Controlled drug delivery Systems

Fundamentals of controlled drug delivery system

1. CONTROLLED DRUG DELIVERY SYSTEMS By Dr. Chinmaya Keshari Sahoo. M.Pharm, Ph.D Associate Professor College of Pharmaceutical Sciences, Puri

2. CONTENTS Introduction Modified Release Drug Delivery System (MRDDS) Terminology/definitions Rationale of CDDS Advantages Disadvantages Selection of drug candidates Physiological properties for CDDS Biological properties for CDDS 2

3. INTRODUCTION Conventional oral drug delivery system offers an immediate release of the drug and cannot maintain effective concentration at the target site for longer period of time. The bioavailability of drugs by conventional drug delivery is less due to presence of food, pH of gastro intestinal tract (GIT), degradation by enzymes of GI fluid, change in GI motility etc . Most conventional oral drug products result in drug absorption problem and decline drug’s pharmacokinetic profile. For avoid these limitations modified release drug delivery system has taken major role in the pharmaceutical development. 3

4. Modified release drug delivery system Modified release drug delivery system (MRDDS) MRDDS is defined as one for which the drug release characteristics of time course and location are chosen to accomplish therapeutic or convenience objectives to influence the release profile of a drug from its delivery system. Classification of MRDDS MRDDS is classified into 3 types such as 1.Extended release dosage form 2.Delayed release dosage form 3.Targeted release dosage form 4

5. Contd. 1. Extended release dosage form (ERDF) ERDF allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate release (conventional) dosage form. The dosage form releases the drug slower than normal manner at predetermined rate. The prolonged action drug product is designed to release the drug slowly and to provide a continuous supply of drug over an extended period. ERDF includes sustained release , and c ontrolled-release dosage forms. 5

6. Contd. Sustained release dosage forms Sustained release system delivers an initial therapeutic dose of the drug (loading dose) followed by slower and constant release of drug. Loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower mainteince dose . These systems maintain the rate of drug release over a sustained period. Sustained-release dosage forms achieve this mostly by the use of suitable polymers , which are used either to coat granules or tablets ( reservoir systems ) or to form a matrix in which the drug is dissolved or dispersed ( matrix systems ). 6

7. Contd. Controlled-release dosage forms Controlled release dosage forms cover a wide range of prolonged action formulations which provide continuous release of their active ingredients at predetermined rate and predetermined time . There is maximum utilization of drug enabling reduction in total amount of dose administered and possibility of delivering drugs having short biological half life. The release kinetics is usually follow zero-order . Controlled drug delivery system (CDDS) can improve the therapeutic efficacy and safety of a drug by precise temporal and spatial placement in the body thereby reducing both the size and number of doses required. 7

8. Contd. Temporal delivery of drug refers to controlling the rate or specific time of drug delivery to the target tissue . Spatial delivery of drugs relates to target a drug to a specific organ or tissue . 8

9. Contd. 2. Delayed release dosage form (DRDF) DRDF can be defined as systems which are formulated to release the active ingredient at a time other than immediately after administration. DRDF can control where the drug is released , e.g. when the dosage form reaches the small intestine (enteric-coated dosage forms) or the colon (colon-specific dosage forms). 3 . Targeted release dosage forms Targeted release dosage forms release drug at or near the intended physiologic site of action . It may have either immediate or extended release characteristics. 9

10. TERMINOLOGY 1. Temporal release 2. Spatial release 3. Loading dose 4. Maintenance dose 5. Sustained release 6. Controlled release 7. Delayed release 8. Targeted release 10

11. Rationale of CDDS The basic  rationale  of a  CDDS  is to optimize the biopharmaceutics , pharmacokinetics (PK), and pharmacodynamics (PD) properties of a  drug  in such a way that its utility is maximized through reduction in side effects and cure or control of disease condition in the shortest possible time by using smallest quantity of drug, administered by most suitable route . Alter PK/PD by: – Design of drug delivery system – Modify drug structure – Modify physiology Duration of drug action is a design property of the rate controlled dosage form and not a property of the drug molecule’s inherent kinetic characteristics. 11

12. ADVANTAGES OF CDDS 1. The frequency of drug administration is reduced . 2. Patient compliance can be improved . 3. The drug administration is more convenient . 4. There is better control of drug absorption. 5. The total amount of drug administration can be reduced . 6 . Safety margin of high potency drugs can be increased. 7. Treatment efficacy is improved. 8. Bioavailability of drugs is improved . 9. Reduction in health care cost by improved therapy and shorter treatment period. 12

13. DISADVANTAGES OF CDDS 1 . Poor in vitro – in vivo correlation is observed. 2.Possibility of dose dumping due to food, physiologic or formulation variables or chewing or grinding of oral formulations by the patient and thus, increased risk of toxicity. 3 . Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. 4 . Increased cost of manufacturing . 5.More rapid development of tolerance and counseling. 13

14. SELECTION OF DRUG CANDIDATES I. Biopharmaceutic Properties Properties of drug Desired features Molecular size Less than 600 D Aqueous solubility More than 0.1 mg/ml Partition coefficient (Ko/w) 1-2 Dissociation constant pKa Acidic drugs pKa ˃ 2.5 , Basic drugs pKa ˂ 11 Ionisation at physiological pH Not more than 95% Stability in GI milieu Stable at both gastric and intestinal pH Absorption mechanism Passive absorption 14

15. Contd. II. Pharmacokinetic (PK) Properties Properties of drug Desired features Absorption rate constant (Ka) High Elimination half life 2-6 h Metabolism rate Not too high Dosage form index 1 15

16. Contd. III. Pharmacodynamic (PD) Properties Properties of drug Desired features Dose Maximum 1000 mg Therapeutic range Wide Therapeutic index Wide PK/PD relation ship Good 16

17. PHYSIOCHEMICAL PROPERTIES OF DRUG FOR CDDS 1. Aqueous solubility of the drug 2. Partition coefficient ( Ko /w) 3. Drug pKa and ionization at physiological pH 4. Drug stability 5. Molecular weight of drug and diffusivity 6.Dose size 7. Protein binding 17

18. CONTD. 1. Aqueous solubility of the drug A drug with good aqueous solubility, especially if pH independent, serves as a good candidates Generally highly soluble drugs are undesirable for formulation in a controlled release product and very poorly soluble drugs are not suitable for controlled release system. Class III (High solubility-low permeability) and Class IV (low solubility-low permeability) drugs are poor candidate for controlled release dosage forms. The drug with solubility <0.1 mg/ml create significant solubilization problem (Lower limit). 18

19. CONTD 2. Partition coefficient ( Ko /w) Partition coefficient is defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase at equilibrium . Drugs with extremely high partition coefficient are very oil soluble and penetrates in to various membranes very easily. Greater the partition coefficient of a drug greater its lipophilicity and thus greater is its rate and extent of absorption. High partition coefficient compound are predominantly lipid soluble and have very low aqueous solubility and thus these compound persist in the body for long periods. Ko /w value between 1 -2 is suitable for CDDS 19

20. CONTD. 3. Drug pKa and ionization at physiological pH Drugs existing largely in ionized form are poor candidates for oral CDDS. The pKa range for acidic drug whose ionization is pH sensitive is around 3.0-7.5 and pKa range for basic drug whose ionization is pH sensitive is around 7.0-11.0 are ideal for optimum positive absorption. For optimum passive absorption the drugs should be non ionized. 20

21. CONTD. 4. Drug stability Drugs unstable in gastrointestinal environment cannot be administered as oral controlled release formulation because of bioavailability problems . A different route can be selected if failed in one route. Drugs stable in stomach gets released in stomach and which are unstable gets released in intestine. Drugs may be protected from enzymatic degradation by incorporation in to a polymeric matrix 21

22. CONTD 5. Molecular weight of drug and diffusivity The ability of a drug to diffuse through membranes is called diffusivity which is a function of molecular weight. Lower the molecular weight faster and more complete absorption. Drugs with large molecular size are poor candidates for oral controlled drug delivery system. The upper limit of drug molecular size for passive diffusion is 600 Daltons. 22

23. CONTD 6.Dose size For those drugs requiring large conventional doses, the volume of sustained dose may be too large to be practical. The compounds that require large dose are given in multiple amounts or formulated into liquid systems. The greater the dose size , greater the fluctuation . So the dose should have proper size. The upper limit of dose size is 1000 mg for CDDS. 23

24. CONTD. 7. Protein binding Drug protein binding acts as depot for drug producing prolonged release profile-high degree of binding occurs . drugs + mucin = increases absorption Charged compounds greater tendency to bind. e.g. Diazepam and novobiocin - 95% protein binding Extensive binding to plasma proteins – long half life of elimination for drugs- most required property for a sustained release. 24

25. BIOLOGICAL PROPERTIES OF DRUGS 1. Absorption 2. Distribution 3. Metabolism 4. Duration of action 5 . Margin of safety 6. Role of disease state 25

26. CONTD. 26

27. CONTD. 1. Absorption Ideal CRDDS should release the complete drug and the released drug should be completely absorbed Drugs with poor absorption – poor candidate for CDDS. The fraction of drug absorbed from the system can be lower than the expected due to: -degradation of drug. Eg - Penicillin G -site-specific, dose-dependent absorption, -poor water solubility -small partition coefficient. 27

28. CONTD. 2.Distribution Distribution refers to the reversible transfer of drug from one location to another inside the body. Depends on affinity of drug to bind with plasma proteins and ability of drug to pass through tissue membranes. Apparent volume of distribution ( Vd ) is defined as the hypothetical volume of body fluids to which a drug is dissolved or distributed . 28

29. CONTD. 3.Metabolism The drug which is extensively metabolized is suitable for CDDS as long as the rate of metabolism is not too rapid . The extent of metabolism should be identical and predictable when the drug is administered by different routes. The drug which is capable of inducing or inhibiting metabolism is a poor candidate for CDDS. Drugs possessing variations in bioavailability due to first-pass effect or intestinal metabolism are not suitable for sustained/controlled drug delivery. Elimination constant or appearance of metabolites – reflects the Metabolism of a drug. 29

30. CONTD. 4.Duration of action The usual goal – maintain therapeutic blood levels to an extended period. Rate of absorption= Rate of elimination Half life of drug range between 2- 6 h. Short half life dose size will increase for large release if CDDS produced. Long half lives more than 6h sustained effect is already there. 30

31. CONTD. 5. Margin of Safety Estimation of relative safety of drug by therapeutic index. Therapeutic index(TI) = TD50/ED50 Where TD50 is toxic dose, ED50 is effective dose Larger the ratio- safer the drug TI> 10 Decisions on the margin of safety is done based on the combination with therapeutically safe and effective plasma concentration . 31

32. CONTD. 6. Role of Disease state Disease acts as a stimulus for the development of CDDS Example: Rheumatoid arthritis- Aspirin Biological half life- 6h Aspirin sustained release preparation –prevents morning stiffness. It can be sustained upto 8-10 h 32

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