BY DIPANKAR SARKHEL

Definitions
Advantages

& disadvantages classification

DEFINITIONS
Sustained-release(SR) drugs are designed so that the drug's active ingredient is released slowly into the body over a period of time, rather than all at once Sustained action (SA) tablets are those that releases its active ingredient in specified doses at timed intervals. Also called sustained-release tablets. Extended-release (ER, XR, or XL) tablets are those that have special coatings or ingredients that control how fast the drug is released from the pill into your body. This may allow you to take certain medications only once or twice a day, instead of more often. Time-release tablets are those in which the drug is released at regular time intervals

Increased patient compliance less frequent dosing more acceptable (e.g., needle-less) Safety can control PK to remain within Therapeutic Index Improved therapy can time release environmentally-responsive systems Decreased cost lower doses->more efficient use of drug Greater profits patent extension for drug controlled release feature more profitable

An Ideal CDDS is the one which delivers the

drug at a predetermined rate, locally or systematically, for a specific period of time.

The CDDS attempts to..

Sustained drug action Localize the drug action Targeted drug action Physiologically/Therapeutically based DDS

CDDS = CONTROLED DRUG DELIVERY SYSTEMS DDS = DRUG DELIVERY SYSTEM

 Total

Drug Local Side Effects Potentiation or Reduction Control of Condition Special Effects Therapeutic Drug Concentration Rates of Extended Duration Activity Dosing and Wasting Economy

 In

vitro-In vivo correlation Dose dumping Retrieval of Drug Cost of Formulation

CONTROLED RELEASE vs IMMEDIATE RELEASE

1. Biopharmaceutic characteristics: Molecular weight of drug Aqueous solubility of drug Apparent partition coefficient of drug Drug pKa and ionization at physiologic pH Drug stability Mechanism and site of absorption

 Absorption

rate Rate of metabolism Elimination half life Dosage form index

 Therapeutic

range Therapeutic index Plasma concentration- response relationship.

1. ROUTES OF DELIVERY (e.g., Oral, Injected, Transdermal...) 2. BODY SITE OF DELIVERY (e.g., Blood, Liver, Lungs, Pancreas) 3. LOCAL SITE FOR ACTION (e.g., Body Fluids, Cell Surface, Intracellular) 4. MECHANISM OF DELIVERY (e.g., Drug Diffusion, Swelling, Degradation..) 5. DISEASE (e.g., Cancer, Glaucoma, Diabetes..)

 Based

on the Route of Administration:

Oral Parenteral Transdermal Ophthalmic Intra-Vaginal & Intra-Uterine

Based

on Mechanism of Delivery

BUCCAL :The tablets are kept in buccal cavity and they are degraded slowly releasing the drug ADVANTAGES : Rapid absorption due to high vascularisation . No First pass hepatic metabolism No degradation of drugs such as in GIT . LIMITATIONS : Limited Mucosal surface . Concern for taste .

 BUCCAL

SUB LINGUVAL:-

Sublingual tablets are kept under the tongue by which drugs diffuse into the blood through tissues under the tongue. ADVANTAGES : Rapid absorption due to high vascularisation . No First pass hepatic metabolism No degradation of drugs such as in GIT . LIMITATIONS : Limited Mucosal surface . Concern for taste .

 SUB

LINGUAL:-

Enteric coated tablets: Controls the location in the digestive system Enteric refers to the small intestine, therefore Enteric coatings prevent release of medication before it reaches the small intestine Advantages: Prolonged action Drugs which are degraded in stomach Drugs which have unpleasant taste or reflux Dis advantages: Enteric coatings take a long time to reach the small intestine where they are absorbed.

ENTERIC COATED TABLETS:-

EXTENDED RELEASE TABLETS: Special coatings or ingredients that control how fast the drug is released from the pill into your body. Medications can be taken once or twice daily instead of frequent dosing Advantages Extended-release products offer 3 potential benefits: sustained blood levels attenuation of adverse effects improved patient compliance

EXTENDED RELEASE TABLETS:-

A medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. These are of two types 1. Monolithic systems 2. Reservoir systems MONOLITHIC (OR MATRIX) SYSTEMS: Used when R2 is rate-controlling step(R2<R1) and the drug has a large therapeutic index Polymers employed for these systems may be hydrophilic or lipophilic They include PVC,PVP, polysaccharides, polyesters, microporous polypropylene and ethylene vinyl acetate copolymers

Drug release is rapid initially and gets falls as the matrix gets depleted Rate of drug release is proportional to the square root of time

RESERVOIR (or MEMBRANE) DEVICES: Used when drug permeation rate is rapid and absorption should be controlled Suitable for potent drugs with low therapeutic index where monitoring drug levels in a narrow range is essential This drug usually contain within a reservoir as suspension in liquid or gel carrier Rate controlling thin polymeric membrane is made of olefinic polymers and copolymers, cellulosic esters, polyamides or PVC Initially it shows rapid release followed by zero order release as the solution inside the reservoir is saturated

MIXED MONOLITHIC-RESERVOIR DEVICES: This has drug release kinetics intermediate between monolithic and reservoir systems In this drug polymer matrix is layered by a rate controlling membrane Initially drug is released later it gets depleted

Advantages: Drugs with very short half lives E.g -nitroglycerine Drugs with narrow therapeutic index can be safely administered The noninvasive nature of these systems permits easy removal and termination of drug action in situations of toxicity Problems encountered with oral administration like degradation, gastric irritation. First pass effect, etc. are avoided

DISADVANTAGES: Large drug dose Drugs having large molecular size Drugs which are skin sensitive and irritating Drugs undergo metabolism in skin Drugs undergoes protein binding in skin

Absorption of ophthalmic drugs across the corneal membrane depends to large extend on 1. Physicochemical properties of permeating molecule 2. Drainage and output of tears High viscous preparations like suspensions and ointments are intended to achieve the purpose Number of ocular drug delivery systems are developed to provide zero-order input like
Ocular insert Occusert

Pilocarpine in treatment of glaucoma Provides relief for two days

 The system is basically a thin, flexible wafer, composed of a drug reservoir core surrounded on either side by rate controlling membranes of ethyl vinyl acetate copolymer Advantages: Rapid absorption sustained blood levels
Dis advantages: Irritation Poor patience compliance

The insertion of drugs into the vagina to treat local infections, neoplasms, or to induce labor. The dosage forms may include
medicated pessaries irrigation fluids suppositories.

Two types of medicated intrauterine devices (IUD) are developed to produce for contraception for 12 months 1. Copper medicated IUD:

Consists of polypropylene or polyethyl plastic (like T shape) with copper wire around them Oxidation of copper in the body fluids release its ions slowly Effective for more than 3 years

2.

Progesterone releasing IUD:

T shaped polyethylene device with progesterone reservoir dispersed in a silicon polymer Effective for one year

INTRA-VAGINAL & INTRA-UTERINE

Advantages: Hepatic first pass elimination of high clearance drugs may be avoided partially. Contact with digestive fluid is avoided, thereby preventing enzymatic degradation of some drugs. Drug delivery can be stopped by removing the dosage form e.g. vaginal rings. Rapid drug absorption and quick onset of action can be achieved. The vaginal bioavailability of smaller drug molecules is good. The bioavailability of larger drug molecules can be improved by means of absorption Self medication is possible.

Dis advantages: Some of the drugs are sensitive at the vaginal pH Local irritation of some drugs. Influence of sexual intercourses. Gender specificity. Personal hygiene. Sometimes leakage of drugs from vagina and wetting of under garments.

Further classified depending on the Mechanism of Delivery Continuous Release Systems Dissolution CRS Diffusion CRS Dissolution & Diffusion CRS Ion-Exchange Resin-Drug Complexes Slow dissolving salts & Complexes pH-Dependent formulations Osmotic Pressure CRS Hydrodynamic Pressure CRS

Delayed Transit & Continuous Release Systems

Altered Density Systems Mucoadhesive Systems Size-based systems Intestinal CRS Colonic CRS

Delayed Release Systems

 Dissolution

Controlled:

Slow the dissolution rate Slow dissolving forms High Aqueous Solubility and Dissolution Rate

Techniques

employed are:

Embedment in the slowly dissolving or erodible matrix Encapsulation or coating with slowly dissolving or erodible matrix

Homogenously dispersed through out a ratecontrolling medium

Waxes as Bees wax, Carnauba wax, hydrogenated castor oil, etc.

Control the drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by altering the porosity of tablet, decreasing its wettability or by itself getting dissolved at a slower rate.

 Reservoir Devices

Drug particles are coated or encapsulated Slowly dissolving materials like Cellulose, PEG, waxes,

Polymethylacrylates, etc.

Pellets resulted may be filled as such in Capsules or compressed into tablets.

Dissolution rate depends on the solubility and thickness of

coating (1-200 microns).

 Diffusion

Controlled:

Slow the diffusion rate Its never a zero-order since the diffusional path length increases with time as the insoluble matrix is gradually depleted of drug.

Techniques

employed are:

Embedment in the reservoir and erodible matrix

Matrix Diffusion Controlled Systems:

Here the drug is dispersed in an insoluble

matrix of rigid non Swellable hydrophobic

materials or Swellable hydrophilic materials.

Diffusion of the dissolved drug through the matrix.

R i g i d M a t r i x : insoluble plastics like PVP and fatty materials like Stearic acid, Bees wax, etc.

Sustaining the release of highly water soluble drugs.

Materials are generally hydrophilic gums (Guar gum, Tragacanth, HPMC, CMC, Poly Acrylamides).

The release of the drug from such initially dehydrated hydro gels involves simultaneous absorption of water and desorption of drug via a swelling controlled diffusion mechanism.

Reservoir Systems:

Laminated matrix devices a reservoirwhether solid drug, dilute solution, or highly

concentrated drug solution within a polymer matrixis

surrounded by a film or membrane(water insoluble) of a rate-controlling material.

HPC, EC, Polyvinyl Acetate. Sudden dumping which is not in matrix devices.

The drug core is encased in a partially soluble

membrane.

An example of such a coating is using a mixture of EC

& PVP or MC.

Pores are thus created due to dissolution of parts of the membrane which:

Permit entry of aqueous medium into the core and

hence drug dissolution, and

Allow diffusion of dissolved drug out of the system.

Complex formation between drug and resins Ionizable acidic drug with insoluble nontoxic anion exchange Ionizable Basic drug with insoluble nontoxic cation exchange Release of drug by diffusion through resin particle structure. No. of basic drugs like Noscapine, Phenylpropanolamine , phentermine. Incubating the drug resin solution or by passing the drug solution through a column of ion-exchange resin. Can be coated with Cellulose or Hard paraffin and formulated as ion free suspension for pediatrics.

Salts or complexes of drugs which are slow soluble in

GI fluids can be used for control release active principle Amine drugs with tannic acid to form poorly soluble complexes that can be formulated as long acting tablets. Penicillin G with N, N- dibenzyl ethylenediamine to give Benzathine Penicillin G- Oral Suspension. Can be obtained by simple acid-base reaction on mixing together solutions of individual compounds.

To eliminate the influence of changing GI pH on

dissolution and absorption of drugs by formulating them with sufficient amount of buffering agents that

adjust the pH to the desired value as the dosage form

passes along the GIT and permit drug dissolution and release at a constant rate independent of GI pH.

Dosage form is coated with a permeable substance

that allows entry of aqueous medium but prevents dispersion of the tablet.

The fabrication of this system comprises of an application of

a semi-permeable membrane (Cellulose ester or ether) around a core of an osmotically active drug or osmotically inactive drug in combination with an osmotically active

salt(KCl or Mannitol).

A delivery orifice is drilled in each system by a laser or by a high-speed mechanical drill(0.4mm). When exposed to the GI fluids, water flows through the semi-permeable membrane into the tablet due to Osmotic pressure difference which dissolves the drug and pumps it out through the orifice by the osmotic force.

Push-Pull Osmotic Pumps

Hydrodynamic pressure generated by swelling of hydrophilic gum.

Construction:

Gum: Polyhydroxyalkyl Methacrylate

Delayed transit time If the residence time of the drug in the stomach and/or intestine is prolonged in some way, the frequency of dosing can be reduced. 3 ways to achieve 1. Altering the density of drug particles: Floating tablets High density: 1.4 g/c.c Iron oxide, titanium dioxide,barium sulfate. Low density : less than 1 g/c.c Poprice and Celluloses Drug is coated on a heavy Core and covered by Diffusion control membrane

The basis of muco adhesion is that a dosage form

can stick to the mucosal surface by different mechanisms.

Examples for Materials commonly used for

bioadhesion are poly(acrylic acid) (Carbopol, polycarbophil), chitosan, Gantrez (Polymethyl vinyl

ether/maleic anhydride copolymers), cholestyramine,

tragacanth, sodium alginate.

 Gastric

emptying of a dosage form can be delayed in fed state if its size is greater than 2mm Dosage form of size 2.5 cm or larger is often required to delay emptying long enough to allow once daily dosing. Such forms are difficult to swallow

 Only

specific site in GIT. Drugs in this type are:

Destroyed in stomach or by intestinal enzymes Cause gastric distress Absorbed from specific internal site Meant to exert local effect at a specific GI site

Two
1. 2.

types of delayed release systems:

Intestinal Release Systems Colonic Release Systems

Enteric coated
Distal end of small intestine for absorption via Peyers patches or Lymphatic system.(absorb macro molecules

by endocytosis ) or (highly lipophilic agents)

Prevents destroying by intestinal enzymes Such a site can be used for oral delivery of Insulin.

2 mechanisms for absorption:

Chylomicrons- fatty vesicles entrap hydrophobic drugs Pinocytic uptake of Macromolecules

Drugs are poorly absorbed through colon but may be delivered to such a site for 2 reasons: Local action as in treatment of Ulcerative colitis with mesalamine Systemic absorption of protein and peptide drugs like Insulin and Vasopressin. Advantage is taken on the following facts: pH sensitive bio-erodible polymers release the medicament only in alkaline pH of the colon Use of divinyl benzene cross-linked polymers that can be cleaved by the azoreductase of colonic bacteria