduces the toxic side effects.

Sequential events of site specific drug delivery

 Localization of drug and carrier within the desired target organ (Organ
targeting)
 Recognition and interaction of the carrier with specific target cell(s) with in
a tissue (Cellular targeting).
 Delivery of the therapeutic concentration of drug to only the target cell/s.
 An advanced strategy is to deliver the drug to different intracellular
compartments within target cells via specific transport pathways.
(Intracellular targeting)
Site-directed drug delivery carriers
 Implants
 Depot formulations either to target high drug concentrations to the immediate
area surrounding the target tissue or to provide sustained drug release for
systemic therapy have been used as implants.
  Clinically, implant systems are applied in situations where chronic therapy is
indicated, such as hormone replacement therapy and chemical castration in
the treatment of prostrate cancer.
 Parenteral implants are designed in the form of highly viscous liquids or
semisolid formulations, both of which may be injected with a needle.
 Alternatively, implants may be in the form of tiny rods impregnated with
drug substances or a liquid which gels in situ (ReGel® -Injectable gel depot).
ReGel® Thermally Gelling Polymer
 –PLGA-PEG-PLGA triblock copolymer
 –Total MW = 4500 Da
 –PEG MW = 1000 Da
 Below gel temperature (0° to 30° C), ReGel® is a liquid. It is easily
administered through a 25 gauge needle, or with needle-free injectors
 Duros® Implant is a miniature cylinder made from titanium alloy, which
protects and stabilizes the drug inside using ALZA’s formulation technology.
 It is designed for long-term delivery of proteins, peptides and
macromolecules like Leuprolide acetate.

 Zoladex® Implant is a subcutaneous rod-shaped implant made using

biodegradable polymer PLGA. It is formulated for one-month delivery of
peptide goserelin acetate.

PARENTAL DEPOT SYSTEM( PDS )

 Depot: Long acting parenteral drug formulation are designed, ideally to
provide slow constant, sustained, prolonged action.
Reason for development of PDS
1. No surgical removal of depleted system is required as it is metabolized in non
toxicological by product.
2. The drug release from this system can be controlled by following
 Diffusion of drug through the polymer
 Erosion of the polymer surface with concomitant release of physically
entrapped drug.
 Cleavage of covalent bond between the polymer bulks or at the surface
followed by diffusional drug loss.
 Diffusion controlled release at the physically entrapped drug with bio
adsorption of the polymer until drug depletion.
Approaches used in Depot formulation
1.Use of low aqueous soluble salt
2.Use of largest particle with crystalinity.
3.The suspension of the drug particle in vegetable oil and especially of gels
with substances such as aluminum monasteries produces prolonged
absorption rates.
TYPES OF DEPOT FORMULATION
On the basis of different mechanism, depot formulation categories into four
types
1) Dissolution controlled depot formulation
2) Adsorption type depot formulation
3) Encapsulation type depot formulation
4) Esterification type depot formulation

1.Dissolution-controlled depot formulations

 In this depot formulation the rate limiting step of drug absorption is the
dissolution of drug particles in the formulation or in the tissue fluid
surrounding the drug formulation. So drug absorption can control by slow
dissolution of drug particle.
 The rate of drug dissolution (Q/t)d under sink conditions is defined by
(Q/t)d = Sa Ds Cs/hd
Sa is the surface area of the drug particles in contact with the medium;
Ds is the diffusion coefficient of drug molecules in the medium;
Cs is the saturation of drug in the medium;
hd is the thickness of the hydrodynamic diffusion layer surrounding each of
the drug particle.
2.Adsorption-type depot preparation:
 This depot preparation is formed by the binding of drug molecules to
adsorbents. In this case only the unbound, free species of the drug is available
for absorption.
 As soon as the unbound drug molecules are absorbed a fraction of the bound
drug molecules is released to maintain equilibrium.
 This depot preparation is exemplified by vaccine preparations in which the
antigens are bound to highly dispersed aluminum hydroxide gel to sustain
their release and hence prolong the duration of stimulation of antibody
formation.
 3.Encapsulation-type depot preparations
 This depot preparation is prepared by encapsulating drug solids within a
permeation barrier or dispersing drug particles in a diffusion matrix.
 The release of drug molecule is controlled by the rate of permeation across
the permeation barrier and the rate of biodegradation of the barrier
macromolecules.
 Both permeation barrier and diffusion matrix are fabricated from
biodegradable or bioabsorbable macromolecules, such as gelatin,
dextran,polylacticacid, lactide-glycolide copolymers, phospholipids, and
long-chain fatty acids and glycerides.
Typical examples are naltrexone pamoate-releasing biodegradable
microcapsule, liposomes.
4.Esterification-type depot preparations
 This depot preparation is produced by esterifying a drug to form a
bioconvertible Prodrug-type ester and then formulating it in an Injectable
formulation.
 This chemical approach depends upon number of enzyme (esterase) present
at the injection site.
 This formulation forms a drug reservoir at the site of Injection.
 The rate of drug absorption is controlled by the interfacial partitioning of
drug esters from the reservoir to the tissue fluid and the rate of bioconversion
of drug esters to regenerate active drug molecules.
 It is exemplified by the fluphenazine enanthate, nandrolone decanoate in
oleaginous solution.
Evaluation of Parenteral Depot System
Viscosity
 The viscosity of intradermal liquid depots were determined by measuring the
time required for liquid to pass between two marks as it flows by gravity
through a vertical capillary tube, known as Ostwald Viscometer.
 The time of flow of the liquid under test is compared with the time required
for liquid known viscosity (distilled water) to pass between the two marks.
 If h1 and h2 are the viscosities of the unknown and the standard liquids, d1 and
d2 are densities of the liquids and t1 and t2 are the respective flow times in
seconds, The absolute viscosity intradermal liquid depots h1 were determined
by substituting the experimental values in the equation

Ostwald viscometers measure the viscosity of a fluid

with a known density
 Drug Content:
 A known amount of formulation of given sample is suitably diluted with
solvent like N-methyl-2-pyrilidone and stirred for 12 hours at 37+1oC.
 The drug content of formulations is determined by measuring the absorbance
of the solution against solvent like N-methyl-2-pyrilidone as a blank using
spectrophotometer at particular wavelength.
 This procedure is followed for determining drug content of all prepared
formulations.
In vitro release study
 Commercial dialysis membrane is employed for the in vitro release study.
 The membrane, which is, used transparent and regenerated cellulose type,
which is permeable to perticular molecular weight substances.
The semipermeable membrane is tied to one end of open ended cylinder
made up of glass (15 mm x 75 mm) which act as a donor compartment.
 Intradermal liquid depot system containing drug placed inside the
compartment. This set up is placed over a beaker containing 100 ml
phosphate buffer saline pH 7.4 and its content were continuously stirred
using a magnetic stirrer at 37+1oC. 5 ml sample is withdrawn from the
receptor compartment at the end of 24 hours interval up to a period of 7
days.
 After each withdrawal an equal volume of phosphate buffer saline pH 7.4
was replaced in the receptor compartment. The collected sample is analyzed
spectrophotometrically at given wavelength nm against blank.
Technologies for parenteral DDS
 A number of technological advances have been made in the area of parenteral
drug delivery, leading to the development of sophisticated systems that allow
drug targeting and the sustained or controlled release of parenteral medicines.
 Parenteral formulations, particularly intravascular ones, offer a unique
opportunity for direct access to the bloodstream and rapid onset of drug
action as well as target to specific organ and tissue sites.
Advanced novel parenteral drug delivery system
1. solid lipid nanoparticles (SLN),
2. In situ forming parenteral drug delivery systems,
 3. organogels,
4. lipid nanodispersions (nanoemulsions and nanosuspensions),
5. niosomes,
6. liposomes.
7. microsphere

1. Solid Lipid Nanoparticles(SLN)

 The concept of lipid nanoparticles for injectable delivery was developed from
submicron sized parenteral fat o/w emulsion used for parenteral nutrition viz.
Intralipid in 1960s.
 This gave birth to the idea of encapsulating lipophilic drugs into oil droplets.
 The only drawback associated with these submicron emulsions was the low
viscosity of the droplets, causing fast release and susceptibility of the
incorporated actives towards degradation by the aqueous continuous phase.
 In 1990s, researchers (Mueller and coworkers and Gasco and coworkers)
started exploring the potential of nanoparticles-based solid lipids or SLNs in
the drug delivery.
 SLN are colloidal particles composed of a biocompatible/biodegradable lipid
matrix that is solid at body temperature and exhibit size range in between 100
and 400 nm
 various drugs incorporated in injectables lipid nanoparticles

Advantages of SLN
 Particulate nature
 Amenability to encapsulate hydrophilic and hydrophobic drugs
 Ability to sustain the release of incorporated drug
 Ability to prevent chemical, photochemical, or oxidative degradation of drug
 Ability to immobilize drug in the solid matrix
 Ease of scale-up and manufacture
 Low cost of solid lipids as compared with phospholipids and biodegradable
polymers
Application of lipid nanoparticles
 Treatment of cancer
SLN have been shown to improve the efficacy and residence time of the
cytotoxic drugs, with concomitant reduction in the side-effects associated
with them. The salient features of SLN
 improved stability of the drug,
 less in vitro toxicity
 , enhanced drug efficacy, and improved pharmacokinetics.
Liver targeting
Particulate carriers (including SLN) usually accumulate in the liver by
passive targeting on parenteral administration. However, passive targeting
leads to entrapment of the drug in the Kupffer cells and not in the
hepatocytes, which is the major target for the treatment of hepatic diseases
such as cancers. Hence, for liver targeting, SLN containing galactosylated or
mannosylated lipids are employed.
Targeting the central nervous system
Various drugs ranging from antipsychotics, antiparkinson, antieschemic to
antibiotics have been encapsulated in lipid nanoparticles with the aim to
either modify the biodistribution or for brain targeting.
Recently, potential of surface-modified SLN has been demonstrated in the
treatment of brain diseases such as cerebral malaria.
 Gupta et al. fabricated transferrin-conjugated SLN and studied their ability
to target quinine hydrochloride to brain by studying biodistribution.
 Treatment of parasitic diseases
Transferrin-conjugated SLN of quinine dihydrochloride, an antimalarial
drug, were prepared to target it to the brain for the management of cerebral
malaria.

Toxicity of lipid nanoparticles

For the successful regulatory clearance of SLN for parenteral delivery, it is

essential to establish their biocompatibility with blood components and other
tissues. Thus, SLN can be used as intravenous carriers because of their
prolonged circulation time and high toxicological acceptance.
2. In Situ Forming Parenteral Drug Delivery Systems
 Biodegradable injectable in situ forming drug delivery systems represent an
attractive alternative to microspheres and implants as parenteral depot
systems. The controlled release of bioactive macromolecules via (semi-) solid
in situ forming systems has a number of advantages, such as:
ease of administration,
 less complicated fabrication,
 less stressful manufacturing conditions for sensitive drug molecules.
 Classification of injectable in situ forming implants
Thermoplastic pastes
Semi-solid polymers can be injected when melted and form a depot upon
cooling to body temperature.
 The requirements for such In Situ Forming Devices (ISFD) include low
melting or glass transition temperatures in the range of 25 to 658°C and an
intrinsic viscosity in the range of 0.05 to 0.8 dl/g.
 Thermoplastic pastes allow local drug delivery at sites of surgical
interventions for the delivery of antibiotic or cytotoxic agents. Alternatively,
they can be used to generate a subcutaneous drug reservoir from which
diffusion occurs into the systemic circulation.

In situ cross-linked polymer systems

The formation of a cross-linked polymer network is advantageous because of
the possibility to control the diffusion of hydrophilic macromolecules. Such a
system could ideally release peptides and proteins over a prolonged period of
time.
In situ cross-linking implants have been a challenging objective, as polymers
containing double-bonds and free radical-initiation are necessary. Various in
situ forming parenteral drug delivery systems are shown in table.

In situ polymer precipitation

A water-insoluble and biodegradable polymer is dissolved in a biocompatible
organic solvent to which a drug is added, forming a solution or suspension
after mixing. When this formulation is injected into the body, the water-
miscible organic solvent dissipates and water penetrates into the organic
phase. This leads to phase separation and precipitation of the polymer,
forming a depot at the site of injection.
 This method has been developed by ARTIX Laboratories and is designated
as the Atrigel technology

Controlled release by Atrigel system

 3.Organogels
 Organogels are semi-solid systems in which an organic liquid phase is
immobilized by a three-dimensional network composed of self assembled,
intertwined gelator fibers. Despite their majoritarily liquid composition, these
systems demonstrate the appearance and rheological behavior of
solids.Detailed classification of organogels is shown in [Figure 2]

Examples
Rivastigmine and leuprolide are used in organogel formulation by
subcutaneous route, in which N-stearoyl l-alanine methyl or ethyl ester is
used as organogelators.
4.Lipid Nano Dispersions
 There are broader applications of lipid systems in parenteral drug delivery.
However, with specific new chemical entities, it has been limited due to the
following reasons:
 Only a small number of parenteral lipid excipients are approved.
 There is increasing number of drugs that are partially or not soluble in
conventional oils and other lipid solvents.
 The ongoing requirement for site-specific targeting and controlled drug
release.
These advanced parenteral lipid nano dispersions include nanoemulsions and
nanosuspensions .
Characteristics of desired parenteral formulation
 Exhibits high drug solubilization/loading capacity.
 Is at least as efficacious as the marketed formulation.
 It has a shelf-life of at least 2 years.
 Should be easily processed and manufactured using standard equipment.
 Is amenable to fast track development status by addressing 'unmet medical
needs.
a. Nanoemulsions
Nanoemulsions or miniemulsions are transparent or translucent oil-in-
water (o/w) or water-in-oil droplets with a mean droplet diameter in the
range between 100 and 500 nm.
They are also known as submicron emulsions and unlike the
thermodynamically stable microemulsions, nanoemulsions are kinetically
stable with great stability in suspension due to their small droplet size.

b.nanosuspension
Nanosuspensions of drugs are submicron colloidal dispersions of drug
particles which are stabilized by surfactants.
Advantages of nanosuspensions
Used to formulate drugs that are insoluble in both water and oil, and are
usually employed when the use of other lipid-based systems are limited.
In the case of high melting point compounds, solubilization in any
solvent is difficult; nanosuspensions can be used to maintain these drugs
in a preferred crystalline state of sufficiently small size for intravenous
administration
Formulation considerations for nanoparticulate systems
 Physical stability is an essential requirement for a nanoparticulate system.
Poorly formulated particles can aggregate over time leading to higher number
of large particles, thereby creating a potential safety concern.
 Nanoparticles may also sediment over time in storage. If not appropriately
stabilized, the sediment may be difficult to resuspend.
 Finally, if the drug has finite solubility in the suspending buffer, the drug
particles can dissolve and recrystallize on large particles, a phenomenon
commonly known as Ostwald ripening.
 Particle size of the final formulation is particularly important for parenteral
dosage forms, because that may also impact safety of the product. Processes
 such as spray drying, freezing, or lyophilization can be implemented to
facilitate stabilization of the particles.
 Excipients and stabilizers have to be carefully chosen to stabilize the particles
and prevent particle size change during processing and storage.

5. Niosomes
 Niosomes are nonionic surfactant vesicles obtained on hydration of synthetic
nonionic surfactants of the alkyl or dialkyl polyglycerol ether class, with or
without incorporation of cholesterol or other lipids.

Application
 Anticancer niosomes
Anticancer niosomes, if suitably designed, will be expected to accumulate
within tumors. For example, niosomal encapsulation of methotrexate and
doxorubicin increases drug delivery to the tumor and tumoricidal activity. It
was reported that doxorubicin niosomes having size 200 nm with a
polyoxyethylene (molecular weight 1000) surface are rapidly taken up by the
liver and accumulate to a lesser extent in tumor; this technology may prove
advantageous for the treatment of hepatic neoplasms.
Niosomes at targeted site
Uptake by the liver and spleen make niosomes ideal for targeting diseases
manifesting in these organs.One such condition is leishmaniasis, and a
number of other studies have shown that niosomal formulations of sodium
stibogluconate improve parasite suppression in the liver, spleen, and bone
marrow. Niosomes may also be used as depot systems for short-acting
peptide drugs on intramuscular administration.
 Niosomes as vaccine adjuvants
 It was studied that niosomal antigens are potent stimulators of the cellular
and humoral immune response. The formulation of antigens as a niosome in
water-in-oil emulsion further increases the activity of antigens and hence
enhances the immunological response.

6.Liposomes
 Liposomes are formed by the self-assembly of phospholipid molecules in an
aqueous environment. The amphiphilic phospholipid molecules form a closed
bilayer sphere in an attempt to shield their hydrophobic groups from the
aqueous environment while still maintaining contact with the aqueous phase
via the hydrophilic head group.

Liposomal anticancer agent

The use of liposomes as anticancer drug delivery systems was originally
hampered by the realization that liposomes are rapidly cleared from the
circulation and largely taken up by the liver macrophage.
It was observed that doxorubicin-loaded stealth liposomes circulate for
prolonged periods, accumulate, and extravagate within tumors and also
improve tumoricidal activity in mice. In one study, it has been reported that
in patients, liposomal doxorubicin accumulates within Kaposi's sarcoma
lesions and produces a good therapeutic response.
Liposomal doxorubicin is now licensed as Caelyx for the treatment of
Kaposi's sarcoma. This formulation is currently in clinical trials for ovarian
cancer and could be approved shortly for use in ovarian cancer patients who
have failed to respond to paclitaxel and cisplatin.
Liposomes as vaccine adjuvants
 Liposomal vaccines can be made by associating microbes, soluble antigens,
cytokines, or DNA with liposomes, the latter stimulating an immune
response on expression of the antigenic protein.
 Liposomes encapsulating antigens are subsequently encapsulated within
alginate lysine microcapsules to control the antigen release and to improve
the antibody response.
 Liposomal vaccines may also be stored dried at refrigeration temperatures
for up to 12 months and still retain their adjuvanticity
Liposomal anti-infective agents
 Liposomal amphotericin B (Ambisome) is used for the treatment of systemic
fungal infection. This is the first licensed liposomal preparation. It was
observed in one study that liposomal amphotericin B, by passively targeting
the liver and spleen, reduces the renal and general toxicity of the drug at
normal doses.
 Some of the actives incorporated in injectable liposomes are presented in
[Table ].

7.MICROSPHERES
 Numerous biodegradable polymers have been investigated for preparation of
microspheres as depot formulation. The application of biodegradable
microspheres to deliver small molecules, proteins, and macromolecules using
multiple routes of administration has been widely investigated and several
products have been brought to market in the last 10–20 years.

Drug Commercial name Company

Risperidone CONSTA® Janseen®/Alkermes, Inc
RISPERDAL®
Naltrexone Vivitrol® Alkermes
Lupron Depot®
Leuprolide Enantone Depot® Takeda
Trenantone®
Minocycline Arestin® Orapharma

Conclusions
 Drug delivery technologies (discussed above) are used to control the delivery
of drug by parenteral administration.
 Parenteral drug delivery systems have grown to become important
technology platforms which are used by pharmaceutical companies in the
recent years.
 So, it is important to study parenteral drug delivery system, as it provides
rapid treatment objective to save valuable life of human being.