oral drug delivery system (odds)

Oral Drug Delivery Systems

Mr. Sagar Kishor Savale[Department of Pharmaceutics]

[email protected]

2015-016

Department of Pharmacy (Pharmaceutics) | Sagar savale

28/05/2016 1SAGAR SAVALE

mailto:[email protected]


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. pka 28/05/2016 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 500.28/05/2016 22SAGAR SAVALE

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/C0Where:

C0= initial drug concentration immediately after an IV bolus injection

In case of two compartment model.28/05/2016 28SAGAR SAVALE

Vss = (1+K12/K21)/V1Where, 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 30SAGAR SAVALE

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 systems28/05/2016 34SAGAR SAVALE

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 theoryLimited 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/diffusivityCs = 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 & fattyacids.

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).28/05/2016 42SAGAR SAVALE

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 SYSTEM 28/05/2016 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 releaseformulation of Bupropion

Bupropion is used in the treatment of majordepressive disorder.

Conventional formulation has to beadministered 3 times daily.

Initially 150 mg ER formulation was introducedfor bid regimen. Later on 300 mg ERformulation was introduced for once dailyregimen

For ER formulation provide similar Cmax andAUC values as compared to immediate releaseformulation 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.

MouthThe 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.28/05/2016 64SAGAR SAVALE

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 diffusionC – 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 system2. 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 marketed28/05/2016 82SAGAR SAVALE

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 systems28/05/2016 85SAGAR SAVALE

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


MatrixDevices

MembraneDevices

Diffusion-Controlled

Controlled Release Systems

BiodegradableSystems

PendantChain Systems

Chemically-Controlled

Solvent-Activated

Osmotically-Controlled

Swelling-Controlled

Rupture-Controlled

PulsatileDelivery

SinglePulse

OsmoticallyRuptured

PolymerDissolution

Erodiblepolymer

MultiplePulse

Electrically-Stimulated

Ultrasonically-

ControlledMagnetically-

Controlled

Temperature-

Controlled

Inflammationinduced

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,pills,powder

TC-S-100 Powder Soluble at pH 7.0 Enteric coating Pellets,granules,tablets,pills,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,tablets

TC-L-12.5 Organic solution Soluble at pH 6.0 Enteric coating Pellets,tablets,granules,pills,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


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oral drug delivery system (odds)

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