Sustained and Controlled Release Drug Delivery Systems

Sustained and Controlled Release Drug Delivery Systems (SR and CR) for M.pharm 1st semester

1. . Presented by- Md. Moidul Islam (M. pharm 1 st Sem) Guided by- Dr. Nitin Sharma(HOD Pharmaceutics ) ISF College of Pharmacy, Moga Sustained Release and Controlled Release Drug Delivery System.

2. Contents: Introduction Definition Compression of drug release profile Advantages and disadvantages Differences between SR and CRDDS Factors affecting in the design of SR and CRDDS Classification of oral SR and CRDDS Conclusion Reference

3. Introduction: Every drug molecule needs a delivery system to carry the drug to the site of action upon administration to the patient. Delivery of the drug can be achieved by using various types of dosage forms including(tablet, capsules, creams, ointments, liquids, injections ,suppositories etc) . conventional dosage form offers few limitations which could be resolved by modifying the existing dosage form. Sustained and controlled drug delivery system helps in maintain of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action.

4. Definition: Sustained release drug delivery system(SRDDS): sustained release are drug delivery system that achieve slow release of drug over an extended period of time after administration of a single dose . Examples: Aceclofenac SR, Indapamide SR Controlled drug delivery system(CRDDS): Drug delivery system in which maintain constant level of drug in blood and tissue for extended period of time. Example: Paroxetine CR, Acelofenac CR

5. Compression of drug release profile.

6. Advantages of SR and CRDDS Reduction in frequency of drug administration. Improvement of patient compliance. Reduction of drug level fluctuation in blood. Reduced local and systemic side effects. Maximum utilization of drug. Better control of disease condition. Reduction in health care cost.

7. Disadvantages of SR and CRDDS Dose dumping. Poor in vitro-in vivo correlation. Increased instability. Patient education is required for successful therapy. Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. Difficulty in dose adjustment .

8. Difference between SR and CRDDS Sustained release dosage form Controlled release dosage form This dosage form provides medication over extended period of time. This dosage maintains constant drug level in blood or tissue. SRDF generally follows first order release kinetics. CRDF generally follows zero order release kinetics. Usually do not contain mechanisms to promote localization of the drug at active site. Contain mechanism to promote localization of the drug at active site.

9. Factors affecting in the design of SR and CRDDS Physicochemical properties of drug. Pharmacokinetics properties of drug. Pharmacodynamics properties of drug. I. Physicochemical properties of drug: There are so many factors which effects on physicochemical properties of drug, these are mention below. Molecular size and weight of the drug: Lower molecular size and weight faster and more complete the absorption. For pore transport mechanism molecular wt. should be 150-400 daltons. For passive transport molecular wt. should be less than 600 daltons. 95% of drugs transported by passive transport.

10. 2. Aqueous solubility of the drug : A drug with good aqueous solubility, especially pH independent, serves as good candidate for SR and CR dosage forms e.g. pentoxiphylline . The solubility of a drug should not be les s than 0.1 mg/ml to be formulated as CRDDS. Apparent partition coefficient of the drug: Greater the apparent partition coefficient of a drug , greater its lipophilicity and thus greater rate and extent of absorption. Such drug can cross BBB Drug pKa and ionisation at physiological PH: The pKa range for acidic drug is 3.0-7.5 and basic drug range 7.0-11. Drug existing largely in ionised forms are poor candidate for SR and CRDDS. E.g. hexamethonium.

11. 5. Drug stability: Drugs unstable in GI can not be administration as oral route SR and CRDDS because of bioavailability problems e.g. nitroglycerine Then a different route of administration should be selected such as transdermal route. Mechanism and site of absorption: The drugs which are absorbed by a narrow therapeutic window, these are poor candidate for SR and CRDDS, E.g. several B vitamins. Biopharmaceutics aspects of route of administration: Oral and parenteral route are most popular followed by transdermal route. Oral route: For a drug to be oral SR and CRDDS formulation, it must get absorbed by through the entire length of GIT. The route is suitable for drugs given in dose as high 1000 mg.

12. b. Intramuscular/subcutaneous routes: These routes are suitable when the duration of action is to be prolonged from 24 hours to 12 months. Only small amount of drug, about 2 ml or 2 gm can be administered by these routes. c. Transdermal route: This route is best for drugs showing extensive first-pass metabolism upon oral administration or drug with low dose, e.g. nitroglycerine. II. Pharmacokinetics properties of the drugs: Absorption rate: For a drug to be administered as SR and CRDDS, its absorption must be efficient. A drug with slow rate of absorption is poor candidate for SR and CRDDS.

13. 2. Distribution: The distribution of drugs into tissue can be a important factors in the overall drug elimination kinetics. It is not only lowers the concentration of the drug but also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently apparent volume of distribution assumes different values depending on time course of drug disposition. For design of SR and CRDDS, one must have information of disposition of drug. Rate of metabolism: A drug capable of inducing or inhibiting metabolism is a poor candidate for SR and CRDDS, because it is difficult to maintaining uniform blood levels of drugs.

14. 3. Rate of metabolism: A drug capable of inducing or inhibiting metabolism is a poor candidate for SR and CRDDS, because it is difficult to maintaining uniform blood levels of drugs. 4.Elimination half life: For drugs with half life less than 2 hours, a very large dose may required to maintained the high release rate for CRDDS. The drugs with short half life are excellent candidates for SRDDS since these can reduce dosing frequency. Drugs with half life 2 to 4 hours are good candidate for CRDDS, e.g. propranolol. 5. Dosages form index(DI): Dosage form index defined as the ratio of C max to C min . The goal of CRDDS is to improved therapy by reducing DI while maintaining the plasma drug level within the therapeutic window. Ideal value of DI for CRDDS should be as close to one as possible

15. 5. Protein binding: Drug binding to plasma protein(albumins) and resulting retention of the drug in the vascular space. Drug-protein complex can serves as reservoir in the vascular space. Charged compounds has greater tendency to bind with protein than the uncharged compounds. E.g. diazepam . III. Pharmacodynamic properties of drugs. Therapeutic range: Drugs having wide therapeutic range good candidate for CRDDS. Therapeutic Index(TI): In general wide therapeutic index safer the drug and narrow TI value poor candidate for SR and CRDDS. Example: digitoxin, phenobarbital.

16. 3. Plasma concentration response(PK/PD) relationship: Drugs such as reserpine whose pharmacological activity is independent of its concentration are poor candidate for SR and CRDDS. Classification of oral SR and CRDDS: SR/CR Continuous release system Delayed transit and continuous release system Delayed release system

17. 1. Continuous release system: Different systems under this class are- Dissolution controlled release system Diffusion controlled release system Erosion controlled release system Dissolution, diffusion and/ or erosion controlled release system Ion exchange drug resin complexes Slow dissolving salts and complexes Osmotic pressure controlled release system PH dependent formulation Hydrodynamic pressure controlled release system

18. 1. Continuous release system . a. Dissolution controlled system b. Diffusion controlled system Reservoir system Matrix system Reservoir system Matrix system Rigid system Swellable system

19. a. Dissolution controlled release system: These system are most commonly employed in the production of enteric dosage forms. Drug present in the system having high aqueous solubility and dissolution rate. Reservoir system: The drug particle are coated or encapsulated by one of the several microencapsulation techniques with slowly dissolving materials like cellulose, PEG, waxes. Reservoir system

20. Matrix system: Matrix system are also called monoliths since the drug is homogenously dispersed throughout a rate controlling medium. E.g. bees wax, carnauba wax, hydrogenated castor oil.

21. b. Diffusion controlled release system: Movement of drug molecule from higher concentration to lower concentration. Reservoir system: These system are hollow containing an inner core of drug surrounded in a water insoluble polymer membrane . Matrix system: Polymer is either water swellable (xanthan gum, guar gum , alginates) Or water non swellable( ethylcellulose )

22. c. Erosion controlled release system: Polymer or wax degradation or hydrolysis is brought about by enzyme, pH change , Osmotic pressure, hydrodynamic pressure etc. Erosion can undergo surface erosion and bulk erosion .

23. d . Dissolution, diffusion and/or erosion controlled DDS: These systems are those where the rate of drug release is controlled by drug or polymer dissolution, drug diffusion and/ or polymer erosion i.e. the system is a combination of two or more three types of system. e. Ion exchange resin-drug complexes: It is based on preparation of totally insoluble ionic material. Resins are insoluble in acidic and basic media they contain ionizable groups which can be exchanged for drug molecule.

24. f. Slow dissolving salt and complexes: Salt or complexes of drug which are slowly soluble in the GI fluid can be used for SR and CRDDS. E.g. penicillin G Osmotic pressure controlled release system:

25. h. PH dependent formulation: Such system are designed to eliminate the influence of GI pH on dissolution and absorption of drugs by formulating then with sufficient amount of buffering agents like salt of phosphoric, citric or tartaric acids . i . Hydrodynamic pressure controlled release system:

26. 2.Delayed transit and continuous release system: These system are designed to prolong release of drug with increase residence time in GIT, such dosage forms are designed to remain in the stomach. Therefore the drugs should be stable in gastric pH. This class includes following system- Altered density system: If the residence time of drug in the stomach or intestine is prolonged in some way, the frequency of dosing can be further reduced. Altering the density of the drug particle, use of mucoadhesive polymers and altering the size of the dosage form. Mucoadhesive system: A mucoadhesive polymer incorporated in a tablet, allow it to adhere to gastric mucosa or epithelial.

27. Size-based system: The diameter of tablet always greater than 2cm which can not pass through pylorus and can’t goes in to intestine. Using polymer HPMC K200 having high swelling property. 3. Delayed release system : These system are fabricated to release the drug only at specific site in the GIT. The two types of delayed release system are- Intestinal release system: A drug may be enteric coated for intestinal release to prevent gastric irritation, destabilization in gastric pH.

28. Colonic release system: Drugs are very poorly absorbed through colon but may be delivered to such site for two reason- Local action as in the treatment of ulcerative colitis Systemic absorption of protein and peptide drug like insulin and vasopressin.

29. Conclusion: The sustained drug delivery system is very helpful in increasing the safety and efficacy of the dose as well as patient compliance. The CRDDS release drug at as particular rate over a extend period of time to maintain the therapeutic level in blood.

30. Reference: D.M. Brahmankar and Sunil B. Jaiswal(2010), Biopharmaceutics and pharmacokinetics a treatise . Delhi, Vallabh Prakashan, 2 nd edition pp. 397-464. Dr. Dheeraj T. baviskar and Dr. Dinesh k Jain ,Novel drug delivery system, Nirali prakashan , 3 rd edition (2016) pp.2.1-2.31 Lachman, The theory and practice of industrial pharmacy, 4 th edition

31. THANK YOU.