Mechanism aspects of Oral drugdelivery formulation

1.Dissolution controlled release system

Matrix dissolution controlled release systemEncapsulation dissolution controlled release system

2.Diffusion controlled release systemMatrix diffusion controlled release system

Reservoir diffusion controlled release system

3.Combination of both dissolution & diffusion.

1

Matrix dissolution

controlled release system

Also called as Monolith dissolutioncontrolled 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 bydissolution rate of polymer.

Examples: Dimetane extencaps,Dimetapp extentabs.

Soluble drug

Slowlydissolvingmatrix

Bees wax, Carnuba wax,

hydrogenated castoroil

2

Encapsulation dissolution

controlled release system

Called as Coating dissolutioncontrolled system.

Dissolution rate of coat dependsupon stability & thickness ofcoating.

Maskscolour,odour,taste,minimising GIirritation.

One of the microencapsulation

Soluble drug

Slowlydissolvingor erodiblecoat

method is used. Polymethacrylates, cellulose

derivatives, Waxes, PEGExamples: Ornade spansules,Chlortrimeton Repetabs

3

Types of Dissolution ControlledSystems

Two types of dissolution-

controlled, pulsed delivery

systems

A: Single bead-type device

with alternating drug and rate

controlling layer

B: Beads containing drug

with differing thickness of

dissolving coats

4

Matrix Diffusion Controlled Types

Rigid Matrix DiffusionMaterials used are insoluble plastics such as PVP & fatty

acids.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

5

Matrix system

Rate controllingstep:

Diffusion ofdissolved drug inmatrix.

6

Reservoir diffusion controlled releasesystem

Also called as Laminated matrix device.Hollow system containing an inner coresurrounded by water insoluble butpermeable membrane.

Polymer can be applied by coating or microencapsulation.

Rate controlling mechanism - partitioninginto membrane with subsequent releaseinto surrounding fluid by diffusion.

Commonly used polymers - HPC, ethylcellulose & polyvinyl acetate.

7

Reservoir System

Rate controllingsteps :

Polymeric content incoating, thickness of

coating, hardness ofmicrocapsule.

8

Dissolution & Diffusion ControlledRelease system

Drug encased in a partially solublemembrane.

Pores are created due to dissolutionof parts of membrane.

It permits entry of aqueous mediuminto core & drug dissolution.

Diffusion of dissolved drug out ofsystem.

Ex- Ethyl cellulose & PVP mixturedissolves in water & create pores ofinsoluble ethyl cellulose membrane.

Insolublemembrane

Entry ofdissolutionfluid

Drugdiffusion

Pore created bydissolution of

soluble fraction ofmembrane

9

Osmosis

- Movement of solvent from lower to higher concentration.

- The passage of solvent into a solution through semi permeable

membrane.

Osmotic pressureIt is the hydrostatic pressure produced by a solution in aspace divided by a semipermeable membrane due to

difference in concentration of solutes.

10

Osmotic Pressure ControlledSystem

Provides zero order release

Drug may be osmotically active, orcombined with an osmotically activesalt (e.g., NaCl).

Semipermeable membrane usuallymade from cellulose acetate.

More suitable for hydrophilic drug.

11

Characteristics of Osmotically ControlledDevices

Advantages- Zero-order release is obtainable

- release of drug is independent of environment of the system

Disadvantages- systems can be very expensive

- quality control is more extensive

12

Types of Osmotically ControlledSystems

Type A contains a osmotic

core with drug

Type B contains the drug

solution in a flexible bag,

with the osmotic core

surrounding

13

Osmotic Pressure ControlledSystem

14

Osmotic Pressure ControlledSystem

15

Modifications

- Immediate release system.

- Osmotically active compartment system

Immediate Release System

Dividing a dose into two parts.

One third immediate release.

Two third controlled release.

Encapsulated into semipermeable

membrane.

e.g. : Phenyl propanolamine.

21

Osmotically active system

Two compartments

separated by movablepartition.

Osmotically active

compartment absorbswater from GIT.

Creates osmotic

pressure.

Partition moves

upward & then drugreleases.

Ex: Nifedipine.

Delivery orifice

Drug compartment

Movablepartition

Osmotically activecompartment

22

pH- activated drug delivery system

This type of chemically activated system permitstargeting the delivery of drug only in the regionwith selected pH range.

It fabricated by coating the drug-containing corewith a pH - sensitive polymer combination.

For instances, a gastric fluid labile drug isprotected by encapsulating it inside a polymermembrane that resist the degradative action ofgastric pH.

23

24

In the stomach, coating membrane resists theaction of gastric fluid (pH<3) & the drugmolecule thus protected from acid degradation.

After gastric emptying the DDS travels to thesmall intestine & intestinal fluid (pH>7.5)activates the erosion of the intestinal fluidsoluble polymer from the coating membrane.

This leaves a micro porous membraneconstructed from the intestinal fluid insolublepolymer, which controls the release of drug fromthe core tablet.

The drug solute is thus delivered at a controlledmanner in the intestine by a combination of drugdissolution & pore-channel diffusion.

25

Ion- activated drug delivery system

26

An ionic or a charged drug can be delivered bythis method & this system are prepared by firstcomplexing an ionic drug with an ion-exchange

resin containing a suitable counter ion.

Ex. By forming a complex between a cationicdrug with a resin having a So3- group or betweenan anionic drug with a resin having a N(CH3)3

group.

The granules of drug-resin complex are firsttreated with an impregnating agent & thencoated with a water-insoluble but water-

permeable polymeric membrane.

27

This membrane serves as a rate-controllingbarrier to modulate the influx of ions as well as

the release of drug from the system.

In an electrolyte medium, such as gastric fluidions diffuse into the system react with drug resin

complex & trigger the release of ionic drug.

Since the GI fluid regularly maintains a relatively

constant level of ions, theoretically the delivery

of drug from this ion activated oral drug deliverysystem can be maintained at a relatively

constant rate.

28

Why Gastroretention?

- Oral Route: ‘the safest’

- More than 50% of pharmaceutical products are orally administered.

Limitations:

- Variability in solubility/permeability characteristics → incomplete

absorption.

- Variability in site of absorption → incomplete absorption.

- Limited GI residence → poor bioavailability.

Gastro retention… a viable, but challenging alternative!

Need for Gastro retentive systems

Conventional system Gastro retentive drug delivery system

Drugs incorporated into GRDDS:

Drugs with narrow absorption window:

Acyclovir, Alendronate, Atenolol, Captopril, Cinnarizine,Ciprofloxacin, Cisapride, Furosemide, Ganciclovir, Glipizide,

Ketoprofen, Levodopa, Melatonin, Metformin, Minocyclin,

Misoprostol, Nicardipine, Riboflavin, Tetracycline, Verapamil,Vitamin E

Ideal Qualities:

- should not intervene with gastric motility

- should not damage GI.mucosa.

- should leave/disintegrate before the second

dose!

Advantages

Improved drug absorption, because of increased GRT and more

time spent by the dosage form at its absorption site.

Controlled delivery of drugs.

Delivery of drugs for local action in the stomach.

Minimizing mucosal irritation by drugs, by drug releasing slowly at a

controlled rate.

Treatment of gastrointestinal disorders such as gastro-esophageal

reflux.

Ease of administration and better patient compliance.

Limitations

They require a sufficiently high level of fluids in the stomach for the

drug delivery buoyancy, to float therein and to work efficiently.

Floating systems are not feasible for those drugs that have stability

problems in gastric fluid.

Drugs which are well absorbed along the entire GI tract and whichundergoes significant first- pass metabolism, may not be desirablecandidates for GRDDS since the slow gastric emptying may lead to

reduced systemic bioavailability.

Drugs that are irritant to gastric mucosa are not suitable for GRDDS.

GASTRORETENTIVE DRUG DELIVERY SYSTEMS

GASTRORETENTIVE TECHNOLOGIES

High density System

Floating Systems:

Floating drug delivery systems in which dosage formdensity is lower than the gastric content making it remain buoyant in thestomach for long duration of time .

FDDS can be divided into three types

i) Non-effervescent systems (Hydro dynamically BalancedSystem)

ii) Gas-generating systemsiii) Low density system

Expandable Systems

Super-porous Hydrogels

Bioadhesive Systems

Schematic localization of an intragastric floating system

and a high-density system in the stomach.

<

High density systems

Gastric contents have a density close to water (~1.004).

A density close to 2.5g cm-3 is necessary for significant

prolongation of gastric residence time.

The commonly used excipients in high density system includes

barium sulphate, zinc oxide, iron powder, and titanium dioxide.

The major drawback with such systems is that it is technicallydifficult to manufacture them with a large amount of drug (>50%)

and to achieve the required density of 2.4-2.8g/cm3.

Floating Systems

Single-unit floating dosage system1.

2.

Noneffervescent systems

Effervescent(gas-generating) systems

Multiple-unit floating dosage system1.

2.

3.

Noneffervescent systems

Effervescent (gas-generating) systems

Hollow microspheres

Raft-forming systems

Single-Unit Floating Dosage System

Noneffervescent Systems

These systems contain one or more hydrocolloids and are made into asingle unit along with drug and other additives.

When coming in contact with water, the hydrocolloids at the surface of thesystem swell and facilitate floating.

The coating forms a viscous barrier, and the inner polymer slowly getshydrated as well, facilitating the controlled drug release. Such systems arecalled “hydrodynamically balanced systems (HBS)”.

the polymers used in this system includeshydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,sodium carboxymethylcellulose, agar, carrageenans, and alginic acid.

Tablets were comprised

of an active ingredient, 0-

80% by weight of inert

materials, and 20-75% by

weight of one or more

hydrocolloids such as

methylcellulose, HPC,

HPMC, HEC, sodium

CMC, which upon

contact with gastric fluid

provided a water

impermeable colloid gel

barrier on the surface of

tablets. These tablets

could be layer-approach

or composite systems

Intra gastric floating tablet and floating bi layer tablet

Sheth and Tossounian, 1978

developed a HBS capsule

containing a mixture of a drug

and hydrocolloids. Upon contact

with gastric fluid, the capsule

shell dissolves; the mixture

swells and forms a gelatinous

barrier thereby remain buoyant

in the gastric juice for an

extended period of time.

Working of Hydrodynamically balanced system

Float Erode Diffuse (FED)Tablets:

1. Absorption window of Cipro:

stomach and duodenum (20-

30 cms long).

2. OD products.. a big challenge.

3. FED approach improved gastricresidence

2.Dissolution of Polymer

1.Floating of tablets 3.Release of Cipro

Gas-Generating Systems

Carbonates or bicarbonates, which react with gastric acid or anyother acid (e.g., citric or tartaric) present in the formulation toproduce CO2, are usually incorporated in the dosage form, thusreducing the density of the system and making it float on the media.

An alternative is incorporation of matrix containing portions of

liquid, which produce gas that evaporates at body temperature.

The main drawback of single unit dosage systems are high

variability of gastrointestinal transit time when orally administered

because of all-or-nothing nature of their gastric emptying.

Gas-generating systems

A multiple-unit oral floating dosage system

Stages of floating mechanism of a multiple-unit oral dosage form: (A) penetration

of water; (B) generation of CO2 and floating; (C) dissolution and diffusion of drug

Hollow Microspheres

Hollow microspheres possess the unique advantages of multiple-unit

systems and better floating properties as a result of the centralhollow space inside the microsphere.

The general techniques involved in their preparation include simple

solvent evaporation and solvent diffusion and evaporation.

The drug release and better floating properties mainly depend on

the type of polymer, plasticizer, and solvent employed for thepreparation.

Polymers such as polycarbonate, Eudragit S, and cellulose acetate

were used in the preparation of hollow microspheres.

Mechanism of the formation of hollow microspheres usinga) DCM+ethanol and b) ethylacetate

Preparation and Mechanism of Microballoon formation

Raft-Forming Systemsthis system is used for delivery of antacids and drug delivery fortreatment of gastrointestinal infections and disorders.

Usually the system contains a gel-forming agent and alkalinebicarbonates or carbonates responsible for the formation of CO2 tomake the system less dense and more apt to float on the gastricfluids.

The mechanism involved in this system includes the formation of aviscous cohesive gel in contact with gastric fluids, wherein eachportion of the liquid swells, forming a continuous layer called raft.

This raft floats in gastric fluids because of the low bulk densitycreated by the formation of CO2.

Expandable systems

These systems include Unfoldable and Swellable systems.

Unfoldable systems are made of biodegradable polymers. The concept is tomake a carrier, such as a capsule, incorporating a compressed systemwhich extends in the stomach.

Swellable systems are retained because of their mechanical properties. Theswelling is usually results from osmotic absorption of water.

The dosage form is small enough to be swallowed, and swells in gastricliquids. The bulk enables gastric retention and maintain the stomach in fedstate.

The whole system is coated by an elastic outer polymeric membrane whichwas permeable to both drug and body fluids and could control the drugrelease.

The device gradually decreases in volume and rigidity as a result depletionof drug and expanding agent and/or bioreosion of polymer layer, enablingits elimination.

Expandable systems

Different geometric forms of unfoldable systems proposed by

Caldwell et al. From Caldwell et al. (1988).

Prior to administration(A) Drug reservoir (B) Swellable expanding agent (C) and the

whole enclosed by elastic outer polymeric envelope. Post administration Pressure of the

expanding agent (B) swells the elastic polymer (C). Drug is released from the dosage form

through the elastic polymeric envelope (C) as indicated by the arrow

As an osmotically controlled floating

system, the device comprised of a

hollow unit that was convertible

from a collapsed to an expanded

position and returnable to collapsed

position after an extended period of

time. A housing was attached to the

deformable unit and was internally

divided into a first and second

chamber with the chambers

separated by an impermeable,

pressure responsive movable

bladder. The first chamber contained

an active drug, while the second

contained a volatile liquid, such as

cyclopentane or ether that vaporizes

at physiological temperature to

produce a gas, enabling the drug

reservoir to float. To enable the unit

to exit from the stomach, device

contained a bioerodible plug that

allowed the vapor to escape.

Superporous hydrogels

Swellable agents with pore size ranging between 10nm and 10µm,

absorption of water by conventional hydrogel is very slow processand several hours may be needed to reach as equilibrium stateduring which premature evacuation of the dosage form may occur.

Superporous hydrogels swell to equilibrium size with in a minute,

due to rapid water uptake by capillary wetting through numerousinterconnected open pores.

They swell to large size and are intended to have sufficient

mechanical strength to withstand pressure by the gastriccontraction.

This is achieved by co-formulation of a hydrophilic particulate

material, Ac-Di-Sol.

A Superporous Hydrogel in its Dry and Transit of the Superporous HydrogelWater-swollen State

Alza’s gastroretentive OROS® system, showed prolonged gastric residence time in adogs (12-24 h).

In humans, in the fasted state, the average gastric residence time for the same

system was 33 minutes!!

Bioadhesive Particulate Carriers (BPCs)Safe and superior to single unit dosage forms.

Types:

1.Non specific Bioadhesive particulates:

- Non specific interaction with mucins

- Eg: coated liposomes, microspheres, nanospheres

2.Specific Bioadhesive particulates:

- Adhesion directly to the surface cells through specific interactions.

- very effective

- limited by their capacity to reach cell surface/toxicity issues.

- Eg: lectin conjugates

Bioadhesion and Mucoadhesion

Targets of orally administered BDDS

• Epithelial cell layer

• continuous mucus layer Bioadhesion• combination of both

Mucoadhesion

65

Mechanisms of Bioadhesion

Step 1 : wetting and swelling of polymer to permit intimate contactwith biological tissue

Step 2 : interpenetration of bioadhesive polymer(BP) chains andentanglement of polymer and mucin chains

66

Step 3 : Formation of chemical bonds between the entangledchains

Chemical bonds can include strong primary bonds (i.e., covalentbonds) as well as weaker secondary forces such as ionic bonds,Van der Waals' interactions, and hydrogen bonds.

67

Theories of Bioadhesion

Although the chemical and physical basis of mucoadhesionare not yet well understood, There are six classical theoriesadapted from studies on the performance of several materialsand polymer-polymer adhesion which explain thephenomenon

Electronic theory

Adsorption theory

Wetting theory

Diffusion theory

68

Electronic Theory

Electronic theory is based on the premise that both mucoadhesiveand biological materials possess opposing electrical charges.Thus, when both materials come into contact, they transfer electronsleading to the building of a double electronic layer at the interface,where the attractive forces within this electronic double layerdetermines the mucoadhesive strength (Mathiowitz, Lehr, 1999).

69

Adsorption Theory

According to the adsorption theory, the mucoadhesive device adheres tothe mucus by secondary chemical interactions, such as in van der Waalsand hydrogen bonds, electrostatic attraction or hydrophobicinteractions.

For example, hydrogen bonds are the prevalent interfacial forces inpolymers containing carboxyl groups.Such forces have been considered the most important in the adhesiveinteraction phenomenon because, although they are individually weak,a great number of interactions can result in an intense global adhesion

Its most widely accepted theory

70

Wetting Theory

The wetting theory applies to liquid systems which present affinity tothe surface in order to spread over it.This affinity can be found by using measuring techniques such as thecontact angle.The general rule states that the lower the contact angle then thegreater the affinity . The contact angle should be equal or close tozero to provide adequate spread ability

71

The Diffusion Theory

Diffusion theory describes the interpenetration of both polymer and mucinchains to a sufficient depth to create a semi-permanent adhesive bondIt is believed that the adhesion force increases with the degree of penetrationof the polymer chains.This penetration rate depends on the diffusion coefficient, flexibility andnature of the mucoadhesive chains, mobility and contact time.According to the literature, the depth of interpenetration required toproduce an efficient bioadhesive bond lies in the range 0.2-0.5 μm.

72