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controlled drug delivery


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“Ideal” Drug Delivery System:

“Ideal” Drug Delivery System Inert Biocompatible Mechanically strong Comfortable for the patient Capable of achieving high drug loading Readily processable Safe from accidental release Simple to administer and remove Easy to fabricate and sterilize Free of leachable impurities 2


Introduction Modified release dosage forms are drug delivery systems (DDS) which, by virtue of formulation and product design , provide drug release in a modified form distinct from that of the conventional dosage forms . Drug release can either be delayed or extended in nature. 3

Traditional vs. Controlled Release:

Traditional vs. Controlled Release With traditional administration, the drug active must remain between a maximum blood level value which may represent a toxic level and a minimum value below which the drug is no longer effective With controlled administration, the blood levels are constant between the desired maximum and minimum for an extended period of time 4

Traditional vs. Controlled Release Drug Dosing:

Traditional vs. Controlled Release Drug Dosing 09/010 5 5

Controlled Drug Delivery:

Controlled Drug Delivery Controlled drug delivery occurs when a polymer is combined with a drug or active agent such that the release from the bulk material is pre-designed. Advantages Eliminate over or underdosing Maintain drug levels in desired range Need for less dosing Increased patient compliance Prevention of side effects 6 6

Design of Controlled Drug Delivery:

Design of Controlled Drug Delivery Biopharmaceutic Characteristics of the Drug Molecular weight, Aqueous solubility, Partition coefficient, Drug Pka and Ionization, Route of administration, Drug stability etc Pharmacokinetic Characteristics of the Drug Absorption rate, Elimination Half-Life, Rate of metabolism etc. Pharmacodynamic Characteristics of the Drug Therapeutic Range, Therapeutic index, Plasma concentration response relatioship 09/08/2010 7 7

Delayed-release products:

Delayed-release products Usually enteric coated tablets or capsules designed to pass through the stomach unaltered to release their medication within the intestinal tract. 8

Extended-release products:

Extended-release products Designed to release their medication in controlled manner , at pre-determined rate, duration and location in the body to achieve and maintain optimum therapeutic blood levels of drug. 9

Rationale for extended release pharmaceuticals:

Rationale for extended release pharmaceuticals Drugs that are not inherently long lasting require multiple daily dosing to achieve the desired therapeutic effects. Multiple daily dosing is often inconvenient and can result in missed doses, made-up doses and patient non-compliant with therapeutic regimen. Blood levels of drugs from conventional immediate-release dosage forms taken more than once daily following definite schedule usually demonstrate sequential peaks and troughs (valleys) associated with each dose. 10

Rationale for extended release pharmaceuticals:

Rationale for extended release pharmaceuticals Extended release tablets or capsules are commonly taken only once or twice daily compared with the conventional dosing of 2 to 4 times daily Products are designed to provide an immediate release of drug which promptly produces the desired therapy, followed by gradual and continual release of additional amounts of drug to maintain this effect over a predetermined period of time. The need for night dosing of drugs may be eliminated 11


Terminology The following terms have been applied to “extended” or “sustained” drug delivery systems: Controlled-release Extended release (ER) Sustained-release (SR) Timed-release (TR) Long-acting (LA) Prolonged-action (PA), and Sustained-action (SA) 12

Extended-release dosage forms:

Extended-release dosage forms The US FDA defines ER dosage form as: one that allows a reduction in dosing frequency to that presented by a conventional dosage form such as a solution or an immediate release dosage forms. 13


Delayed-release These are dosage forms designed to release the drug at a time other than promptly after administration. The delay may be time-based or based on the influence of environmental conditions such as g.i. pH, enzyme, pressure, etc 14

Repeat action:

Repeat action These are dosage forms usually containing 2 single doses of medication, one for immediate and the second for delayed release e.g. bi-layered tablets. 15

Targeted release:

Targeted release Drug release that is directed towards isolating or concentrating a drug in a body region, tissue, or site for absorption or drug action 16

Extended-release Oral Dosage Forms:

Extended-release Oral Dosage Forms The general properties of drugs best suited for ER product design are : They exhibit neither very slow nor very fast rates of absorption and excretion They are uniformly absorbed from the g.i.t. They are administered in relatively small doses. They possess a good margin of safety i.e. Therapeutic Index (TI) 17

Technology of ER Dosage Forms:

Technology of ER Dosage Forms ER Coated Beads, Granules or Microspheres – Granules of drug may be coated with lipid materials such as beeswax, carnuba wax, glyceryl monostearate, cetyl alcohol, etc. Careful blending of coated and un-coated granules and with coatings of different thicknesses will provide drug release of desired characteristics. 18

Technology of ER Dosage Forms - Multitablet system :

Technology of ER Dosage Forms - Multitablet system 19

Technology of ER Dosage Forms:

Technology of ER Dosage Forms Embedding drug in slowly eroding or hydrophilic matrix system – The design comprises of the drug substance plus excipient material that slowly erodes in body fluids thereby progressively releasing the drug for absorption E.g. Quinidex ® Quinine SO 4 tablets (Robins); Oramorph ® SR Morphine SO 4 tabs. Roxane ® 20

Technology of ER Dosage Forms: ER Microencapsulated Drug :

Technology of ER Dosage Forms: ER Microencapsulated Drug –Microencapsulation is a process by which solids, liquid and semi-solid substances may be encapsulated into microscopic size particles through the formation of thin coating of “wall” material around the substance. Different rate of drug release can be obtained by changing the core to wall ratio, the type of polymer coat and the method of microencapsulation. E.g. K- Dur ® Microburst Release System ( KCl ) tabs. (Key) 21

Other methods :

Other methods Embedding drug in an inert plastic matrix – e.g. Desoxyn ® (methamphetamine HCl) tabs (Abbott); Procanbid ® (procainamide HCl tabs. (Parke-Davis) Complex formation Ion exchange resins 22

Kinetics of Drug release:

Kinetics of Drug release Drug release from conventional dosage forms, like the other processes of ADME, are governed by the first-order kinetics model. In First-order model, drug release is dependent on the amount of drug available for release and therefore the rate of release declines exponentially with time . 23

PowerPoint Presentation:

The models are : Zero order release model First order release model Hixson - Crowell release model Higuchi release model Korsemeyer – Peppas release model

Zero order release model:

Zero order release model The equation is, Q t = Q 0 + k 0 t where, Q 0 = initial amt of drug Q t = cumulative amt of drug release at time t K 0 = constant t = time (hrs) Here, the release rate is independent of its concentration.

PowerPoint Presentation:

The plot between t(hrs) Qt gives straight line that starts from origin. APPLICATION : Modified release dosage forms like coated form, osmotic systems, transdermal systems etc…

First order release model:

First order release model The equation is, log Q t = log Q 0 + kt/2.303 Where, Q0 = initial concentration Qt = cumulative amt of drug release at time t K = constant t = time (hrs) Here, the release rate is depends on its concentration.

PowerPoint Presentation:

The plot between Time (hrs) Vs log cumulative % of drug remaining to be release gives straight line. APPLICATION : Water soluble drugs in porous matrix. TIME LOG CUM.%DRUG

Hixson – Crowell release model:

Hixson – Crowell release model The equation is, W 0 1/3 - W t 1/3 = ks t Where, W 0 = initial amt of drug W t = remaining amt of drug ks = constant t = time (hrs)

PowerPoint Presentation:

The plot of cube root of initial conc. Minus cube root of % remaining VS time. APPLICATION : Used for drug release by dissolution mechanism. TIME CUBE ROOTIFINITIAL-CUBRRR0T %OFREMAINING

Higuchi release model:

Higuchi release model The equation is, Q = ( t D Cs (2C – Cs)) 1/2 Where, D = diffusion coefficient The higuchi model is applicable to drug release by diffusion mechanism.

PowerPoint Presentation:

APPLICATION : Water soluble drugs and also to low water soluble drugs incorporated to solid/semisolid polymer matrix.

Korsemeyer – Peppas release model:

Korsemeyer – Peppas release model The equation is, F = (M t /M) = k m t n Where, F = fraction of drug release at time t Mt = amt of drug release at time t M = total amt of drug in dosage form K = constant

PowerPoint Presentation:

‘n’ is estimated from linear regression of log (Mt/M) Vs log t. If n = 0.45 indicates fickian diffusion. 0.45<n<0.89 indicates non fickian diffusion. Non fickian diffusion refers to combination of both diffusion and erosion controlled rate release. APPLICATION : Use to analyze the release of p’ceutical polymeric dosage form. When the release mechanism is not known or when more than one type of release phenomena could be involved.

PowerPoint Presentation:


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