Professional Documents
Culture Documents
Controlld Dds PDF
Controlld Dds PDF
Debjit Bhowmik 1*, Harish Gopinath 1, B. Pragati Kumar 1, S. Duraivel 1, K. P. Sampath Kumar 2
Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or
systemically, for a specified period of time. Continuous oral delivery of drugs at predictable and
reproducible kinetics for predetermined period throughout the course of GIT. Controlled release drug
delivery employs drug-encapsulating devices from which therapeutic agents may be released at controlled
rates for long periods of time, ranging from days to months. Such systems offer numerous advantages
over traditional methods of drug delivery, including tailoring of drug release rates, protection of fragile
drugs and increased patient comfort and compliance.
Keyword: Controlled Drug Delivery, High Blood Level, Extended Release, Drug Toxicity
a toxic level, and a minimum value, below which performance when compared with that presented
the drug is no longer effective. as a conventional dosage form (a solution or a
prompt drug-releasing dosage form). The terms
POLYMER USED IN CONTROL DRUG “controlled release (CR)”, “prolonged release”,
DELIVERY SYSTEM “sustained or slow release (SR)” and “long-acting
Polymers are becoming increasingly important in (LA)” have been used synonymously with
the field of drug delivery. The pharmaceutical “extended release”.
applications of polymers range from their use as
binders in tablets to viscosity and flow Nearly all of the currently marketed monolithic
controlling agents in liquids, suspensions and oral ER dosage forms fall into one of the
emulsions. Polymers can be used as film coatings following two technologies:
to disguise the unpleasant taste of a drug, to 1. Hydrophilic, hydrophobic or inert matrix
enhance drug stability and to modify drug release systems: These consist of a rate controlling
characteristics. The review focuses on the polymer matrix through which the drug is
significance of pharmaceutical polymer for dissolved or dispersed.
controlled drug delivery applications.Sixty 2. Reservoir (coated) systems where drug-
million patients benefit from advanced drug containing core is enclosed within a polymer
delivery systems today, receiving safer and more coating. Depending on the polymer used, two
effective doses of the medicines they need to types of reservoir systems are considered.
fight a variety of human ailments, including (a) Simple diffusion/erosion systems where a
cancer. Controlled Drug Delivery (CDD) occurs drug-containing core is enclosed within
when a polymer, whether natural or synthetic, is hydrophilic and/or water-insoluble polymer
judiciously combined with a drug or other active coatings. Drug release is achieved by diffusion of
agent in such a way that the active agent is the drug through the coating or after the erosion
released from the material in a predesigned of the polymer coating.
manner. The release of the active agent may be (b) Osmotic systems where the drug core is
constant over a long period, it may be cyclic over contained within a semi-permeable polymer
a long period, or it may be triggered by the membrane with a mechanical/laser drilled hole
environment or other external events. In any case, for drug delivery. Drug release is achieved by
the purpose behind controlling the drug delivery osmotic pressure generated within the tablet core.
is to achieve more effective therapies while
eliminating the potential for both under and Advantages and Limitations of Control
overdosing. Release Dosage Forms
Clinical Advantages2, 6
Reduction in frequency of drug
CONTROL RELEASE DOSAGE FORM administration
The United States Pharmacopoeia (USP) defines1 Improved patient compliance
the modified-release (MR) dosage form as “the Reduction in drug level fluctuation in
one for which the drug release characteristics of blood
time course and/or location are chosen to Reduction in total drug usage when
accomplish therapeutic or convenience objectives compared with conventional therapy
not offered by conventional dosage forms such as Reduction in drug accumulation with
solutions, ointments, or promptly dissolving chronic therapy
dosage forms”. One class of MR dosage form is Reduction in drug toxicity
an extended-release (ER) dosage form and is (local/systemic)
defined as the one that allows at least a 2-fold Stabilization of medical condition
reduction in dosing frequency or significant
(because of more uniform drug levels)
increase in patient compliance or therapeutic
Potential Limitations
Delay in onset of drug action BIOPHARMACEUTIC AND
Possibility of dose dumping in the case of PHARMACOKINETIC ASPECTS IN THE
a poor formulation strategy DESIGN OF CONTROLLED RELEASE PER
Increased potential for first pass ORAL DRUG DELIVERY SYSTEMS
metabolism
Greater dependence on GI residence time Controlled release drug delivery systems9, 21 are
of dosage form dosage forms from which the drug is released by
Possibility of less accurate dose a predetermined rate which is based on a desired
adjustment in some cases therapeutic concentration and the drug’s
Cost per unit dose is higher when pharmacokinetic characteristics
compared with conventional doses
Biological half-life (t ½ )
Not all drugs are suitable for formulating
The shorter the t ½ of a drug the larger will be the
into ER dosage form
fluctuations between the maximum steady state
concentration and maximum steady state
Selection of drug for formulation into extended
concentration upon repetitive dosing. Thus drug
release dosage form is the key step. Following
product needs to be administered more
candidates are generally not suitable for ER
frequently.
dosage forms
Minimum effective concentration (MEC)
Characteristics That May Make A Drug
If a minimum effective concentration, MEC is
Unsuitable For Control release Dosage Form
required either frequent dosing of a conventional
Short elimination half-life3, 4, 5. drug product is necessary or a controlled release
Long elimination half-life preparation may be chosen.
Narrow therapeutic index
Poor absorption Dose size and Extent of duration
Active absorption The longer the extent of duration the larger the
Low or slow absorption total dose per unit delivery system needs to be.
Extensive first pass effect Hence there is a limitation to the amount of drug
that can be practically incorporated into such a
Control release dosage form Release system.
Formulation Designs
1. Dissolution controlled release8
Relatively long t1/2 or fluctuation desired at at various pH values. If the solubility is less than
steady state 0.1 μg/ml (in acidic medium) one may expect
It is the belief of some that neither a SR nor a variable and reduced bioavailability. If the
CRDDS is needed or useful for drugs having a t solubility is less than 0.01 μg/ml absorption and
½ of 12 hours or more. This is not so because availability most likely become dissolution
there are two cases for which a 12 or 24 CRDDS limited dissolution limited. Hence driving force
seems to be indicated: for diffusion may be inadequate.
1. A drug having a t ½ between 12 and 72 It seems that drugs are well absorbed by passive
hours may be designed for a CRDDS diffusion from the small intestine upon per oral
permitting application for every two to administration if at least 0.1 to 1% is non ionised
three days. The decline of the blood level form.
time curve after release of the drug from
the system will depend on the drug’s t ½. Apparent partition coefficient (APC)
Naturally, fluctuation between Css max Drugs being absorbed by passive diffusion must
and Css min may accordingly be have a certain minimal APC. The higher the APC
relatively large in other words on adds in an n-octanol/buffer system the higher is the
slow release to the slow elimination flux across a membrane for many drugs. The
process. APC should be determined for the entire pH
range in the GI tract. The APC must also be
For some drugs having a t1/2 between 20 and 100 applied for partition of the drug between CRDDS
hrs ,and which are intended for long term use and the biological fluid.
,one may desire small fluctuations between peaks
and troughs at steady General absorption mechanism
For a drug to be a variable candidate for per oral
2. states either to achieve a certain CRDDS, its absorption mechanism must be by
therapeutic effect or because the diffusion throughout the entire GI tract. The term
therapeutic range is narrow. diffusion here refers to the dual pathway of
absorption either by partitioning into the lipid
DESIRED BIOPHARMACEUTIC membrane (across the cells) or by passing
CHARACTERISTICS OF DRUG TO through water filled channels (between the cells).
QUALIFY FOR CDDS It is also important that absorption occurs from all
segments of the GI tract which may depend on
Molecular weight or size the drug’s pKa, the pH in the segment, binding of
Small molecules may pass through pores of a drug to mucus, blood flow rate, etc. The
membrane by convective transport. This applies absorption process seems to be highly dependent
to both, the drug release from the dosage form on the hydrodynamics in the GI lumen.
and the transport across a biologic membrane. For
biologic membranes the limit may be a molecular Even though that first order and square root of
weight of 150 and 400 respectively for spherical time release can result in highly effective drug
molecules and chain like compounds delivery systems it is widely believed that the
respectively. ultimate goal is zero order release profile.
homogeneous with respect to absorption, and (2) concentration as that found in blood. It is the
drug release rate is the rate limiting step in the proportionality constant relating the amount of
absorption process. drug in the body to the measured concentration in
the blood.
With first order release on the other hand, smaller
and smaller amounts are released per unit of time Among the trio CL, Vz, and t ½, the former two
with increasing time. Assuming that rate of parameters are the independent variables and the
absorption gets slower past the small intestine last one is the dependent variable.
due to increased viscosity, decreased mixing, and The Vz or CL is required to predict the
decreased intestinal surface area, less drug is concentration time profile.
absorbed.
Absolute bioavailability (F)
In any case, the drug release from the CRDDS The absolute bioavailability is the percentage of
should not be influenced by pH changes within drug taken up into systemic circulation upon
the GI tract, by enzymes present in the lumen, extravascular administration. For drugs to be
peristalsis, etc suitable for CRDDS one wants an F value to be
close to 100%.
For all practicality, the one compartment open
model is quite suitable to design CRDDS for Intrinsic absorption rate constant (Ka)
most drugs. The intrinsic absorption rate constant of the drug
administered peroral in the form of a solution
Pharmacokinetic parameters should be high, generally by an order of
Elimination half life (t ½) magnitude higher than the desired release rate
Drugs having a t ½ and 8 hours are ideally suited constant of the drug from the dosage form, in
for CRDDS. If the t ½ is less than 1 hour the dose order to insure that release process is the rate
size required to be incorporated for a 12 hour or controlling step.
24 hour duration dosage form may be too large. If
the t ½ is very long there is usually no need for a Therapeutic concentration (Css)
CRDDS, unless it is simply intended for a The therapeutic concentrations are the desired or
reduction in fluctuation of steady state blood target steady state peak concentrations (Css max),
levels. the desired or target steady state minimum
concentrations (Css min), and the mean steady
Total clearance (CL) state concentration (Css avg). The difference
CL is a measure of the volume of distribution between Css max and Css min is the fluctuation.
cleared of drug per unit of time. It is the key The smaller the desired fluctuation the greater
parameter in estimating the required dose rate for must be the precision of the dosage form
CRDDS, and predicting the steady state performance.
concentration.
The lower Css, the smaller Vz, the longer t ½, the
Terminal disposition rate constant (Ke or λz) higher F and The less amount of drug is required
The terminal disposition rate constant or to be incorporated into a CRDDS.
elimination rate constant can be obtained from
the t ½ and is required to predict a blood level
time profile. POLYMERS AS BIOMATERIALS FOR
DELIVERY-SYSTEMS
Apparent volume of distribution (Vz) A range of materials have been employed to
The Vz is the hypothetical volume of a drug control the release of drugs and other active
would occupy if it were dissolved at the same agents. The earliest of these polymers were
originally intended for other, nonbiological uses, Originally, polylactides and polyglycolides were
and were selected because of their desirable used as absorbable suture material, and it was a
physical properties, for example: natural step to work with these polymers in
controlled drug delivery systems. The greatest
Poly(urethanes) for elasticity. advantage of these degradable polymers is that
Poly(siloxanes) or silicones for insulating they are broken down into biologically acceptable
ability. molecules that are metabolized and removed from
Poly(methyl methacrylate) for physical the body via normal metabolic pathways.
strength and transparency. However, biodegradable materials do produce
Poly(vinyl alcohol) for hydrophilicity and degradation by-products that must be tolerated
strength. with little or no adverse reactions within the
Poly(ethylene) for toughness and lack of biological environment.
swelling.
Poly(vinyl pyrrolidone) for suspension These degradation products both desirable and
capabilities. potentially nondesirable must be tested
thoroughly, since there are a number of factors
To be successfully used in controlled drug that will affect the biodegradation of the original
delivery formulations, a material must be materials. The various important factors
chemically inert and free of leachable impurities. indicating the breadth of structural, chemical, and
It must also have an appropriate physical processing properties that can affect
structure, with minimal undesired aging, and be biodegradable drug delivery systems are listed
readily processable. Some of the materials that below:
are currently being used for controlled drug
delivery include Chemical structure
Chemical composition
Poly(2-hydroxy ethyl methacrylate) Distribution of repeat units in multimers
Poly(N-vinyl pyrrolidone). Presence of ionic groups
Poly(methyl methacrylate). Presence of unexpected units or chain
Poly(vinyl alcohol). defects.
Poly(acrylic acid). Configuration structure.
Polyacrylamide. Molecular weight.
Poly(ethylene-co-vinyl acetate). Molecular-weight distribution.
Poly(ethylene glycol). Morphology (amorphous/semi crystalline,
Poly(methacrylic acid). microstructures, residual stresses).
Presence of low-molecular-weight
However, in recent years additional polymers compounds.
designed primarily for medical applications have Processing conditions.
entered the arena of controlled release. Many of Annealing.
these materials are designed to degrade within the Sterilization process.
body, few of them among these include: Storage history.
Shape.
Polylactides (PLA). Site of implantation.
Polyglycolides (PGA). Adsorbed and absorbed compounds
Poly(lactide-co-glycolides) (PLGA). (water, lipids, ions, etc.).
Polyanhydrides. Physicochemical factors (ion exchange,
Polyorthoesters. ionic strength, pH).
Physical factors (shape and size changes,
variations of diffusion coefficients,
CONLUSION
The best new therapeutic entity in the world is of
little value without an appropriate delivery
system. Tablet delivery system can range from
simple immediate release formulations to
complex extended or modified release dosage
forms. The most important role of drug delivery
system is to get the drug delivered to the site of
action in sufficient amount & at the appropriate
rate. However it should meet other important
criteria such as physical & chemical stability,
ability to be mass-produced in a manner that
assures content uniformity.
REFERENCE
3. Howard C. Ansel, NIcholos G. Popvich,
lyold V. Allen , pharmaceutical dosage
forms and Drug Delivery system. 1st ed.;
1995.p.78.
4. Jain N.K and Sharma S.N. A text book of
professional pharmacy. 1st ed.; 1995.p.78.
5. Samuel Harder and GlennV. Buskirk.
Pilot Plant Scale-Up Techniques. In The
Theory and Practice of Industrial
Pharmacy. 3rd ed., 1991, p. 687-702
6. Remington, “The Science and Practice of
pharmacy”, 20 th Edn, vol.I, pg.no.903-
913.
7. Lachman et al Theory and Practice of
Industrial Pharmacy. 3rd ed Philadelphia,
1991, p. 303-314.
8. Lachman et al Theory and Practice of
Industrial Pharmacy. 3rd ed Philadelphia,
1991, p. 314-317.
9. Lachman, L.; Lieberman, H. A.; Kanig J.
L. Eds.; Theory and Practice of Industrial
Pharmacy. 3rd ed Philadelphia, 1991, p.
346-373.
10. Lutfi Genç, Hadi Bilaç and Erden Güler
Preparation of controlled release dosage
forms of diphenhydramine was prepared
with different polymers. International
Journal of Pharmaceutics, Volume 169,
Issue 2, 15 July 1998, Pages 232-235.