ORAL CONTROLLED DRUG DELIVERY SYSTEM

Oral route has been the most popular and successfully used for controlled delivery of drugs because of convenience and ease of administration, greater flexibility in dosage form design and ease of production and low cost of such a system. The controlled release systems for oral use are mostly solids and based on the dissolution, diffusion or combination of both mechanisms in the control of release rate of drug. Definitions Diffusion: - A process of mass transfer of individual molecules of Substances. Membrane: - ormally used to a film separating phases. Diffusant: - !aterial that undergoes the transport is "nown as #iffusant $ %ermeant $ %enetrant !aterial transport across the film may be of passive &or' facilitated system. (n this system release rate of drug determined by diffusion through water insoluble polymer. 1. Diffusion controlled drug delivery system: These systems are broadly classified in to two categories: reservoir systems and monolithic systems. The mechanisms of both systems are )uite different Types of Diffusion Reservoir device: A core of drug surrounded by a polymeric membrane. Matrix device: (n which dissolved &or' dispersed drug distributed uniformly in act inert polymer matrix. *ate controlling step is not the dissolution rate but the diffusion of dissolved drug through a polymeric barrier. The drug release rate is never +ero order since diffusional path length increases with time as the insoluble matrix is gradually depleted of drug.

a). Reser oir !ontro""e# #ru$ #e"i ery syste%

(n a membrane controlled reservoir system the therapeutic agent is contained in a core surrounded by a thin polymer membrane and the active agent is released to the surrounding environment by diffusion process through the rate limiting membrane. ,or the reservoir type of systems the drug delivery rate remains fairly constant. These systems consist of a reservoir either solid drug dilute solution or highly concentrated drug solution within a polymer matrix, which in turn is surrounded by a film or membrane of a rate controlling of material. The drug release limiting structure is the polymer layer surrounding the reservoir. Since the polymer coating is essentially uniform the diffusion rate of active agent can be "ept fairly stable throughout the lifetime of the drug delivery system. Methods -' !icro encapsulation of drug particles .' %ress / coating of tablets. a' %articles coated by micro / encapsulation form a system in which drug is contained in coating film as well as in core of capsule. b' #rug release involves combination of #issolution 0 #iffusion. #issolution is a process that controls rate of drug delivery.

Polymers:

1ardened gelatin, !ethyl &or' 2thyl cellulose, %oly hydroxyl

methacrylate, 1ydroxy propyl cellulose, %oly vinyl acetate and 3axes. Rate controlling factors %olymer content of drug Thic"ness of coating 1ardness of microcapsule Disadvantage: 4hance of sudden drug dumping. Examples Products ico / 566 !easurin tab ctive !ngredient icotinic acid Acetyl salicylic acid M"# 7ones marion. Sunafi / 3inthdrop

b$ 1ere, the drug is dispersed in an insoluble matrix of rigid non swelloable hydrophobic material or swellable hydrophilic substances. !aterials used for rigid matrix are insoluble plastics such as %84 and fatty materials li"e stearic acid, bees wax, etc. 3ith plastic materials, the drug is generally "neaded with the solution of %84 in an organic solvent and granulated. 3axy matrix is prepared by dispersing the drug molten fat followed by congealing. The granules are then compressed in to tablets. %&ellable matrix systems are

popular for sustaining the release of highly water-soluble drugs. The material for such devices are generally hydrophilic gums and may be of natural origin &guar gum, tragacanth' semi synthetic &1%!4, 4!4, xanthan gum', or synthetic &polyacrylamide'. The gum and drug are granulated together with a solvent such as alcohol and compressed in to tablets. The release of drug from such initially dehydrated hydro gels involves absorption of water and desorption of drug via a swelling controlled diffusion mechanism. As the gum swells and the drug diffuses through it, the swollen mass, devoid of drug appears transparent or glassli"e and thereof the system is sometimes called as glassy hydrogel. #rug release follows ,ic"ian first order diffusion under e)uilibrium condition. '. Dissolution controlled drug delivery system A number of technical advancements have been recently made in developing new techni)ue. This techni)ue capable of regulating the rate of drug delivery, sustaining the duration of therapeutic action and targeting the delivery of drug to a tissue. -' 4ontrolled administration of therapeutic dose at a desirable delivery etc. .' !aintained of drug concentration within optimal therapeutic range for prolonged duration of treatment. 9' !aximi+ation of efficacy dose relationship. 5' *eduction of adverse side effects. :' !inimi+ation of the needs for fre)uent dose inta"e. ;' 2nhancement of patient compliance. Such systems are easiest to prepare. The drug present in such system may be the one: A slowly dissolving drug such as digoxin, salisylamide, gresiofulvin< such drugs acts as natural prolonged released products.

 #rug li"e ferrous sulfate that produce slow dissolving forms when it comes in contact with =( fluids. #rug li"e pentoxifylline having high a)ueous solubility and dissolution rate. (n case of systems, where the rate of diffusion from the solid surface through as unstirred li)uid film towards the bul" solution is rate limiting, i.e. the dissolution process is diffusion controlled, the flux >7? is expressed as: 7 @ -# &d4$dx' 3here, # @ diffusion coefficient d4$dx @ concentration gradient between the solid surface and bul" of the solution. (n term of flow rate of material &dm$dt' through unit area &A', the flux can be given as 7 @ &-$A' dm$dt ,or the system with linear concentration gradient and thic"ness of the diffusion layer >h? dc$dx @ &4b-4s'$h 3here, 4s represents the concentration at the solid surface, 4b is the bul" solution concentration. A combined e)uation for flow rate of material is given as dm$dt @ - &#A$h' &4b-4s' dm$dt @ "A &4s- 4b'

3here, " is intrinsic dissolution rate constant. !ostly dissolution controlled release products are divided in to two classes< En!apsu"ation #isso"ution !ontro" an# %atri& #isso"ution !ontro".

(t is governed by ,ic"?s Aaw of #iffusion. #rugs from a region of high conc to lower conc. until e)uilibrium is attained and that the rate of diffusion is directly proportional to the conc. gradient.

7 @ - #d 4m ( dx

--------- &-'

7 @ ,lux of drug across a membrane direction of decrease conc. # @ #iffusion co / efficient of drug in the membrane # cm $ dx @ change in conc of drug in memebrane over distance x.

(f it is assumed that drug on either side of membrane is in e)uilibrium with respective surface layer of membrane. Then 4onc inside the membrane surface can be related to 4onc is adBacent region by C @ 4m &6' $ 4o at D @ 6 C @ 4m & l ' $ 4l at D @ l 3here, C is %artition co / efficient, Assuming that # and C are constant 2)uation 1 integrated

7 @ - # C E4 $ l
E4 is the concentration difference across the membrane

(f the activity of drug inside the reservoir is maintained constant and value of C is less than unity Fero order release can be achieved. #rug is present as solid i.e its activity is unity for slab geometry, than describe below. dmt $ dt
@

A#C E4

$ l where, mt / is mass of drug released after time b

dmt $ dt - is steady release after time t.
A - Surface area of device #, C, l are defined

Matri& #isso"ution !ontro""e# syste%s

!atrix systems are also called as monoliths since the drug is homogeneously dispersed throughout a rate controlling medium. They are very common employ waxes such as beeswax, carnauba wax, hydrogenated castor oil, etc. which control 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. The wax embedded drug is generally prepared by dispersing the drug in molten wax and congealing and granulating the same. The drug release is often first-order from such matrices.

En!apsu"ation'!oatin$ #isso"ution !ontro""e# syste% (reser oir #e i!es)

1ere, the drug particles are coated or encapsulated by one of the several microencapsulation techni)ues with slowly dissolving materials li"e cellulose, %2=s, %oly methacrylate, waxes, etc. The resulting pellets may be filled as such in hard gelatin capsules or compressed in to tablets. The dissolution rate of coat depends upon the solubility and thic"ness of the coating which may range from 1 to 200 microns. (f drug released from matrix diffusion control Amt of drug release 8s S)uare root of time ------G Ainear. ) Dissolution and diffusion controlled drug delivery system: (nsoluble membrane %ore created by dissolution of soluble fraction of membrane 2ntry of dissolution fluid #iffusion of dissolved drug (n such system, the drug core is encased in a partially soluble membrane. %ores are thus created due to dissolution of parts of the membrane which: %ermit entry of a)ueous medium into the core and hence drug dissolution, and allow diffusion of dissolved drug out of the system.

An example of obtaining such a coating is using a mixture of ethyl cellulose with %8% or methyl cellulose< the latter dissolves in water and creates pore in the insoluble ethyl cellulose membrane. (n this, rate controlling factor is fraction of soluble polymer in the coat.

*smotic Drug Delivery

)RINCI)LE O* OSMOSIS Osmosis refers to the process of movement of solvent from lower concentration of solute towards higher concentration of solute across a semipermeable membrane.

dvantages -' #elivers drugs at +ero order release "inetics. .' Attainable delivery rate is significantly greater compared to diffusion based systems. 9' #elivery rate is independent of p1. 5' (nsitu prepared li)uid dosage forms. :' %ossible to design an osmotic pump for drugs with wide range of water Solubility. +imitations -' *e)uirement of special e)uipment. .' *esidence time varies. 9' (rritation or ulcer. *smotic gents ,ompound or mixture *smotic -atm$ pressure

%odium chloride "ructose Potassium chloride %ucrose Dextrose Potassium sulphate Mannitol

)./ ).. '0. 1.1 2' )3 )2

"ormulation : Osmotic pumps essentially contains, #*H=, S2!(%2*!2AIA2 !2!I*A 2. (f the drug does not possess any osmogenic property, the osmogenic salt &osmotic agent' 0 other sugars can be incorporated in the formulation Essential materials %emipermeable membrane 4ydrophilic and hydrophobic polymers 5ic6ing agents %olubili7ing agents %urfactants ,oating solvents Plastici7ers "+89 regulators Pore forming agents

Referen!es+
-. 8yas S%, Char *C. 4ontrolled drug delivery concept and advanced. pra"ashan< #elhi .66..pp. 6J/... - st 2dition, 8allabh

.. Irahman"ar #!, 7aiswal SI. Iiopharmaceutics and pharmaco"inetics - st 2dition, 8allabh pra"ashan< #elhi .66:.pp. 95K/:9.

9. 4hein L3. ovel drug delivery systems. .nd 2dition, ew Lor" -JJ.. pp. -9J/:K.