MODIFIED RELEASE DRUG DELIVERY SYSTEM

An overview about modified drug delivery,types and its technology.

1. A SEMINAR ON MODIFIED RELEASE DRUG DELIVERY SYSTEM PRESENTED BY : SHIV KUMAR M . P HARM ( P HA R MACEU TI C S ) DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY,MRSPTU

2. CONTENTS: INTRODUCTION TYPES OF MODIFIED RELEASE DOSAGE FORM DRUG CANDIDATE FOR ER PRODUCTS TECHNOLOGY FOR ER DRUG RELEASE EVALUATION OF MODIFIED RELEASE DOSAGE FORM

3. INTRODUCTION The term “modified release” refers to both delayed and extended release systems for oral administration as well as other delivery systems designed specifically to modify the release of poorly water-soluble drugs. 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. Modified release dosage forms are those that alter the timing and/or the rate of release of drug substance.

4. Examples of modified release dosage forms Systems Examples of drugs Oral drug products Diltiazem HCL (extended release) Diclofenac sodium (delayed release) Ondansetron (oral soluble film) Transdermal drug delivery system Clonidine (transdermal therapeutic system) Opthalmic drug delivery Controlled release pilocarpine

5. TYPES OF MODIFIED RELEASE DOSAGE FORM Delayed release Extended release Repeat action Targeted action

6. EXTENDED RELEASE One that allows a reduction in dosing frequency to that presented by a conventional dosage form. 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 . Examples-controlled release, sustained release and long acting drug products. 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 GI, pH, enzyme, pressure, etc. E.G – E nteric coated dosage forms like enteric coated aspirin, other NSAIDS, etc.

7. 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 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

8. D r u g - ca n d i d a t e s f o r ex t e n d e d release products 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) T h e y a r e u s e d i n t h e t r e a t m e n t o f chronic rather than acute conditions.

9. ER Coated Granules or Microspheres – Granules of drug may be coated with lipid materials such as beeswax, carnuba wax, glycerylmonostearate, acetyl alcohol, etc. Careful blending of coated and un-coated granules and with coatings of different thicknesses will provide drug release of desired characteristics. Examples: Toprol-XL ( M etoprolol succinate) tabs. (Astra); Indocin SR (indomethacin capsules (Merck); Technology of ER Dosage Forms

10. Technology of ER Dosage Forms 2.Embedding drug in slowly eroding or hydrophilic matrix system – The design comprises of the drug substance with 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 tablets( Roxane )

11. 3. Multitablet system S m a l l s ph e ro i d c o m p r e s s e d t a b l e t s 3 to 4 mm in diameter may be prepared to have varying drug release characteristics . T h e y m a y b e p l a c e d i n g e l a ti n capsule shells to provide the d esired pattern of drug release . E a c h c a p s u l e m a y c on t a i n 8 t o 1 minitablets, som e uncoated for immediate release and others coated for extended drug release.

12. 4. M ic r o e n c a p s u l a t e d d r u g MICROENCAPSULATION is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material. The product obtained by this process is called as Microcapsules .

13. The typical encapsulation process usually begins with dissolving the w a l l m a t e r i a l , s a y g e l a ti n , i n w a t e r . T h e m a t e r i a l t o b e e n c a p s u l a t e d i s added and the two-phase mixture thoroughly stirred . With the material to be encapsulated broken up to the d e si r e d p a r ti c l e si ze ,a s o l u ti o n o f a second material, usually acacia is added.

14. T h i s a ddi t i v e m a t e r i a l c o n c e n t r a t e s t h e gelatin into tiny liquid droplets . One of the advantages of microencapsulation is that the a d m i ni s t e r e d do s e o f a d r u g i s s ubdi v i d e d in t o sm a l l uni t s t h a t a r e spread over a large area of the gastrointestinal tract, which may e n h a n c e a b s o r p t io n b y d i m i ni s h i n g localized drug concentration .

15. 5. O s m o t i c p u m p OROS is the trademarked name owned by ALZA Corporation,which pioneered the use of osmotic pumps for oral drug delivery. The system is composed of a core t a bl e t s u rr o u n d e d b y a s e m i p e r m e a b l e membrane coating have a 0.4 mm di a m e t e r ho l e p r o du c e d b y l a s e r b e a m .

16. Osmotic core containing drug Osmotic delivery orifice Semi p erme a b l e membrane Osmotic pressure-controlled drug delivery system

17. The system is designed such that only a few drops of water are drawn into the tablet each hour. The rate of inflow of water and the function of the tablet depends upon the existence of an osmotic gradient between the contents of the bi-layer core and the fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant.

18. The drug release rate may be altered by o f t h e Changing the surface area , T h e thickness o r c o m p osit i on membrane , Changing the diameter of the drug release orifice.

19. SOME EXAMPLE OF OSMOTIC PUMP SYSTEM TRADE NAME MAUFACTURE GENERIC NAME Acutrim Ciba Phenylpropanolamine Covera-HS Searle verapamil Dynacirc CR Sandoz Isradipine Glucotrol XL Pfizer glipizide

20. I n vi t r o / I n v i v o c or r e l a ti on s (IVIVCs) I VIV C s i s c r i t ic a l t o t h e d e v e l op m e n t o f oral extended-release p r o d u c t s . A ss e ss i n g I V I VC s i s important t h r ou g hou t t h e p e r i o d s of product d e v e lo p m e n t , c li n ic a l e v a l u a t i o n , s ub m i ssi o n o f a n a pp li c a t i o n f o r FD A - a p p r o v a l f o r m a r k e t i ng , a n d du r i n g po s t- a pp r o v a l f o r a n y f o rm u l a t i o n m a nu f a ct u r i ng c h a n g e s. Three categories of IVIVCs are included in the document: LEVEL A LEVEL B LEVEL C EVALUATION OF MODIFIED-RELEASE DRUG PRODUCTS

21. Level A A predictive mathematical model for the relationship between the entire in vitro dissolution/release time course, e.g., the time course of plasma drug concentration or amount of drug absorbed. L e v e l B A predictive mathematical model of the r e l a t i o n s h i p b e t w ee n s u m m a r y parameters that characterize the in vitro and in vivo, time courses. Level C A predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time (or T 50 %) and a summary parameter that characterizes the in vivo time course (e.g. C max or AUC).

22. 2. DISSOLUTION STUDIES Reproducibility of the method Proper choice of the medium Maintainence of sink condition Dissolution rate as function of pH, ranging from 1-8

23. 3. EVALUATION OF IN-VIVO BIOAVAILABILITY DATA 1. PHARMACOKINETIC PROFILE Plasma drug conc.-time curve should adequately define bioavailabilty of drug from dosage form. The bioavailability data should demonstrate the extended release characteristics of the dosage form compared to reference/immediate release product.

24. 2 . RATE OF DRUG ABSORPTION For a extended release drug product to claim zero-order absorption . 3 . OCCUPANCY TIME The time required to obtain plasma drug levels within therapeutic window is known as occupancy time. For drugs whose therapeutic window are known , plasma drug conc. c an be m aintained above the minimum effective drug concentration .

25. REFERENCE Shargel leon, WU Pong Susanna, B.C. YU Andrew, Applied Biopharmaceutics and Pharmacokinetics, 5 th edition,rights by McGraw-hill, page no.- 516-551 . http :// accesspharmacy.mhmedical.com/content.aspx?bookid=513&sectionid=41488035 https :// en.wikipedia.org/wiki/Modifiedrelease_dosage https :// www.slideshare.net/arijabuhaniyeh/modified drug-release-pharmaceutics http :// gpublication.com/index.php/crbps/article/ download/476/186

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