Oral drug delivery system (ODDS)

Oral Drug Delivery Systems
Mr. Sagar Kishor Savale
[Department of Pharmaceutics]
avengersagar16@gmail.com
2015-016
Department of Pharmacy (Pharmaceutics) | Sagar savale
28/05/2016 1SAGAR SAVALE

Contents
 Drug Delivery Systems (DDS)
 Sustained and Controlled Release Drug Delivery System (SRDDS & CRDDS)
 Continuous Release System (CRS)
 Delayed Transit & Continuous Release System (Gastroretentive DDS)
 Pulsatile Drug Delivery System (PDDS)
 Delayed Release Systems: (Intestinal specific and Colon Specific)

DRUG: Drug is any substance is intended is used as orally applied a topically for the purpose of used of mitigation, treatment,
prevention, cure and Diagnosis of disease and disorder and maintain the good quality of health is known has Drug.
DOSAGE FORM - Dosage forms are the means by which drug molecules are delivered to sites of action within the body.
Drug Active pharmaceutical + Excipients
ingredient (API)
DRUG DELIVERY SYSTEMS
The system to deliver the drug to the body to produced desired therapeutic action and activity against diseases and disorders is
known as Drug delivery system.
TYPES OF DRUG DELIVERY SYSTEM
1. Conventional Drug Delivery System
2. Oral Drug Delivery System
3. Sustained Drug Delivery System
4. Controlled Drug Delivery System
5. Targeted Drug Delivery System

Plasma concentration Curve

Plasma concentration time profile (Sustained Release Drug)

HISTORY
The history of controlled release technology is divided into three time periods
 From 1950 to 1970 was the period of sustain drug release
 From 1970 to 1990 was involved in the determination of the needs of the control drug delivery
 Post 1990 modern era of controlled release technology
INTRODUCTION
In the conventional therapy aliquot quantities of drugs are introduced into the system at specified intervals of time with the result
that there is considerable fluctuation in drug concentration level as indicated in the figure.
HIGH HIGH
LOW LOW

However, an ideal dosage regimen would be one, in
which the concentration of the drug, nearly coinciding
with minimum effective concentration (M.E.C.), is
maintained at a constant level throughout the treatment
period. Such a situation can be graphically represented
by the following figure
CONSTANT LEVEL
Plasma Profile of different dosage

Different Order Release pattern
Drug levels in the blood with
(a) Traditional drug dosing- the
level rises after each
administration of the drug
and then decreases until the
next administration
(b) Controlled-delivery dosing

Sustain Release Drug Delivery System
Definition: “Drug Delivery system that are designed to achieve prolonged therapeutic effect by continuously releasing
medication over an extended period of time after administration of single dose” is known as Sustained drug Delivery system.
 The basic goal of therapy is to achieve steady state blood level that is therapeutically effective and non toxic for an extended
period of time.
 The design of proper dosage regimen is an important element in accomplishing this goal.
Controlled Release Drug Delivery System
Definition: “Drug Delivery System in which maintain constant level of drug in blood and tissue in extended period of time” is
known as Controlled release system.
 Delivers the drug at a pre determined rate for a specified period of time
 Controlled release is perfectly zero order release that is the drug release over time irrespective of concentration.

Sustained release Drug Delivery System Controlled release Drug Delivery System
“Drug Delivery system that are designed to achieve prolonged
therapeutic effect by continuously releasing medication over an
extended period of time after administration of single dose” is
known as Sustained drug Delivery system.
“Drug Delivery System in which maintain constant level of drug
in blood and tissue in extended period of time” is known as
Controlled release system.
Slow release of drug in extended period of time Maintain constant level of drug in Prolonged Period of Time
First order Kinetic Process Zero order kinetic Process
Drug release is based on concentration Drug release is not concentration dependent
It is not site specific delivery of drug It is having site specific delivery of drug
It is reproducible and re-predictable It is Producible and Predictable
Differences between sustained and controlled Release drug delivery system

Synonyms of Sustained & Controlled release drug delivery system
 Slow release DDS
 Programmed Release
 Timed release
 Repository Dosage Forms
 Prolonged Release
 Extended Release
 Depot Formulations
 Delayed release
 Modified release
 Targeted drug delivery
Objective of SR/ CR DDS
To control the drug delivery to ensure safety and enhance
efficacy of drug with improved patient compliance.

Concept of sustained release formulation
Mechanism: The Concept of sustained release formulation can be divided in to two considerations i.e. release rate & dose
consideration
A] Release rate consideration: In conventional dosage form Kr>Ka in this the release of drug from dosage form is not rate
limiting step.
The above criteria i.e. (Kr>Ka) is in case of immediate release, where as in non immediate (Kr<Ka) i.e. release is rate limiting
step.
So that effort for developing S.R.F must be directed primarily altering the release rate. the rate should be independent of drug
removing in the dosage form over constant time.
The release rate should follow zero order kinetics
Kr = rate in = rate out = KeVd.Cd
Where, Ke = overall elimination (first order kinetics), Vd = total volume of distribution, Cd = desired drug concentration.

B] Dose consideration
To achieve the therapeutic level & sustain for a given period of time for the dosage form generally consist of 2 part
1. Initial (primary) dose 2. Maintenance dose
Therefore the total dose ‘W’ can be.
W = Di + Dm
In a system, the therapeutic dose release follows zero order process for specified time period then,
W= Di + K0 r. Td
Td = time desired for sustained release from one dose.
If maintenance dose begins to release the drug during dosing t=O then,
W = Di + K0 r Td – K0 r Tp
Tp = time of peak drug level.
However a constant drug can be obtained by suitable combination of Di & Dm that release the drug by first order process, then
W = Di + ( Ke Cd /Kr ) Vd

 Sustained release, sustained action, prolonged action, controlled release, extended action, time release dosage
formed are terms used to identify drug delivery system that are designed to achieve a prolonged therapeutic effect
by continuously releasing medication over an extended period of time after administration of single dose.
 In case of injectable dosage form, this period may vary from days to month, in case of orally administrated
forms, however, this period is measured in hours & critically depends on the residence time of the dosage form in
GI tract.
 In some case, control of drug therapy can be achieved by taking advantage of beneficial drug interaction that
affect drug disposition and elimination. E.g.:- the action of Probenecid, which inhibit the excretion of penicillin,
thus prolonging it’s blood level. Mixture of drug might be utilized to attend, synergize, or antagonize given drug
action.
 Sustained release dosage form design embodies this approach to the control of action i.e. through a process of
either drug modification, the absorption process, and subsequently drug action can be controlled.

Repeat-action versus sustained-action drug therapy
 A repeat-action tablet may be distinguished from its sustained-
release product by the release of the drug in slow controlled
manner and consequently does not give a plasma concentration
time curve which resemble that of a sustained release product.
 A repeat action tablet usually contains two dose of drug; the
1st being released immediately following oral administration in
order to provide a repeat onset of therapeutic response. The
release of second dose is delayed, usually by means of an
enteric coat.
 Consequently, when the enteric coat surrounding the second
dose is breached by the intestinal fluid, the second dose is
release immediately.
 figure shows that the plasma concentration time curve obtained
by the administration of one repeat- action preparation exhibit
the “PEAK & VALLY”. Profile associated with the
intermittent administration of conventional dosage forms.
 The primary advantage provide by a repeat-action tablet over a
conventional one is that two (or occasionally three) doses are
administration without the need to take more than one tablet.

Difficulties arise in maintaining the drug concentration in the therapeutic range
Patient incompliance due to increase frequency of dosing, therefore chances of missing the dose of the drugs with short half
life.
Difficulty to attain steady state drug concentration.
Fluctuation may lead to under medication or over medication.
These difficulties may be overcome by
Developing the new better and safer drug with long half life & large therapeutic indices.
Effective and safer use of existing drugs through concept and techniques of controlled and targeted drug delivery.

Advantages of Sustained and Controlled Release drug delivery System
Improved patient convenience and compliance due to less frequent drug administration.
Reduction in fluctuation in steady-state level and therefore better control of disease condition.
Increased safety margin of high potency drug due to better control of plasma levels.
Maximum utilization of drug enabling reduction in total amount of dose administered.
Reduction in health care cost through improved therapy, shorter treatment period.
Less frequency of dosing and reduction in personnel time to dispense, administer monitor patients.
Better control of drug absorption can be obtained, since the high blood level peaks that may be observed after administration
of a dose of high availability drug can be reduced.

Disadvantages of Sustained and Controlled release drug delivery System
Decreased systemic availability in comparison to immediate release conventional dosage forms; this may be due to incomplete
release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site specific
absorption, pH dependent solubility etc.,
Poor in-vivo, in-vitro correlation.
Possibility of dose dumping due to food, physiologic or formulation variable or chewing or grinding of oral formulation by the
patient and thus increased risk of toxicity.
Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reaction.
The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form design.
Sustained release forms are designed for the normal population i.e. on the basis of average drug biologic half-life’s.
Consequently disease states that alter drug disposition, significant patient variation and so forth are not accommodated.
Economics factors must also be assessed, since more costly processes and equipment are involved in manufacturing many
sustained release forms.

CHARACTERITICS OF DRUG FOR FORMULATION AS SUSTAINED RELEASE
DOSAGE FORM
Drug should exhibit neither very fast rate of absorption nor excretions:
Drug with slower rate of absorption and excretion are usually inherently long acting and their formulation in SRDF is not
necessary, as they remain longer time in the body.
e.g.- Diazepam and Phenytoin
Drug with short half life less then 2 hrs. are difficult to formulate as system requires a larger unit dose size and may contribute to
patient complains problem and also difficult to control the release rate of drug.
Drug should be uniformly absorbed throughout GI tract:
Drug that are absorbed poorly and at unpredictable rate are not good candidate for SRDF because there release rate and absorption
are depending on the position of drug in the GI tract and rate movement of drug.
e.g.- Riboflavin is not absorbed in GI tract.
They should require relatively small doses:
Some drug like sulfonamide require larger dose for therapeutic activity so this kind of drug are difficult to form in SRDF as unit
dose increases to an extent where it is difficult to swallow by patient.
•They should have good margin of safety i.e. that their therapeutic index should be relative range.
•The drug should not show any cumulative action, any undesired side effect as in case of dose dumping it might produce toxicity.28/05/2016 19SAGAR SAVALE

DRUG Selection Crate Area for Sustained and Controlled Release System

Drug properties relevant to sustained release formulation
 The design of sustained release delivery system is subjected to several variables and each of variables are inter-related.
 For the purpose of discussion it is convenient to describe the properties of the drugs as being either Physico-chemical or
biological ,these may be divided in two types:
1. Physicochemical properties
2. Biological properties
Factors to be considered In SR & CR Dosage Forms
1.Biological Factors
1. Absorption
2. Distribution
3. Metabolism
4. Biological half life (excretion)
5. Margin of safety
2. Physiological Factors
1. Dosage size
2. Partition coefficient and molecular size Aqueous
Solubility
3. Drug stability
4. Protein binding
5. pka28/05/2016 21SAGAR SAVALE

Physiological Factors
 In general a single dose of 0.5 - 1.0 gm is considered for a conventional dosage form this also holds for sustained release
dosage forms.
 If an oral product has a dose size greater that 500mg it is a poor candidate for sustained release system, Since addition of
sustaining dose and possibly the sustaining mechanism will, in most cases generates a substantial volume product that
unacceptably large.
Dosage size
Partition coefficient and molecular size
When the drug is administered to the GIT ,it must cross a variety of biological membranes to produce therapeutic effects in another
area of the body. It is common to consider that these membranes are lipidic, therefore the Partition coefficient of oil soluble drugs
becomes important in determining the effectiveness of membranes barrier penetration. Partition coefficient is the fraction of drug
in an oil phase to that of an adjacent aqueous phase. High partition coefficient compound are predominantly lipid soluble and
have very low aqueous solubility and thus these compound persist in the body for long periods. Partition coefficient and
molecular size influence not only the penetration of drug across the membrane but also diffusion across the rate limiting
membrane. The ability of drug to diffuse through membranes its so called diffusivity & diffusion coefficient is function of
molecular size (or molecular weight). Generally, values of diffusion coefficient for intermediate molecular weight drugs, through
flexible polymer range from 10-8 to 10-9 cm2 / sec. with values on the order of 10-8 being most common for drugs with molecular
weight greater than 500.

Thus high molecular weight drugs or polymeric drugs should be expected to display very slow release kinetics in sustained release
device using diffusion through polymer membrane. Phenothiazine's are representative of this type of compound
Aqueous Solubility
Since drugs must be in solution before they can be absorbed, compounds with very low aqueous solubility usually suffer oral
bioavailability Problems, because of limited GI transit time of undissolved drug particles and limited solubility at the absorption
site. E.g.: Tetracycline dissolves to greater extent in the stomach than in the intestine, there fore it is best absorbed in the intestine.
Most of drugs are weak acids or bases, since the unchanged form of a drug preferentially permeates across lipid membranes
drugs aqueous solubility will generally be decreased by conversion to an unchanged form. for drugs with low water solubility will
be difficult to incorporate into sustained release mechanism.
Aqueous solubility and pKa
These are the most important to influence its absorptive behavior and its aqueous solubility ( if it’s a weak acid or base) and its
pKa
The aqueous solubility of the drug influences its dissolution rate which in turn establishes its concentration in solution and hence
the driving force for diffusion across the membranes as shown by Noye’s Whitney’s equation which under sink condition that
is
dc/dt= Kd.A.Cs
Where, dc/dt = dissolution rate, Kd= dissolution rate constant, A = total surface area of the drug particles, Cs= aqueous
solubility of the drug

Dissolution rate (dc/dt) is constant only when Surface Area A is the initial rate is directly proportional to the Aqueous solubility
(Cs) hence Drug with low aqueous solubility have low dissolution rate and its suffer low bioavailability problem.
The aqueous solubility of weak acid and bases are controlled by pKa of the compound and pH the medium.
For weak acids
St= So(1+Ka/H+) = So (1+10pH-pKa )
Where St = total solubility of weak acid.
So = solubility of unionized form
Ka= Acid dissociation constant
H+= H ion concentration
Similarly for Weak Bases
St = So (1+H+/Ka) = So (1+10pKa-pH )
if a poorly soluble drug was consider as a suitable candidate for formulation into sustained release system.
Since weakly acidic drugs will exist in the stomach pH 1-2 , primarily in the unionized form their absorption will be favored from
this acidic environment on the other hands weakly basic drugs will be exist primarily in the ionized form (Conjugate Acids) at the
same site, their absorption will be poor.
in the upper portion of the small intestine the pH is more alkaline
pH 5-7 and the reverse will be expected for weak acids28/05/2016 24SAGAR SAVALE

Drug stability
The stability of drug in environment to which it is exposed, is another physico-chemical factor to be considered in design at
sustained/ controlled release systems, drugs that are unstable in stomach can be placed in slowly soluble forms or have their
release delayed until they reach the small intestine.
Orally administered drugs can be subject to both acid, base hydrolysis and enzymatic degradation. Degradation will proceed
at the reduced rate for drugs in the solid state, for drugs that are unstable in stomach, systems that prolong delivery ever the entire
course of transit in GI tract are beneficial.
Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered form a
sustaining dosage from. This is because more drug is delivered in small intestine and hence subject to degradation.
However for some drugs which are unstable in small intestine are under go extensive Gut –Wall metabolism have decreased the
bio availability .
When these drugs are administered from a sustained dosage form to achieve better bio availability, at different routes of the
drugs administered should be chosen
Eg. Nitroglycerine
The presence of metabolizing enzymes at the site or pathway can be utilized.

Protein binding
It is well known that many drugs bind to plasma protein with the influence on duration of action.
Drug-protein binding serve as a depot for drug producing a prolonged release profile, especially it is high degree of drug
binding occurs.
Extensive binding to plasma proteins will be evidenced by a long half life of elimination for drugs and such drugs generally
most require a sustained release dosage form. However drugs that exhibit high degree of binding to plasma proteins also might
bind to bio-polymers in GI tract which could have influence on sustained drug delivery. The presence of hydrophobic moiety
on drug molecule also increases the binding potential.
The binding of the drugs to plasma proteins(Eg. Albumin) results in retention of the drug into the vascular space the drug
protein complex can serves as reservoir in the vascular space for sustained drug release to extra vascular tissue but only for those
drugs that exhibited a high degree of binding.
The main force of attraction are Wander- vals forces , hydrogen binding, electrostatic binding.
In general charged compound have a greater tendency to bind a protein then uncharged compound, due to electrostatic effect.
Eg. amitriptyline, cumarin, diazepam, digoxide, dicaumarol, novobiocin.

Pka: (dissociation constant)
The relationship between Pka of compound and absorptive environment, Presenting drug in an unchanged form is
adventitious for drug permeation but solubility decrease as the drug is in unchanged form.
An important assumption of the there is that unionized form of the drug is absorbed and permeation of ionized drug is negligible,
since its rate of absorption is 3-4 times lesser than the unionized form of the drug.
The pka range for acidic drug whose ionization is PH sensitive and around 3.0- 7.5 and pka range for basic drug whose ionization
is pH. sensitive around 7.0- 11.0 are ideal for the optimum positive absorption
Biological Factors
Absorption
Absorption of drug need dissolution in fluid before it reaches to systemic circulation. The rate, extent and uniformity in absorption
of drug are important factor when considering its formulation in to controlled release system. Absorption= dissolution. The
characteristics of absorption of a drug can be greatly effects its suitability of sustained release product. The rate of release is much
slower than rate of absorption. The maximum half-life for absorption should be approximately 3-4 hrs. otherwise, the device
will pass out of potential absorptive region before drug release is complete. Compounds that demonstrate true lower absorption
rate constants will probably be poor candidates for sustaining systems.

The rate, extent and uniformity of absorption of a drug are important factors considered while formulation of sustained release
formulation. As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than
absorption. It we assume that transit time of drug must in the absorptive areas of the GI tract is about 8-12 hrs. If the rate of
absorption is below 0.17/hr and above the 0.23/hr then it is difficult to prepare sustained release formulation. an another important
criteria is the through absorption of drug in GIT tract, drug like Kanamycin and gentamycin shows absorption are different sites,
Riboflavin like drug absorbed effectively by carrier transport and at upper part of GIT that make it preparation in SRDF difficult.
As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than absorption.
Rapid rate of absorption of drug, relative to its release is essential if the system is to be successful.
Distribution
The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. Since it not only lowers the
concentration of drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently
apparent volume of distribution assumes different values depending on time course of drug disposition. For design of sustained/
controlled release products, one must have information of disposition of drug. Two parameters that are used to describe
distribution characteristics are its apparent volume of distribution and the ratio of drug concentration in tissue that in plasma at the
steady state the so- colled T/P ratio. The apparent volume of distribution Vd is nearly a proportional constant that release drug
concentration in the blood or plasma to the amount of drug in the body. In case of one compartment model
Vd = dose/C0
Where:
C0= initial drug concentration immediately after an IV bolus injection
In case of two compartment model.

Vss = (1+K12/K21)/V1
Where, V1= volume of central compartment, K12= rate constant for distribution of drug from central to peripheral, K21= rate
constant for distribution of drug from peripheral to central, Vss= estimation of extent of distribution in the body. Vss results
concentration in the blood or plasma at steady state to the total mount of the drug present in the body during respective dosing or
constant rate of infusion. Equation 2 is limited to those instance where steady state drug concentration in both the compartment has
been reached. At any other time it tends to overestimate or underestimate. To avoid ambiguity inherent in the apparent volume of
distribution as an estimation of the amount of drug in the body. The T/P ratio is used.
The amount of drug in the body can be calculated by T/P ratio as given bellow.
T/P = K12 (K21-β)
Where, β = slow deposition constant, T= amount of drug in peripheral.
Metabolism
There are two areas of concern relative to metabolism that significantly restrict sustained release formulation:
If drug upon chronic administration is capable of either inducing or inhibition enzyme synthesis it will be poor candidate for
sustained release formulation because of difficulty of maintaining uniform blood levels of drugs. If there is a variable blood level
of drug through a first-pass effect, this also will make preparation of sustained release product difficult. Drug that are
significantly metabolized before absorption, either in lumen of intestine, can show decreased bio-availability from slower-
releasing dosage forms. Most intestinal wall enzymes systems are saturable. As drug is released at a slower rate to these regions
less total drug is presented to the enzymatic. Process device a specific period, allowing more complete conversion of the drug to its
metabolite.

Biological half life
The usual goal of sustained release product is to maintain therapeutic blood level over an extended period, to this drug must
enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by
the half-life (t1/2)
Therapeutic compounds with short half life are excellent candidates for sustained release preparation since these can reduce
dosing frequency.
Drugs with half-life shorter than 2 hours. Such as e.g.: Furosemide, levodopa are poor for sustained release formulation because
it requires large rates and large dose compounds with long half-life. More than 8 hours are also generally not used in sustaining
forms, since their effect is already sustained.
E.g.; Digoxin, Warfarin, Phenytoin etc.
Margin of safety
In general the larger the volume of therapeutic index safer the drug. Drug with very small values of therapeutic index usually are
poor candidates for SRDF due to pharmacological limitation of control over release rate .e.g.- induced digtoxin, Phenobarbital,
phenytoin.
= TD50/ED50
Larger the TI ratio the safer is drug.
It is imperative that the drug release pattern is precise so that the plasma drug concentration achieved in under therapeutic range.

28/05/2016 SAGAR SAVALE 31
Evaluation of Sustained and controlled drug delivery system
1. Physical Appearance or Morphological studies
2. Hardness
3. Thickness
4. Friability
5. Weight variation
6. Tablet density
7. Drug Content
8. In – vitro drug release
9. Kinetic model
10. In – vivo studies: (Pharmacokinetic, Pharmacodynamics)
11. Ragio selective studies
12. Ex- vivo Studies
13. Diffusion Studies (in vitro, in vivo, ex Vivo)
14. Stability or Accelerated Stability Studies
15. Bioadesion and Mucoadesion test
16. In vitro – in vivo studies (IVIVC)

Classification of oral sustained/controlled released system
Mechanism: it is based on Drug Release

Continuous Release Oral Drug Delivery System
This system release the drug for a prolonged period of time along the entire length of GI tract with normal transit of dosage form.
There are various systems under this class as follows:
 Dissolution controlled release systems
 Diffusion controlled release systems
 Dissolution and diffusion controlled release system
 Ion exchange resin drug complexes
 Slow dissolving salts and complexes
 pH independent formulation
 Osmotic pressure controlled systems
 Hydrodynamic pressure controlled systems

Dissolution Controlled Release Systems
Solid substances solubilizes in a given solvent.
Mass transfer from solid to liquid.
Rate determining step: Diffusion from solid to liquid.
Several theories to explain dissolution –
Diffusion layer theory (imp)
Surface renewal theory
Limited solvation theory.
Noyes Whitney Equation
dc/dt = kD.A (Cs – C )
dc/dt = D/h A. (Cs – C)
dc/dt = Dissolution rate.
k= Dissolution rate constant (1st order).
D = Diffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. Of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.

Matrix Type
Soluble drug
Slowly dissolving matrix
Also called as Monolith dissolution controlled system.
Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
First order drug release.
Drug release determined by dissolution rate of polymer.
Examples: Dimetane extencaps, Dimetapp extentabs.
Encapsulation
Soluble drug
Slowly dissolving or
erodible coat
Called as Coating dissolution controlled system.
Dissolution rate of coat depends upon stability & thickness of
coating.
Masks Colour, Odour, taste, minimizing GI irritation.
One of the microencapsulation method is used.
Examples: Ornade spansules, Chlortrimeton Repetabs

Diffusion Controlled Release Systems
 Major process for absorption.
 No energy required.
 Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attained.
 Directly proportional to the concentration gradient across the membrane.
Matrix Diffusion Types
A] Rigid Matrix Diffusion: Materials used are insoluble plastics such as PVP & fatty
acids.
B] Swellable Matrix Diffusion: 1. Also called as Glassy hydrogels. Popular for sustaining the release of highly water soluble
drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum, Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL Rate controlling step: Diffusion of dissolved drug in matrix28/05/2016 37SAGAR SAVALE

Reservoir System
Also called as Laminated matrix device.
Hollow system containing an inner core surrounded in water insoluble membrane.
Polymer can be applied by coating or micro encapsulation.
Rate controlling mechanism - partitioning into membrane with subsequent release into surrounding fluid by diffusion.
Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate.
Examples: Nico-400, Nitro-Bid
Rate controlling steps : Polymeric content in coating, thickness
of coating, hardness of microcapsule.

Dissolution & Diffusion Controlled Release system
 Drug encased in a partially soluble membrane.
 Pores are created due to dissolution of parts of
membrane.
 It permits entry of aqueous medium into core & drug
dissolution.
 Diffusion of dissolved drug out of system.
 Ex- Ethyl cellulose & PVP mixture dissolves in water
& create pores of insoluble ethyl cellulose membrane
Insoluble membrane
Entry of dissolution fluid
Drug diffusion
Pore created by dissolution of soluble fraction of membrane

Ion-exchange resin-drug complexes
Controlled delivery of ionizable ACIDIC and BASIC drugs can be obtained by COPLEXATION to insoluble
nontoxic anionic or cationic resin.
 Drug is released slowly by diffusion through the resin particle structure. It can be understand by following reaction
NH2R’ + RSO3H RSO-
3NH3
+ R’
RSO-
3NH3
+ R’ + A+B- RSO-
3A+ + NH3 + R’ B-
Drug + Resin Drug – Resin Complex
Resin Complex + A+B- Drug + Resin
Where A+B- are ionic compounds in the GI tract such as gastric HCl/intestinal NaCl

Slow dissolving salts and complexes
Salt and complexes of drugs i.e. slowly soluble in the GI fluid can be used for controlled release of the active principle.
Eg : like Amine drugs reacted with Tannic acid they form poorly soluble complexes.

pH-Independent Formulations
Drug is designed that its dissolution is independent of environmental pH of GI tract.
 To make the drug pH resistant sufficient amount of buffering agent is used.
The dosage form containing drug and buffer is coated with permeable substance that allow entry of aqueous medium but
prevent dispersion of tablet.
Osmotic Pressure Controlled Drug Delivery System
Osmosis: Movement of solvent from lower to higher concentration, The passage of solvent into a solution through semipermeable membrane.
Semipermeable Membrane: Molecules are permitted only to one component (Water).
Osmotic pressure: It is the hydrostatic pressure produced by a solution in a space divided by a semipermeable membrane due to difference in
concentration of solutes. (The pressure is exerted in the walls of semipermeable membrane is known as Osmotic Pressure)
Provides zero order release
Drug may be osmotically active, or combined with an osmotically active salt (e.g., NaCl).

 Semipermeable membrane usually made from cellulose acetate.
 More suitable for hydrophilic drug.
 Examples: Glucotrol XL, Procardia XL,
 In osmotic controlled release system in case of Parenteral Nacl isotonic solution is act has a osmogen.
 In case of oros tablet Kcl and Mannitol is act has osmogen, this osmogen is responsible for osmotic pressure.
 It is mainly applicable for solids.

Hydrodynamic Pressure Controlled Systems
 Hydrodynamic pressure generated by swelling of a hydrophilic gum (PHAMA Polymer is responsible for Hydrostatic Pressure)
 The device comprises of a rigid, shape retaining housing enclosing a collapsible, impermeable containing liquid drug
 The gun imbibes water in GIT through an opening at the lower side of external housing and swells creating an hydrodynamic
pressure
 The pressure thus created squeeze the collapsible drug reservoir to release the medicament through the delivery orifice
Fig : HYDRODYNAMIC PRESSURE CONTROL SYSTEM28/05/2016 50SAGAR SAVALE

Some Popular Brand names
used for OCDDS
 Spansule capsule (SK & F)
 Sequal capsule (Lederle)
 Extentab tablets (Robins)
 Timespan tablet (Roche)
 Dospan tablet (Merrell Dow)
 Chronotab tablet (Schering)
 Plateau capsule (Marion)
 Tempule capsule (Armour)
Some Examples of OCDDS
 Propranolol (Inderal LA)
 Methyiphenidate HCl (RitalinSR)
 Iron (Slow-Fe)
 GITS- Prazosin (Minipress)
 Morphine sulfate (Roxanol SR)
 Potassium (Micro-K, Slow-K, Klotrix)
Recent Trends : Extended release
formulation of Bupropion
 Bupropion is used in the treatment of major
depressive disorder.
 Conventional formulation has to be
administered 3 times daily.
 Initially 150 mg ER formulation was introduced
for bid regimen. Later on 300 mg ER
formulation was introduced for once daily
regimen
 For ER formulation provide similar Cmax and
AUC values as compared to immediate release
formulation at steady state.
Recent Trends : Extended release formulation of Bupropion28/05/2016 51SAGAR SAVALE

Marketed drug product
Composition of tablet Product name Manufacture
Carbamazepine Zenretard Intas
Diazepam Calmrelease_TR Nacto
Diclofenac sodium Dis-SR Deepharma
Diclofenac sodium Nac-SR Systopic
Diltiazem Dilzem SR Torrent

DELAYED TRANSIT & CONTINUOUS
RELEASE SYSTEM

ANATOMY AND PHYSIOLOGY OF GIT
Parts Of Gastrointestinal Tract
Main Parts:
 Mouth
 Esophagus
 Stomach
 Small Intestine
 Large Intestine
Accessory Parts:
 Liver
 Pancreas
 Gall bladder
 Salivary Gland

Introduction To Gastrointestinal System

Stomach:
 pH- 1-3
 Surface Area- Not too Large
 Drug Absorbed- Lipophilic, Neutral and Acidic (Lesser than that from Intestine)
Large Intestine:
 pH- 7.9-8
 Surface Area- Small
 Drug Absobed- All types of Drug (But to a lesser extent)
Small Intestine:
 pH- 5-7.5
 Surface area- Very Large
 Drug Absorbed- All types of drugs
Three major components GI Tract

Anatomical and Functional differences
Parameters Stomach Small Intestine Large Intestine
pH range 1-3 5-7.5 7.9-8
Length (cms) 20 285 110
Diameter (cms) 15 2.5 5
Surface Area (sq.M) 0.1-0.2 200 0.15
Blood flow (L/min.) 0.15 1 0.02
Transit time (hrs.) 1-5 3-6 6-12

Introduction to the gastrointestinal system
The gastrointestinal tract (GIT) consists of a hollow muscular tube starting from the oral cavity, where food enters the mouth,
continuing through the pharynx, esophagus, stomach and intestines to the rectum and anus, where food is expelled.
There are various accessory organs that assist the tract by secreting enzymes to help break down food into its component
nutrients. Thus the salivary glands, liver, pancreas and gall bladder have important functions in the digestive system.
Mouth
The oral cavity or mouth is responsible for the intake of food. It is lined by a stratified squamous oral mucosa with keratin
covering those areas subject to significant abrasion, such as the tongue, hard palate and roof of the mouth.
There are two main process are takes place :
1. Mastication
- Mechanical breakdown of food by chewing and chopping actions of the teeth.
- Increases surface area of food particles .
2. Secretion of Saliva
- Contains salivary amylase (ptyalin) that
digests starch to maltose.
- Provides an alkaline medium.
- Lubricants and moistens food.

Esophagus
Esophagus is a muscular tube of approximately 25cm in length and 2cm in diameter.
It extends from the pharynx to the stomach after passing through an opening in the diaphragm.
There occurs a process knows as Peristalsis.
Peristalsis
It is an involuntary process of muscular contraction forcing the bolus (food) down to the stomach.
Stomach
The stomach is a J shaped , hollow, muscular holding pouch for food.
The stomach has three main regions
 The cardia
 The Fundus
 The body
 The pylorus
The functions of the stomach include:
1. The short-term storage of ingested food.
2. Mechanical breakdown of food by churning and mixing motions.
3. Chemical digestion of proteins by acids and enzymes.
4. Stomach acid kills bugs and germs.
5. Some absorption of substances such as alcohol.

Small Intestine
The small intestine is composed of the
Duodenum: It is the proximal C-shaped section
that curves around the head of the pancreas.
Jejunum: The start of the jejunum is marked by
a sharp bend, the duodenojejunal flexure.
Ileum: Is the longest segment and empties into
the caecum at the ileocaecal junction.

Absorption
It occurs within the ileum in finger-like projection known as Villi.

 The small intestine performs the majority of digestion and absorption of nutrients.
 Partly digested food from the stomach is further broken down by enzymes from the pancreas and bile salts from the liver and
gallbladder.
 After further digestion, food constituents such as proteins, fats, and carbohydrates are broken down to small building blocks
and absorbed into the body's blood stream.
 The lining of the small intestine is made up of numerous permanent folds called plicae circulares.
 Each plica has numerous villi (folds of mucosa) and each villus is covered by epithelium with projecting microvilli (brush
border).
 This increases the surface area for absorption by a factor of several hundred.
 The mucosa of the small intestine contains several specialized cells. Some are responsible for absorption, whilst others secrete
digestive enzymes and mucous to protect the intestinal lining from digestive actions.

Large Intestine

 The large intestine is horse-shoe shaped and extends around the small intestine like a frame.
 It consists of the appendix, caecum, ascending, transverse, descending and sigmoid colon, and the rectum.
 It has a length of approximately 1.5 m and a width of 7.5 cm.
 The caecum is the expanded pouch that receives material from the ileum and starts to compress food products into faecal
material.
 Food then travels along the colon.
 The rectum is the final 15cm of the large intestine.
 It expands to hold faecal matter before it passes through the anorectal canal to the anus.
 Thick bands of muscle, known as sphincters, control the passage of faeces.
 The mucosa of the large intestine lacks villi seen in the small intestine.
 Numerous goblet cells line the glands that secrete mucous to lubricate faecal matter as it solidifies.
The functions of the large intestine can be summarized as:
 The accumulation of unabsorbed material to form faeces.
 Some digestion by bacteria. The bacteria are responsible for the formation of intestinal gas.
 Reabsorption of water, salts, sugar and vitamins.

LIVER
 It is the largest organ in the mammalian body.
 It secretes bile which is stored in the gall bladder.
 Bile breaks down fats into tiny droplets through emulsification.

FUNCTION OF THE LIVER
1. It acts as a mechanical filter by filtering blood that travels from the intestinal system.
2. It detoxifies several metabolites including the breakdown of bilirubin and estrogen.
3. In addition, the liver has synthetic functions, producing albumin and blood clotting factors.
4. However, its main roles in digestion are in the production of bile and metabolism of nutrients.
5. All nutrients absorbed by the intestines pass through the liver and are processed before traveling to the rest of the body.
6. The bile produced by cells of the liver, enters the intestines at the duodenum. Here, bile salts break down lipids into smaller
particles so there is a greater surface area for digestive enzymes to act.
Pancreas
Finally the pancreas is a lobular , pinkish-grey organ that lies behind the stomach. Its head communicates with the duodenum and
its tail extends to the spleen. The organ is approximately 15 cm in length, It is an endocrine gland because it secretes Insulin
hormone which converts excess glucose into glycogen for storage. It is also an exocrine gland because it secretes pancreatic
juice in the duodenum. pancreatic juice contains lipase, trypsin and pancreatic amylase for digestion of lipids , proteins and
starch.

Salivary Gland

 Three pairs of salivary glands communicate with the oral cavity.
 They produce and secrete saliva, a substance that helps with chewing and swallowing by moistening the food .
 Salivation occurs in response to the taste, smell or even appearance of food. This occurs due to nerve signals that tell the
salivary glands to secrete saliva to prepare and moisten the mouth. Each pair of salivary glands secretes saliva with slightly
different compositions.
Gall bladder
 The gallbladder is a pear-shaped sac that is attached to the visceral
surface of the liver by the cystic duct.
 It consists of a fundus, body and neck.
 The principal function of the gallbladder is to serve as a storage
reservoir for bile.
 Bile is a thick yellowish-green fluid produced by liver cells that
contains enzymes to help dissolve fat in the intestines.
 The main components of bile are water, bile salts, bile pigments, and
cholesterol.

DELAYED TRANSIT & CONTINUOUS RELEASE SYSTEM
INTRODUCTION
Synonyms: “Gastroretentative Drug Delivery System”, gastro Targeting, Gastro Specific.
Definition: This are the drug delivery system in which drug can specifically targeted at the site of GI Tract (Stomach) is known
has Gastroretentative drug delivery system.
Mechanism: Drug Release at the site of Stomach.
Gastro retentive drug delivery is an approach to prolong gastric residence time, there by controlling the site-specific drug release in
the upper gastrointestinal tract (GIT) for local or systemic effects.
Gastro retentive dosage forms can remain in the gastric region for long periods and hence significantly prolong the gastric
retention time (GRT) of drugs.

Drug selection crate area for Gastroretentative Drug Delivery System
 Drugs those are locally active in the stomach.
 Drug was targeted at the site of GI Tract.
 Drug should not targeted at the site of Small intestine and colon.
 Drug was solubilized in pH 1.2 acidic buffer.
 Drug was not solubilized in pH 6.8 and pH 7.4 phosphate buffer.
 Drug is only stabilized in pH 1.2 acidic buffer.
 Drug is not stabilized in pH 6.8 and pH 7.4 phosphate buffer.
 Drug is Non toxic, Non irritant, Non reactive.
 Drug is free from microbial contamination.
 It is applicable to reduced toxicity, and increases the therapeutic activity.

Need For Gastric-Retention
 Drugs that are absorbed from the proximal part of the GIT.
 Drugs that are less soluble or are degraded by the alkaline pH.
 They encounters at the lower part of GIT.
 Drugs that are absorbed due to variable gastric emptying time.
 The CDDS is not able to deliver the drug for longer time at the target.
 Particularly useful for the treatment of disease caused by H. pylori Infection.

Salient Features Of Upper Gastrointestinal Tract
Selection Length (m) Transit time
(h)
pH Microbial
count
Absorbing
surface area
(m2)
Absorption
pathway
Stomach 0.2 Variable 1-4 <103 0.1 P C A
Small Intestine 6-10 3± 1 5-7.5 103-1010 120-200 P C A I CM
P – Passive diffusion
C – Aqueous channel transport
A – Active transport
I – Ion-pair transport CM – Carrier mediated transport

Advantages of Gastro retentive Delivery Systems
 Improvement of bioavailability and therapeutic efficacy of the drugs and possible reduction of dose e.g. Furosemide
 Maintenance of constant therapeutic levels over a prolonged period and thus reduction in fluctuation in therapeutic levels
minimizing the risk of resistance especially in case of antibiotics. e.g. b-lactam antibiotics (penicillin's and cephalosporin's)
 Retention of drug delivery systems in the stomach prolongs overall.
 Increase in Gastrointestinal transit time thereby increasing bioavailability of sustained release delivery systems intended for
once-a-day administration. e.g. Ofloxacin
Dis-Advantages of Gastro retentive Delivery Systems
 The stomach should be faded with water (500 ml of water).
 The Absorption of drug is hindered in absence of food material.
 The stomach should be faded or empty is instruction on basis of drug system.

Factors Affecting Gastric Retention
1. Density: GRT is a function of dosage form buoyancy that is dependent on the density.
2. Size: Dosage form units with a diameter of more than 15mm are reported to have an increased GRT compared with
those with a diameter of less than 7mm.
3. Single or multiple unit formulation: Multiple unit formulations show a more Predictable release profile and
insignificant impairing of performance due to failure of units, allow co- administration of units with different release
profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure
compared with single unit dosage forms.
4. Nature of meal: feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach
to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
5. Age: Elderly people, especially those over 70, have a significantly longer GRT.

Classification of Gastroretentive drug delivery system
Gastroretentive drug delivery system is mainly dived by two types,
1. Effervescent system
2. Non- Effervescent system
1. Effervescent System: This are the drug delivery system in which drug can come into contact with water and aq. Acidic media
it can generate effervescent and drug was rapidly releases is known has Effervescent System.
It is simple reaction between Acid and Base effervescent was generated and tablet was rapidly dissolved.
Acid (citric acid or Tartaric acid) + Base (sodium bicarbonate) Effervescent is generated (effervescent
of carbon dioxide.
Example: Ciprofloxacin HCL Effervescent Tablet. (Effervescent time 2 – 5 min) (Time at which tablet can generate Effervescent in
particular period of time)

Gastro retentive Drug Delivery Systems (Effervescent and Non Effervescent)

2. Non- Effervescent system
Synonyms: “Floating System”
Important crate area: It is “Density” based system (density less than 1 or density more than 1)
Non- Effervescent system: This are the drug delivery system in which drug can come in to contact with media it can floated at the
surface of the media is known has Non- Effervescent system.
Density less than 1: Incorporation various swellable Polymers such as HPMC K 4M, HPMC K 15M, HPMC K 100M, HPMC K
200M, Ethyl cellulose, chitosan (R & S), Methyl cellulose, Ethyl Cellulose, Hydroxy Propyl Methyl cellulose (HPMC), Hydroxy
Propyl cellulose (HPC).
Density more than 1: Incorporation of acidic and basic material in tablet, In which, the simple reaction between acid and base
material in bulk of Tablet is responsible for reducing the bulk of tablet (density of tablet was reduced under acid and base reaction
of tablet material) and Tablet was easily Floated. Eg. Citric acid, sodium bicarbonate.
Example: Metformin HCL Floating Tablet.

Approaches of Gastro retentive Drug Delivery Systems
 Altered density systems
 Floating systems
 Bioadhesive or mucoadhesive systems
 Expanded or Swelling systems
 Magnetic systems
ALTERED DENSITY SYSTEM
It mainly consist of 2 systems:
 High Density System
 Low Density System

High-density systems
Sedimentation of pellets near the pyloric region of the stomach
Dense pellets (approximately 3g/cc) trapped in fold also tend to withstand the peristaltic movements of the stomach wall.
With pellets, the GI transit time can be extended from an average of
5.8 – 25 hours, depending more on density than on diameter of the pellets.
Commonly used excipients are barium Sulphate, zinc oxide, titanium dioxide and iron powder, etc.
Although encouraging results were reported in ruminants, effectiveness in human subjects beings was not observed and no system
has been marketed

Low density system
 Gas-generating systems invariably have a lag time before floating on the stomach contents, during which the dosage form may undergo
premature evacuation through the pyloric sphincture.
 Hence, Low-density systems (< 1 g/cm3) with immediate buoyancy have therefore been developed.
 They are made of low-density materials, entrapping oil or air.
 Most are multiple unit systems, and are also called ‘‘ Microballoons ’’ because of the low-density core.
 Generally, techniques used to prepare hollow microspheres involve simple solvent evaporation or solvent diffusion/ evaporation methods.
 Polycarbonate, Eudragit S, cellulose acetate, calcium alginate, agar and low methoxylated pectin are commonly used as polymers.

Floating systems
These have a bulk density lower than the gastric content. They remain, buoyant in the stomach for a prolonged period of time, with
the potential for continuous release of drug.
Approaches used in designing Intragastric floating systems are as follows:
1. Hydrodynamically balanced systems
2. Gas-generating systems
3. Raft-forming systems
Hydrodynamically balanced systems
These are single-unit dosage forms, containing one or more gel-forming hydrophilic polymers,
 Hydroxy propyl methyl cellulose (HPMC)
 Hydroxy ethyl cellulose (HEC)
 Hydroxy propyl cellulose (HPC)
 Sodium Carboxy methyl cellulose (NaCMC)
 Agar, Carrageenans or alginic acid.28/05/2016 84SAGAR SAVALE

 The polymer is mixed with drug and usually administered in a gelatin capsule. The capsule rapidly dissolves in the gastric
fluid, and hydration and
 swelling of the surface polymers produces a floating mass. Continuous erosion of the surface allows water penetration to the
inner layers, maintaining surface hydration and buoyancy.
 e.g.- floating Ampicillin tablet
Incorporation of fatty excipients gives low-density formulations and reduced penetration of water, reducing the erosion.
Ex.-Misoprostol against gastric ulcers, floating ampicillin tablet Gas-generating systems

e.g.- ciprofloxacin

Raft-forming Systems
 Here, a gel-forming solution swells and forms a viscous cohesive gel containing entrapped CO2 bubbles on contact with gastric
fluid.
 Formulations also typically contain antacids such as aluminum hydroxide or calcium carbonate to reduce gastric acidity.
Because raft-forming systems produce a layer on the top of gastric fluids, they are often used for gastro esophageal reflux
treatment as with Liquid.
 e.g.- Gaviscon (GlaxoSmithKline).
Bioadhesive or Mucoadhesive systems
 Bio-adhesive Systems - Systems that adhere to the biological substrates.
 Mucoadhesive Systems – Systems that adhere to the mucus.
 Mucosal layer lines number of regions of the body including; GI tract, the air ways, the ear, nose and eye.

Expandable System
 A dosage form in the stomach will withstand gastric transit if it is bigger than the pyloric sphincter.
 The dosage form must be small enough to be swallowed, and must not cause gastric obstruction.
 The concept is to make a carrier, such as a capsule, incorporating a compressed system which expands in the stomach.
 Drawback :- Permanent retention of rigid large-sized single unit forms can cause bowel obstruction, intestinal adhesion.
Underlying principle
Three configurations:
 A small which enables convenient oral intake.
 Expansion in stomach thus prevents passage through
pyloric sphincter.
 Finally another small configuration for evacuation from
stomach after complete drug release.
Can be achieved by;
 Swelling
 Unfolding (mechanical shape memory)

Swellable system

Unfoldable systems
Unfoldable systems are made of biodegradable polymers. The concept is to make a carrier, such as a capsule, incorporating a
compressed system which extends in the stomach.

Different Geometric Forms of Unfoldable Systems

Magnetic systems
 This system is based on a simple idea:
 The dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach.
 e.g., In vivo human studies showed that, in the presence of magnet, the plasma concentrations of acyclovir were significantly
higher after 7, 8, 10 and 12 h.
Magnet

Matrix
Devices
Membrane
Devices
Diffusion-
Controlled
Controlled
Release
Systems
Biodegradable
Systems
Pendant
Chain Systems
Chemically-
Controlled
Solvent-
Activated
Osmotically-
Controlled
Swelling-
Controlled
Rupture-
Controlled
Pulsatile
Delivery
Single
Pulse
Osmotically
Ruptured
Polymer
Dissolution
Erodible
polymer
Multiple
Pulse
Electrically-
Stimulated
Ultrasonically
-
ControlledMagnetically
-
Controlled
Temperature
-
Controlled
Inflammation
induced
pH-
Sensitive
94

Introduction
Pulsatile drug delivery are the system in which rapid & transient release of an active molecule within a short time period
immediately after a predetermined off release period. i.e. lag time
The Pulsatile effect i.e. the release of drug as a “pulse” after a lag time has to be designed in such a way that complete and rapid
drug release should follow the lag time. Such systems are also called time-controlled as the drug release is independent of the
environment.
The system deliver the drugs at:
right time
right place
right quantity

NEED OF PULSATILE DRUG DELIVERY SYSTEM
 Avoiding drug degradation in GIT.
Drugs which develop biological tolerance.
Drug with extensive first pass metabolism .
Drug targeted to specific site in the intestinal tract.
Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology.

CHRONOPHARMACOTHERAPY

Disease Chronological behavior Drugs used
Peptic ulcer Acid secretion is high in the afternoon
and at night
H2 blockers
Asthma Precipitation of attacks during night or
at early morning hour
β-2 agonist, Antihistaminic
Cardiovascular diseases BP is at its lowest during the sleep
cycle and rises steeply during the
early morning
Nitroglycerin, Calcium channel
blocker, ACE inhibitors etc.
Arthritis Pain in the morning and more pain at
night
NSAIDs, Glucocorticoids
Diabetes mellitus Increase in the blood sugar level after
meal
Sulfonylurea, Insulin, Biguanide
Attention deficit syndrome Increase in DOPA level in afternoon Methylphenidate
Hypercholesterolemia Cholesterol synthesis is generally
higher during night than during day
time
HMG-CoA-reductase inhibitors

ADVANTAGES OF PULSATILE SYSTEM
Reduced dosage frequency.
Reduction in dose size.
Extended daytime or night time activity.
Improved patient compliance .
Drug loss is prevented by first pass metabolism.
It can give “a new lease of life” & a “new therapeutic dimension” for existing drug molecule.

Methodologies for PDDS
There are innumerable approaches for PDDS. In a broad point of view methodologies for PDDS can be categorized in to 3
ways:
I. Time controlled systems
II. Stimuli induced systems
III. Hydrogel systems

Time controlled Pulsatile drug delivery
Osmotic Pressure based systems
Systems with Rupturable coatings
Systems with Erodible/swellable coatings
Capsular systems with polymeric plugs

Osmotic Pressure based system
 The Port System constitute of a gelatin capsule coated with a semi permeable membrane (e.g., cellulose acetate) housing an
insoluble plug (e.g., lipidic) and an osmotically active agent with the drug formulation.
 Mechanism
Upon contact with the aqueous medium, water diffuses across the semi permeable membrane, resulting in increased inner pressure
that ejects the plug after a lag time.
The lag time is manipulated controlled by coating thickness.

Pulsatile System with Rupturable Coatings
 These systems depend on the disintegration of the coating for the release of drug.
 The pressure necessary for the rupture of the coating can be achieved by the effervescent excipients, swelling agents, or
osmotic pressure.
 An effervescent mixture of citric acid and sodium bicarbonate was incorporated in a tablet core coated with ethyl cellulose.
 Mechanism: The carbon dioxide gas developed after penetration of water into the core resulted in a pulsatile release of drug
after rupture of the coating. Lag time increases with increasing coating thickness and increasing hardness of the core tablet.

Pulsatile System with Erodible Coatings
 Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer.
 This barrier erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly.
 The time lag depends on the thickness of the coating layer

Capsular Systems
 A general -design of such systems consists of an insoluble capsule body housing a drug and a plug.
 The plug is removed after a predetermined time lag due to swelling, erosion, or dissolution.
 The Pulsincap® system is an example of such a system that is made up of a water-insoluble capsule body filled with drug
formulation.
 Upon contact with dissolution medium or gastro-intestinal fluids, the plug swells, pushing itself out of the capsule after a time
lag.
Plug Material
a) Insoluble but permeable and swellable polymer, e.g., polymethacrylates
b)Erodible compressed polymers, e.g., Hydroxy propyl methyl cellulose, polyvinyl alcohol, polyethylene oxide
c) Enzymatically controlled erodible polymer, e.g., pectin

Sigmoidal Release System
 This consists of pellet cores comprising drug and succinic acid coated with ammonia-methacrylate copolymer USP/NF type B.
 The time lag is controlled by the rate of water influx through the polymer membrane. The water dissolves acid and the drug in
the core.
 The acid solution in turn increases permeability of the hydrated polymer film.
 The different types of acids that can be used include succinic acid, acetic acid, glutamic acid, tartaric acid, maleic acid, or citric
acid

Highly Responsive Hydrogel
 Hydrogel : A polymer network that is not soluble in water, but is super-absorbent.
 Stimuli responsive hydrogels can absorb or release their contents based on environmental conditions.
 Stimuli include:
1. Temperature
2. pH
3. Ionic Strength
4. Presence of certain chemicals

They are insoluble due to the tie points i.e., physical cross links like entanglement.
Examples include:
PIPAAm
PEO-PPO-PEO
PLGA-PEO-PLGA grafted co-polymers.

Thermo responsive hydrogel system
 In these systems the polymer undergoes swelling or deswelling phase in response to the temperature which modulates drug
release in swollen state.
For example polyN-isopropylacrylamide (PIPAAm) responds to a specific range of temperature.
 Below 32 C PIPAAm forms a “skinny layer” & changes to hydrophobic which is impermeable to water.

pH responsive hydrogel system
x
Low pH
High pH
Protect drug
Release drug
113

Stimuli induced pulsatile release system
Release of the drug after stimulation by an biological factor or external stimuli .
It is classified into two types
stimuli induced pulsatile system
External stimuli
i. Micro electro release system
ii. Electro Responsive release
iii. Magnetically induced release
i. pH sensitive drug delivery system .
ii. Inflammation-induced system
iii. Glucose responsive insulin release
iv. Drug release from gels responding
to antibody concentration
Chemical stimuli induced pulsatile system

Glucose-responsive insulin release device
The system include insulin immobilized in the hydrogel
Glucose
Glucose oxidase
Gluconic acid
Change in pH
Swelling of the polymer
Insulin release

Insulin by virtue of its action reduces blood glucose level & consequently Gluconic acid level also get decreased & system turns
to the deswelling mode thereby decreasing the insulin release.
Examples of the pH sensitive polymers include N, N-dimethyl laminoethyl methacrylate, chitosan, polyol etc.
Pulsatile release by external stimuli
Electro responsive pulsatile release
Electrically responsive delivery systems are prepared from polyelectrolytes (polymers which contain relatively high concentration
of ionizable groups along the backbone chain) and are thus, pH- responsive as well as electro-responsive.
Examples of naturally occurring polymers include hyaluronic acid, chondroitin sulphate, agarose, carbomer, xanthan gum and
calcium alginate.
The synthetic polymers are generally acrylate and methacrylate derivatives such as partially hydrolyzed polyacrylamide, poly
dimethyl amino propyl acrylamide

Micro electro mechanical systems (MEMS
 A micro fabricated device has the ability to store and release multiple chemical substances on demand.
 Another development in MEMS technology is the microchip.
 The microchip consists of an array of reservoirs that extend through an electrolyte-impermeable substrate.
 The microchip consists of an array of reservoirs that extend through an electrolyte-impermeable substrate.
 The prototype microchip is made of silicon and contains a number of drug reservoirs, each reservoir is sealed at one end by a
thin gold membrane of material that serves as an anode in an electrochemical reaction and dissolves when an electric potential
is applied to it in an electrolyte solution.
 When release is desired, an electric potential is applied between an anode membrane and a cathode, the gold membrane anode
dissolves within 10-20 seconds and allows the drug in the reservoir to be released.
 This electric potential causes oxidation of the anode material to form a soluble complex with the electrolytes which then
dissolves allowing release of the drug.

EVALUATION
 Dissolution studies.
 Simulated rupture tests with polymer films
 Lag time and drug release of pulsatile capsules
 Water uptake studies with the pulsatile tablets.
 gamma scinitgraphic technology

Simulated rupture tests with polymer films

Lag time and drug release of pulsatile capsules
 The lag time of pulsatile release tablets is defined as the time when the outer coating starts to rupture.
 The lag time of the pulsatile capsules was determined by visual observation in a USP paddle apparatus (medium: phosphate
buffer USP pH 7.4, 37°C, and rotation speed 50 rpm).
 We can go either with plcebo or with the drug itself.
Water uptake studies with the pulsatile tablets
 The %water uptake of pulsatile release tablets was determined in medium-filled containers placed in a horizontal shaker (100
ml of 0.1 N HCl, 37 0C, 74 rpm, n = 3).
 At predetermined time points, the tablets were removed from the dissolution medium, carefully blotted with tissue paper to
remove surface water, weighed and then placed back in the medium up to the time when the coating of the tablet ruptured. The
%water uptake was calculated as follows:
The %water uptake was calculated as follows:

Gamma scinitgraphic technology
Image (a) was taken immediately
Image (b) was taken at 3 hrs.
Image (c) & (d) at 5 & 6 hrs respectively.
a b c d

Recent Techniques of Pulsatile Technology
 Spheroidal Oral Drug Absorption System (SODAS)
 Chronotherapeutic Oral Drug Absorption System (CODAS)
 EURANDs pulsatile and chrono release System
 Magnetic Nanocomposite Hydrogel
 GEOCLOCK® Technology

Technology used Drugs marketed
CODAS Verelan® PM
EURANDS Propranolol hydrochloride (CRR)
GEOCLOCK Lodotra™
PULSYS™ Moxatag™
Marketed drug product

Delayed Release Systems
It can dived into two types :
1. Drug Delivery to Small Intestine
2. Drug Delivery to Colon (Large intestine)

DRUG DELIVERY TO SMALL INTESTINE
INTRODUCTION
Synonyms: “Enteric Drug Delivery System”, Intestinal Targeting, Intestinal Specific.
Definition: This are the drug delivery system in which drug can specifically targeted at the site of Small Intestine is known has
Intestinal drug delivery system.
Mechanism: Drug Release at the site of Small Intestine.
Example: Cellulose acetate phthalate (CAP), Shellac, Zen, Poly Vinyl Acetate Phthalate (PVAP), Acrylic Polymers.

ENTERIC COATING DRUG DELIVERY
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed.
Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.
Most enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach, but breaks down
rapidly at a less acidic (relatively more basic) pH. For example, they will not dissolve in the acidic juices of the stomach (pH ~3),
but they will dissolve in the alkaline (pH 7-9) environment present in the small intestine. Materials used for enteric coatings
include waxes, shellac and plastics, plant fibers. Drugs that have an irritant effect on the stomach, such as aspirin, can be coated
with a substance that will only dissolve in the small intestine. Similarly, certain groups of azoles (esomeprazole, omeprazole,
pantoprazole and all grouped azoles) are acid-unstable. For such types of drugs, enteric coating added to the formulation tends to
avoid the stomach's acidic exposure, delivering them instead to a basic pH environment (intestine's pH 5.5 and above) where they
do not degrade, and give their desired action. Recently, some companies have begun to utilize enteric coatings on fish oil (omega 3
fatty acids) supplements. The coating prevents the fish oil capsules from being digested in the stomach, which has been known to
cause a fishy reflux. Sometimes the abbreviation "EC" is added beside the name of the drug to indicate that it is enteric coated.

Ideal Properties
 Permeable to intestinal fluid
 Compatibility with coating solution and drug
 Formation of continuous film
 Nontoxic
 Cheap and ease of application
 Ability to be readily printed
 Resistance to gastric fluids

Drug selection crate area for Intestinal Drug Delivery System
 Drugs those are locally active in the Small intestine.
 Drug was targeted at the site of Intestinal Tract.
 Drug should not targeted at the site of Stomach and colon.
 Drug was solubilized in pH 6.8 phosphate buffer.
 Drug was not solubilized in pH 1.2 acidic and pH 7.4 phosphate buffer.
 Drug is only stabilized in pH 6.8 phosphate buffer.
 Drug is not stabilized in 1.2 acidic and pH 7.4 phosphate buffer.

Shellac
 Material of natural origin- purified resinous secretion of the insect Laccifer lacca.
 Oldest known material used for enteric coatings.
 Suited for drug targeting in the distal small intestine as soluble at pH 7.0
 Its use is now less popular in commercial pharmaceutical applications for enteric coatings.
 Due to poor batch to batch reproducibility, which is a crucial requirement.

Cellulose Acetate Phthalate (CAP )
 Chemical name: Cellulose acetate phthalate
 Trade name: CAP, Aquateric
 Application form: organic or aqueous dispersion
 Functional groups: acetyl, phthalyl.
 Soluble above pH: 6
 Additional remarks: sensitive to hydrolysis.
 Plasticizer: 5-30% required.
 Dosage form: Capsule, Tablets, Pellets.

Poly-Vinyl Acetate Phthalate (PVAP )
 Chemical name: polyvinyl acetate phthalate.
 Trade name: Opadry enteric (aqueous), Coloron.
 Application form: organic solution, aqueous dispersion.
 Functional groups: acetyl, phthalate, vinyl acetate : crotonic acid ratio 90:10.
 Soluble above pH: 5.
 Additional remarks: Plasticizer is required.
 Dosage form:- Capsule (hard and soft gelatin).

Acrylic Polymers
 Chemical name: Methacryclic
 Trade name: Eudragit®
 Application form: organic solution or aqueous dispersion.
 Functional groups: meth acrylic acid
 Soluble above pH: 5 * depends on co- polymers used.

EUDRAGITS
TYPES SOLUBILITY APPLICATION
EUDRAGIT® E 12.5 Soluble in gastric fluid to pH 5 Film coating
EUDRAGIT® E 100 Soluble in gastric fluid to pH 5 Film coating
EUDRAGIT® L 12.5 P Soluble in gastric fluid from pH 6 Enteric coating
EUDRAGIT® L 12.5 Soluble in gastric fluid from pH 6 Enteric coating
EUDRAGIT® L 100 Soluble in gastric fluid from pH 6 Enteric coating
EUDRAGIT® L 100-55 Soluble in gastric fluid from pH5.5 Enteric coating
EUDRAGIT® L 30D-55 Soluble in gastric fluid from pH5.5 Enteric coating
EUDRAGIT® S 12.5 P Soluble in gastric fluid from pH 7 Enteric coating
EUDRAGIT® S 12.5 Soluble in gastric fluid from pH 7 Enteric coating
EUDRAGIT® S 100 Soluble in gastric fluid from pH 7 Enteric coating

Grades Of TITAN COAT (From TITAN PHARMA)
Grades Physical form Properties Application Dosage forms
TC-L-100 Powder Soluble at pH 6.0 Enteric coating Pellets,granules,tablets,p
ills,powder
TC-S-100 Powder Soluble at pH 7.0 Enteric coating Pellets,granules,tablets,p
ills,powder
TC-L-100-55 Powder Soluble at pH 5.5 Enteric coating Pellets,granules,capsule,
pills,powder
TC-L-30 D Aqueous dispersion Soluble at pH 5.5 Enteric coating Pellets,granules,pills,tabl
ets
TC-L-12.5 Organic solution Soluble at pH 6.0 Enteric coating Pellets,tablets,granules,p
ills,powders

Use Of Plasticizers:
 Capable of diffusional movement into the capsule shell.
 Necessary for the formation of smooth films that are free of cracks and other defects.
 It affect the Mechanical, Adhesive and Drug-release characteristics.
 Mechanical- Soft gelatin capsule becomes less Elastic. e.g. TEC (Triethyl Citrate),
TBC (Tribute Citrate)
 Tensile Strength and Tensile Toughness- Increased with TEC than TBC.
 Adhesion- may Leads to accumulation of moisture. Affect the stability of drug.
Coating Processes:
 Single/ Multiple layer Coating:
 Contain Enteric polymer, plasticizer, glidant, sometimes colorant.
 Polymer applied from aqueous or organic solvents.
 Sometimes HPMC is used for “SUBCOAT”.
 e.g.- Lansoprazole
 EUDRAGIT L 30 D-55 and mg. carbonate added as Alkaline Stabilizer.
 HPC was added to reduce the friability of granules.
Organic or Aqueous Coating:
 Film formation takes place when solvent evaporates.
 Concentration of Organic solution- 20%
 Concentration of Aqueous solution- 10%
Dry Coating:
 For HPMC acetate succinate, novel method has
been developed.
 Enteric polymer is added in Dry Powder form.
 Plasticizer is diluted with paraffin is spraying
separately.
 Rates of powder feeding and spraying have to be
adjusted such that two process start and end
simultaneously.

COLON SPECIFIC DRUG DELIVERY

INTRODUCTION
Synonyms: “Large Intestinal Drug Delivery System”, Intestinal Targeting, Intestinal Specific.
Definition: This are the drug delivery system in which drug can specifically targeted at the site of Large Intestine (colon) is known
has colon specific drug delivery system.
Mechanism: Drug Release at the site of Large Intestine (colon).
Example: Polymethylmethacrylate (Eudragit)
Drug release mechanism: drug containing polymeric system is Cross - Linked with divenyl benzene under in presence of
Azoreductase enzyme (it is key for colonic drug release) and drug was releases.

INTRODUCTION
 The colonic delivery systems are important for the systemic delivery of protein and peptides.
 It is because of rapid development of biotechnology and genetic engineering resulting in the availability of peptides and protein
drugs at reasonable cost.
 The peptide and protein drugs are destroyed and inactivated in acidic environment of the stomach or by pancreatic enzymes in
the small intestine.
 So colon is considered to be more suitable for delivery of peptides and protein compared to small intestine.
 The Colon-DDS drug release and absorption should not occur in the stomach as well as small intestine, but only released and
absorbed once the system reaches to the colon.

Drug selection crate area for Intestinal Drug Delivery System
 Drugs those are locally active in the large intestine (colon)
 Drug was targeted at the site of Colon.
 Drug should not targeted at the site of Stomach and small intestine.
 Drug was solubilized in pH 7.4 phosphate buffer.
 Drug was not solubilized in pH 1.2 acidic and pH 6.8 phosphate buffer.
 Drug is only stabilized in pH 7.4 phosphate buffer.
 Drug is not stabilized in 1.2 acidic and pH 6.8 phosphate buffer.

Need of Colonic Drug Delivery System
 Ensure direct treatment at the disease site.
 Lower dosing and less side effects.
 Beneficial in the treatment of colon diseases.
 Suitable absorption site for protein and peptide drugs.
 Used to prolong the drug therapy.

ADVANTAGES
Drug directly available at the target site.
Decreased dose to be administered.
Decreased side effect.
Improved drug utilization.
DISADVANTAGES
 Transit through the colon more rapid than normal in
patients with colon disease.
 pH levels in the small intestine and colon vary between
and within individuals.
 pH levels in the end of small intestine and caecum are
similar poor site specific
Applications
 It is used has colonic disorder such as Ulcerative
Colitis, Crohn’s Disease,
 It is also applicable for Inflammatory bowel disease

 Y. W. Chien, Novel drug delivery system , volume 50,Page no.225-34.
 Leon Lachman , Herbert A. Lieberman, Joseph L. Kanig, The theory & practice of industrial pharmacy, 3 rd edition.
 V. R. Gudsoorkar & D. Rambhau The Eastern pharmacist, November 1993 Sustained release drugs, page 27-32.
 www.google.com
 Tortora G.J.;Derrickson B.H.;Principles of Anatomy And Physiology, 12th Edition,Volume 2, p. 921-966
 Swarbrick J.;Boylan J.C.;Encyclopedia of Pharmaceutical Technology, Second Edition;Volume 1;p.886-904
 Brahmankar D. M. and Jaiswal S. B. in “Biopharmaceutics and Pharmacokinetics”,Vallabh Prakashan, 1st edn, 1995, 347- 352.
 Robinson JR, Lee VHL. Controlled drug delivery: fundamentals and applications, 2nd ed. Marcel Dekker; New York : 1987. p.373-432.
 N.K. Jain, Gastroretentive Drug Delivery Systems, “Progress in Controlled Drug Delivery Systems”, CBS Publication ,76-96.
 J.swarbrick, J.C.Boylan, “Encyclopedia of pharmaceutical technology”,2nd edition,vol-2, Marcel Dekker Inc. ,892-896.
 Nayak.A, Maji.M, Das.B, 2010, “Gastroretentive drug delivery systems: A review” , Asian Journal of Pharmaceutical and Clinical Research,
vol.3, Issue 1.
 P.L. Bardonnet a,b, V. Faivre a,*, W.J. Pugh c, “Gastroretentive dosage forms: Overview and special case of Helicobacter
 pylori”, Journal of Controlled Release 111 (2006) 1 –18.
 D.M. Brahmankar, Sunil B. Jaiswal, “BIOPHARMACEUTICS AND PHARMACOKINETICS –A TREATISE”, Vallabh Prakashan, 2005
Edition, (pg.no- 50- 56).
 S. P. Vyas and Roop. K. Khar, “Controlled Drug Delivery Concepts and Advances”, 1st Edition 2002,New Delhi, 196-217.
 Gerard J. Tortora, Bryan H. Derricksonn, “PRINCIPLES OF ANATOMY AND PHYSIOLOGY”, 12 th Edition, vol-1, (pg.no- 922- 971)
 Brogmann .B, Beckert. TE, “DRUG TARGETING TECHNOLOGY “ , Marcel Dekker, (pg.no- 7)
 McGinity. WJ, Felton.LA, “ENTERIC FILM COATING OF SGC” ,Drug Delivery Technology vol- 3 2003 Edition.
 Wilding.IR, Coupe.Aj, Davis.SS, “ENTERIC COATING OF SOFT GELATIN CAPSULES”, J.Pharm Pharmaceutical sci.
(www.cspscanada.org) 9 (3) : 327-338, 2006.
 “ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY”
 I.R. Wilding , A.J. Coupe , S.S. Davis “THE ROLE OF Y-SCINTIGRAPHY IN ORAL DRUG DELIVERY”, Advanced Drug Delivery Reviews
46 (2001) 103–124.
 Kah-Hay Yuen, “ THE TRANSIT OF DOSAGE FORMS THROUGH SMALL INTESTINE”, International Journal of Pharmaceutics, 395
(2010) 9–16.
References

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