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Controlled Release Oral Drug Delivery System:

Controlled Release Oral Drug Delivery System Represented By: Ambore S. M. Guidance By : Patwekar S. L. S.R.T.M. UNIVERSITY, NANDED.

Contents:

2 Contents Overview of Digestive system Introduction Advantages Disadvantages Mechanisms 1.Dissolution 2.Diffusion 3.Combination of Dissolution & Diffusion 4.Osmotic pressure controlled system 5. ion exchange controlled system References

Digestive System:

3 Digestive System

Concept:

4 Concept Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time. Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of GIT.

Plasma concentration time profile:

5 Plasma concentration time profile

Challenges in Oral Drug Delivery:

6 Challenges in Oral Drug Delivery Development of drug delivery system Delivering a drug at therapeutically effective rate to desirable site . Modulation of GI transit time Transportation of drug to target site. Minimization of first pass elimination

Advantages:

7 Advantages Total dose is low. Reduced GI side effects. Reduced dosing frequency. Better patient acceptance and compliance. Less fluctuation at plasma drug levels. More uniform drug effect Improved efficacy/safety ratio.

Disadvantages:

8 Disadvantages Dose dumping. Reduced potential for accurate dose adjustment. Need of additional patient education. Stability problem.

Mechanism aspects of Oral drug delivery formulation:

9 Mechanism aspects of Oral drug delivery formulation 1.Dissolution : 1.Matrix 2.Encapsulation 2.Diffusion : 1.Matrix 2.Reservoir 3.Combination of both dissolution & diffusion. 4.Osmotic pressure controlled system

Dissolution Definition::

10 Dissolution Definition : Solid substances solubilizes in a given solvent. Mass transfer from solid to liquid. Rate determining step: Diffusion from solid to liquid. Several theories to explain dissolution – Diffusion layer theory (imp) Surface renewal theory Limited solvation theory.

Matrix Type:

11 Matrix Type Also called as Monolith dissolution controlled 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 by dissolution rate of polymer. Examples: Dimetane extencaps, Dimetapp extentabs. Soluble drug Slowly dissolving matrix

Encapsulation:

12 Encapsulation Called as Coating dissolution controlled system. Dissolution rate of coat depends upon stability & thickness of coating. Masks colour,odour,taste,minimising GI irritation. One of the microencapsulation method is used. Examples: Ornade spansules, Chlortrimeton Repetabs Soluble drug Slowly dissolving or erodible coat

Diffusion:

13 Diffusion Major process for absorption. No energy required. Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attainded. Directly proportional to the concentration gradient across the membrane.

Matrix Diffusion Types:

Matrix Diffusion Types Rigid Matrix Diffusion Materials 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 14

Matrix system:

15 Matrix system Rate controlling step: Diffusion of dissolved drug in matrix.

Higuchi Equation:

16 Higuchi Equation Q = DE/T (2A.E Cs)Cs.t) 1/2 Where , Q=amt of drug release per unit surface area at time t. D=diffusion coefficient of drug in the release medium. E=porosity of matrix. Cs=solubility of drug in release medium. T=tortuosity of matrix. A=concentration of drug present in matrix per unit volume.

Reservoir System:

Reservoir System Also called as Laminated matrix device. Hollow system containing an inner core surrounded in water insoluble membrane. Polymer can be applied by coating or micro encapsulation. Rate controlling mechanism - partitioning into membrane with subsequent release into surrounding fluid by diffusion. Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate. Examples: Nico-400, Nitro-Bid 17

Reservoir System:

18 Reservoir System Rate controlling steps : Polymeric content in coating, thickness of coating, hardness of microcapsule.

Dissolution & Diffusion Controlled Release system:

19 Dissolution & Diffusion Controlled Release system Drug encased in a partially soluble membrane. Pores are created due to dissolution of parts of membrane. It permits entry of aqueous medium into core & drug dissolution. Diffusion of dissolved drug out of system. Ex- Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane. Insoluble membrane Pore created by dissolution of soluble fraction of membrane Entry of dissolution fluid Drug diffusion

Osmotic Pressure Controlled Drug Delivery System:

20 Osmotic Pressure Controlled Drug Delivery System Definition Procedure Diagram Modifications

Slide 21:

21 Osmosis - Movement of solvent from lower to higher concentration. - The passage of solvent into a solution through semipermeable membrane. Semipermeable Membrane Molecules are permitted only to one component (Water). Osmotic pressure It is the hydrostatic pressure produced by a solution in a space divided by a semipermeable membrane due to difference in concentration of solutes.

Osmotic Pressure Controlled System:

31/12/2009 Nepal Pharmaceutical Ltd., Nepal 22 Osmotic Pressure Controlled System Provides zero order release Drug may be osmotically active, or combined with an osmotically active salt (e.g., NaCl). Semipermeable membrane usually made from cellulose acetate. More suitable for hydrophilic drug. Examples: Glucotrol XL, Procardia XL,

Equation:

23 Equation (Q/t) z = Pw Am/ hm ( π s- π e ) (Q/t)= Rate of zero order drug release. Pw, Am & hm= water permeability, effective surface area & thickness of semipermeable membrane. π s= osmotic pressure of saturated solution of osmotically active drug or salt in system. π e = osmotic pressure of GI fluid.

Osmotic Pressure Controlled System:

24 Osmotic Pressure Controlled System

Osmotic Pressure Controlled System:

25 Osmotic Pressure Controlled System

Modifications:

Modifications - Immediate release system. - Osmotically active compartment system

Immediate Release System:

27 Immediate Release System Activation of system is done. Dividing a dose into two parts. One third immediate release. Two third controlled release. Encapsulated into semipermeable membrane. e.g. : Phenyl propanolamine.

Osmotically active system:

28 Osmotically active system Two compartments separated by movable partition. Osmotically active compartment absorbs water from GIT. Creates osmotic pressure. Partition moves upward & then drug releases. Ex: Nifedipine. Movable partition Delivery orifice Osmotically active compartment Drug compartment

Ion-Exchange Systems:

Ion-Exchange Systems Ion-exchange systems generally use resins composed of water soluble cross-linked polymers These polymers contain salt forming functional groups in repeating position on the polymer chain The drug is bound to the resin and released by exchanging with appropriately charged ions in contact with the ion exchange groups Resin + - drug - + X - resin + - X - + drug - Where X- are ions in the GI tract 29

Membrane permeation-controlled drug delivery system:

Membrane permeation-controlled drug delivery system In this type, drug is totally or partially encapsulated within drug reservoir. Its drug release surface is covered by a rate-controlling polymeric membrane having a specific permeability. Drug reservoir may exist in solid, suspension or solution form. 30

Slide 31:

Release of drug molecules is controlled by : Partition coefficient of the drug molecule. Diffusivity of the drug molecule. The thickness of the rate controlling membrane 31/12/2009 Nepal Pharmaceutical Ltd., Nepal 31

Slide 32:

The drug reservoir is a suspension of progesterone & barium sulphate in silicone medical fluid & is encapsulated in the vertical limb of a T-shaped device walled by a non-porous membrane of ethylene-vinyl acetate co-polymer. It is designed to deliver natural progesterone continuously in uterine cavity at a daily dosage rate of at least 65 μ g/day to achieve contraception for 1 year. Ex. Progestasert IUD 32

pH- activated drug delivery system:

pH- activated drug delivery system This type of chemically activated system permits targeting the delivery of drug only in the region with selected pH range. It fabricated by coating the drug-containing core with a pH – sensitive polymer combination. For instances, a gastric fluid labile drug is protected by encapsulating it inside a polymer membrane that resist the degradative action of gastric pH. 33

Slide 34:

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Slide 35:

In the stomach, coating membrane resists the action of gastric fluid (pH<3) & the drug molecule thus protected from acid degradation. After gastric emptying the DDS travels to the small intestine & intestinal fluid (pH>7.5) activates the erosion of the intestinal fluid soluble polymer from the coating membrane. This leaves a micro porous membrane constructed from the intestinal fluid insoluble polymer, which controls the release of drug from the core tablet. The drug solute is thus delivered at a controlled manner in the intestine by a combination of drug dissolution & pore-channel diffusion. 35

Some Popular Brand names used for OCDDS:

36 Some Popular Brand names used for OCDDS Spansule capsule ( SK & F ) Sequal capsule (Lederle ) Extentab tablets ( Robins ) Timespan tablet ( Roche ) Dospan tablet ( Merrell Dow ) Chronotab tablet ( Schering ) Plateau capsule ( Marion ) Tempule capsule ( Armour )

Some Examples of OCDDS:

37 Some Examples of OCDDS Propranolol (Inderal LA) Methyiphenidate HCl (RitalinSR) Iron (Slow-Fe) GITS-Prazosin (Minipress) Morphine sulfate (Roxanol SR) Decongestant & antihistamine (Resaid SR, Novafed SR Dristan) Pseudoephedrine HCI (Sudafed SA) Potassium (Micro-K, Slow-K, Klotrix) Antitussive combinations (Rescap, Ornade Spansules) Chlorpheniramine maleate (ChlorTrimeton) Decongestant, antihistamine and anticholinergic (Dallergy, Supres)

Recent Trends : Extended release formulation of Bupropion:

38 Recent Trends : Extended release formulation of Bupropion Bupropion is used in the treatment of major depressive disorder. Conventional formulation has to be administered 3 times daily Initially 150 mg ER formulation was introduced for bid regimen Later on 300 mg ER formulation was introduced for once daily regimen For ER formulation provide similar Cmax and AUC values as compared to immediate release formulation at steady state.

Recent Trends : Extended release formulation of Bupropion:

Recent Trends : Extended release formulation of Bupropion

Recent Trends: OROS Technology (ALZA corporation):

40 Recent Trends: OROS Technology (ALZA corporation) Single layer tablet: Drug core (water soluble drug with or without excipients) Semipermeable membrane with a drilled orifice Water imbibition by the core because of osmotic action results in drug dissolution, which is released at a controlled rate through the orifice Not suitable for water insoluble drugs. Examples: Sudafed 24 hours (Pseudoephedrine); Volmax (Salbutamol) ELEMENTARY OSMOTIC PUMP

Recent trends: Geomatrix® (SKY Parma):

41 Recent trends: Geomatrix® (SKY Parma) This technology Controls amount, timing and location of release in body. -Formulation with predictable and reproducible drug release profile. Controls rate of drug diffusion throughout release process, ensuring 100% release Products Products in market: Cordicant -uno® Madopar DR SULAR ER

References:

31/12/2009 Nepal Pharmaceutical Ltd., Nepal 42 References Novel drug delivery system , volume 50, Y.W.Chien The theory & practice of industrial pharmacy, Leon Lachman , Herbert A.Lieberman, Joseph L.Kanig,3 rd edition. The Eastern pharmacist, november 1993. Sustained release drugs, V R.Gudsoorkar & D.Rambhau page 27-32 Biopharmaceuitics & pharmacokinetics, D M.Brahmankar & Sunil B. Jaiswal. www.google.com

Slide 43:

43 Thank you for listening me………