PARENTRAL CONTROLLED DRUG
Routes for parentral drug delivery
Approaches to design controlled release parentral dosage
Routes for Parenteral Delivery
- used rarely for the administration of liposomes,
nanoparticles, erythrocytes and polypeptides.
- particle size is an important consideration.
- volume of injection should not exceed 2ml.
- volume of injection between 0.5 to 1.5 ml
- poorly perfused with blood.
- to target antineoplastic agents into the lymphatic
Extended duration of action for days, months or years.
Act as circulating depots.
- the drug cannot be easily removed if an undesirable
action is precipitated.
It is described in terms of acute & chronic local inflammatory
Polyhydroxyethyl methacrylate & ethylene vinyl acetate
copolymer were found non-inflammatory.
Polyacrylamide & PVP produced significant inflammation.
Also, polybutylcyanoacrylate, polymerized gelatin & poly
lactic acid caused joint inflammation while polymerized
albumin did not.
It can also be measured in terms of sensitivity reactions &
Major of the sensitivity reactions were caused by implants.
Rough or porous surface of implants is more prone to cause
Biocompatibility can be improved by heparinizing the
Parentral dosage forms
The drug release from the aqueous solutions is controlled in
1) Formulating high viscosity products
- it reduces the diffusion of drug ,thereby delaying
the drug transfer.
examples of viscosity agents: methylcellulose,
2) By complex formation:
- role of plasma protein & tissue binding in prolonging
drug action is well known.
- using the same principle, a dissociable complex of drugs is
formed with MC, Na CMC, PVP for IM administration.
3) by forming complex which controls the release of drug ,
not by dissociation but by decreasing the solubility of parent
e.g.- protamine zinc insulin, cyanocobalamine zinc tannate,
Gives longer duration of action than aqueous solution when
given intramuscularly or subcutaneously.
The drug is continuously dissolving to replenish what is being
Dissolution rate of drug can be described by Noyes-Whitney
dissolution rate= DA ( Cs-C)
where, D- diffusion coefficient
A- surface area available for dissolution
(Cs-C) – difference in conc between diffusion
layer & bulk solution.
h – thickness of diffusion layer.
- formulation parameters that can be changed to obtain the
objective are particle size, diffusion coeff. & concentration to
- These parameters are subject to constraints imposed by
stability, syringeability, pain upon injection.
- Crystalline & stable polymorphs of drug are chosen rather
than amorphous forms for delay release
- Viscosity builders can be used to increase viscosity & reduce
diffusion coeff of drug.
The solid content in the parentral suspensions should fall
between 0.5 and 5%.
To minimize pain & irritation, it is recommended that the
particle size should be below 10µm
Drug release is controlled by partitioning of drug out of oil
into the surrounding aqueous medium.
Vegetable oils like arachis oil, cottonseed oil are used.
Drug release from oil suspensions combines the principles
involved in aqueous suspensions & oil solution.
Suspended particles act as drug reservoir.
The process of drug availability consists of dissolution of drug
particles followed by partitioning of drug from oil solution to
Administered IV in total parentral nutrition.
Fortner et al obtained satisfactory results with IV emulsion of
antineoplastic agent for the treatment of cancer.
Limitations of cancer therapy:
- systemic toxicity on normal replicating cells.
To reduce the drug toxicity, LDL are used as novel carriers for
antineoplastic drugs because of greater uptake and
metabolism of LDL by tumours than normal cells.
1) O/W or W/O emulsions:
- Salk et al found a 10 fold rise in antibody titer using
emulsified influenza vaccine with persistance of high titers
upto 4 years after injection.
- multiple emulsions have been developed to control or
sustain the release the drug. (o/w/o emulsion or w/o/w
- it introduces additional reservoir into which drug can
partition thus effectively retard its release.
- prolongation of action of chemotherapeutic agents like
methotrexate,vinblastine sulfate & bleomycin have been
2) Magnetic emulsions:
- ideal to deliver anticancer agents only to localized tumour
- it describes magnetically responsive o/w emulsion which
localize the drug 1-(2-chloroethyl)-3-(trans-4-methyl
cyclohexyl)-1-nitrosourea i.e. methyl CCNU by magnetic
means to specified target tissues.
- it consists of ethyl oleate based magnetic fluid as dispersed
phase & caesin solution as continous phase.
F) Resealed erythrocytes
The erythrocytes are ruptured by immersing them in
hypotonic solutions & the drug is loaded into it.
The cells are then resealed by restoring the isotonicity &
incubation at 37˚c.
The damaged erythrocytes are removed by liver & spleen
3)Act as circulatory depots
4) protect the entrapped drug from immunological &
Does not require the drug to be chemically modified.
Drug release from these carriers may occur by:
- simple diffusion
- transport out of the cell by some specific
Hydrated liquid crystals formed when phospholipids are
allowed to swell in an aqueous media
Sphingolipids, Glycolipids & Sterols have also been used to
Structurally liposomes are classified as-
1) Multilamellar Vesicles (MLV) :
Made of series of concentric bilayers of lipid enclosing
a small internal volume.
2) Oligolameller Vesicles (OLV):
Consist of 2 to 10 bilayers
3) Unilameller Vesicles (ULV):
Made of single bilayer . It is again classified into
i) Small unilmeller vesicle : 20 to 40 nm
ii) Medium unilameller Vesicle : 40 to 80 nm
iii) Large unilameller vesicle: 100 to 1000 nm
iv) Giant unilameller vesicle : > 1000 nm
Drug such as antineoplastic antibiotics peptides viruses,
bacterias & enzymes can be incorporated in liposomes.
1. Versatality in size & electrical charge
2. Ability to encapsulate both hydrophilic & lipophilic drugs
3. Non Toxicity
4. Protect labile drugs from inactivation in blood by isolating
them from surrounding medium
Product Molecule Year
Amelcet ® Amphotericin B 1995
Doxil/caelyx® Daunorubicin 1995
DaunoXome® Daunorubicin 1996
Amphotec® Amphotericin B 1996
Ambisome® Amphotericin B 1997
Depocyt® cytarabine 1999
These are carrier for drugs & other active molecule in nm
-capable of being stored for a period up to 1 year.
-Can be selectively targeted to liver and to cells that
are active phagocytically.
- Placed subcutaneously to sustain drug release via
the mechanism of drug diffusion, Polymer
dissolution or both.
- Polydimethyl siloxane, a non biodegaradable
polymer deliver drug by simple diffusion at a rate
dependent on drug solubility .
- it includes: i) osmotic pumps
ii) vapour pressure activated system.
a] Alzamer Depot Technology - consist of biodegradable
polymer, solvent & drug particle injected subcutaneously &
drug is released by diffusion.
- Solvents of low water miscibility are used.
b] Atrigel Drug Delivery System
- developed by Dunn & co-workers.
- a drug consists is incorporated in polymer solution. This
drug is then placed into the body using std needles &syringes
- the polymer solution is such that it gets solidified upon
contact with biological fluids.
-Thus, the drug becomes trapped within the polymer matrix
as it solidifies.
Polymers used: polyhydroxyacids, polyorthoesters,
hydrophilic- DMSO, N-methyl-2-pyrrolidone, tetraglycol &
hydrophobic- propylene carbonate, triacetin, ethyl acetate,
benzyl benzoate, etc.
1) Atridox - peridontal treatment product with subgingival
delivery of doxycycline.
2) Eligard- leuprolide acetate for treatment of prostatic
c] Duros implant:
- osmotically driven
e.g. Viadur- leuprolide acetate implant provide zero