Novel Drug delivery system, Controlled drug delivery system

Controlled Drug delivery System

1. Controlled Drug Delivery System BY MOHAMMAD ALI ASSISTANT PROFESSOR BHARATHI COLLEGE OF PHARMACY BHARATHINAGARA - 571422

2. INTRODUCTION DRUG DELIVERY SYSTEM Is a formulation or device that delivers the drug in site-directed application or provides timely release of the drug. The system, is not pharmaceutically active, but improves the efficacy and safety of the Drug that it carries. Controlled drug delivery can be achieved by; SPACIAL PLACEMENT TEMOPORAL DELIVERY

3. INTRODUCTION IDEAL CHARACTERISTICS OF DRUG DELIVERY: Reduce drug toxicity Increase the absorption of a n insoluble drug. Improve the drug release profile. Create truly best-in-class products. Reduce price. Control the drug release. The ability to target.

4. TERMINOLOGY 1. Delayed Release: Delayed release systems are those that use repetitive, intermittent dosing of drug from one or more immediate release units incorporated into a single dosage form. E.g., Repeat action tablet, Enteric coated tablet 2. Sustained Release: Sustained release systems include any drug delivery system that achieves slow release of drug over extended period of time. E.g., Zenretard SR (Carbamazepine)

5. 3. Site specific and Receptor Targeting: Site specific and receptor targeting refers to targeting of a drug delivery to a certain biological location. CONTROLLED DELIVERY CAN BE DEFINED AS: CDDS is the one which delivers the drug at a predetermined rate, locally or systemically, for a specific period of time. TERMINOLOGY

6. Conventional Drug Therapy

7. Multi Dose Therapy

8. Controlled Release System

9. Avoid patient compliance problems. Employ less total drug. Improve efficiency in treatment. Economic. Reduced GI side effects and irritation. Increased safety margin of high potency drugs. ADVANTAGES

10. Dose dumping. Poor in vitro – in vivo correlation. Dose adjustment is difficult. Retrieval of drug is difficult once administered. Chance of incomplete release of drug from the device. DISADVANTAGES

11. In general the drugs best suited for CDDS products should have the following characteristics. They exhibit neither very slow nor very fast rates of absorption and excretion. They are uniformly absorbed from the GI Tract. They are administered in relatively small doses. Drugs with a dose of <100 mg. Drugs with a half life of 3-6 hrs and specifically defined minimum therapeutic levels. Drugs that possess a good margin of safety Drugs with low protein binding properties. They are used in the treatment of chronic rather than acute condition SELECTION OF DRUG CANDIDATE

12. Drugs with an elimination half life of < 2 hrs. Drugs with an elimination half life of >8 hrs. Drugs that are administered in large doses. Highly potent drugs. They may prove risky in case of dose dumping. DRUG CANDIDATE UNSUITABLE FOR CDDS

13. RATIONALE AND SELECTION OF DRUG CANDIDATE

14. Various factors that effect the design and performance of OCDDS are listed below: (a) Physico-chemical property Aqueous solubility Molecular weight of the drug Partition co-efficient of the drug Drug pKa and ionization at physiologic pH. Drug stability RATIONALE AND SELECTION OF DRUG CANDIDATE

15. (b) Biological factors Adsorption Metabolism Elimination half life Dosage form index (c) Pharmacodynamic factors Therapeutic Index

16. The design and fabrication of controlled release system can be classified based on the mechanism of drug release. Dissolution controlled release. Diffusion controlled release. Diffusion and dissolution controlled release. Ion exchange resins. pH dependent formulations. Osmotically controlled release Altered density formulation/Buoyant systems. APPROACHES TO DESIGN OF CONTROLLED RELEASE FORMULATIONS

17. These system are easy to design. In this system solid substances solubilize in a given solvent (dissolution). i.e., Mass transfer form solid surface to the liquid phase. The rate determining step, is diffusion of the soluble solute from the solid surface to the bulk of the solution through stagnant layer. This dissolution process at steady state is described by the Noyes and Whitey equation. DISSOLUTION CONTROLLED RELEASE SYSTEMS

18. Noyes – Whitney Law Solution of the solid to form a thin film at S/L interface called Stagnant film. Which gets saturated with the drug (Rapid ) Diffusion of the soluble solute from the stagnant layer to the bulk solution (Rate Determine Step )

19. Where, = Dissolution rate k D = Dissolution rate constant D = Diffusion coefficient Cs= Saturation solubility of the solid C = Concentration of solute in the bulk sol. A = Surface area of the exposed solid   Noyes – Whitney Equation

20. Here, the formulation are designed in such a way that it can decrease the rate of dissolution of the drug. This can be achieve by preparing appropriate salts or derivatives, coating the drug with a slowly dissolving material, or incorporating it into a tablet with a slowly dissolving carrier. DISSOLUTION CONTROLLED RELEASE SYSTEMS

21. Classification: The two types of dissolution controlled release systems are : Matrix/Monolith dissolution controlled system. Encapsulation/coating dissolution controlled system/reservoir devices. DISSOLUTION CONTROLLED RELEASE SYSTEMS

22. Matrix/Monolith Dissolution Controlled System: The drug is homogeneously dispersed throughout a rate controlling medium. Use of waxes such as beeswax, carnauba wax, Hydrogenated castor oil, etc. These things control drug dissolution by controlling the rate of dissolution (fluid penetration) into the matrix by: Altering porosity of tablet Decreasing its wettability Dissolving at slower rate. DISSOLUTION CONTROLLED RELEASE SYSTEMS

23. Slowly Dissolving Matrix DISSOLUTION CONTROLLED RELEASE SYSTEMS Soluble Drug Drug release determined by dissolution rate of polymer

24. Preparation Method: Prepared by dispersing the drug in molten wax and congealing (solidify). The drug release is often first order from such matrices. DISSOLUTION CONTROLLED RELEASE SYSTEMS Molten Wax Drug Mix Solidify Granulation

25. (b) Encapsulation/Coating Dissolution Controlled System/Reservoir Devices: Here the drug particles are coated or encapsulated with slowly dissolving materials like, cellulose, poly ethylene glycol (PEGs), Polymethacrylates, waxes etc. Dissolution rate of coat depends upon solubility and thickness of coating which may range from 1-200 μ . DISSOLUTION CONTROLLED RELEASE SYSTEMS Soluble Drug Slowly dissolving or Erodible coat

26. Applications: Masks Colour, Odour and Taste. Minimizes GI irritation. The pellets may be filled in Hard gelatin capsules. It may be compressed into tablets. DISSOLUTION CONTROLLED RELEASE SYSTEMS

27. The rate-controlling step is not the dissolution rate but the diffusion of dissolved drug through a polymer barrier. Usually, this barriers is an insoluble polymer. The process of diffusion is generally described by Fick’s first Law. This states that “the amount of drug passing across a unit area is proportional to the concentration difference across the plane” DIFFUSION CONTROLLED RELEASE SYSTEMS

28. The equation is given as: Where, J = Flux D = Diffusion coefficient of the drug in the membrane = The rate of change in concentration C relative to a distance X in the membrane The drug release rate is never zero order since the diffusional path length increases with time as the insoluble matrix is gradually depleted of drug.   DIFFUSION CONTROLLED RELEASE SYSTEMS

29. Classification: The two types of diffusion controlled Systems are: Matrix diffusion controlled systems. Reservoir devices/laminated matrix devices. (a)Matrix Diffusion Controlled Systems: It consists of drug dispersed homogeneously throughout a polymer matrix. This polymer matrix may be rigid, non-swellable. It consists of hydrophobic materials or swellable hydrophilic substances. DIFFUSION CONTROLLED RELEASE SYSTEMS

30. DIFFUSION CONTROLLED RELEASE SYSTEMS Fig: Polymer Used

31. Preparation Method: Method 1 : With plastic materials, the drug is generally kneaded with the solution of PVC in an organic solvent and granulation. Method 2: Waxy matrix is prepared by dispersing the drug in molten fat followed by congealing and granulation. Method 3: Gum and the drug are granulated together with a solvent such as alcohol and compressed into tablets. DIFFUSION CONTROLLED RELEASE SYSTEMS

32. Rate Controlling Step: Diffusion of dissolved drug through the matrix. DIFFUSION CONTROLLED RELEASE SYSTEMS Time = 0 Time = t (a) Rigid Matrix Polymer Drug

33. DIFFUSION CONTROLLED RELEASE SYSTEMS (b) Swellable Matrix Swollen glassy hydrogel From which drug has to c ompletely diffuse Swellable gum matrix Drug Fig: Diffusion Controlled Devices

34. (b) Reservoir Devices/Laminated Matrix Devices: Reservoir devices are characterized by a core of drug, the reservoir, surrounded by a polymeric membrane. The nature of the membrane determines the rate of drug release from the system. Technique used to apply polymer is coating or microencapsulation. Drug release mechanism involves partitioning of drug into the membrane with subsequent release into the surrounding. The polymer commonly used in such devices are: HPC EC and PVA DIFFUSION CONTROLLED RELEASE SYSTEMS

35. Rate controlling step: Polymer content in coating, thickness of the coating and hardness of microcapsule. DIFFUSION CONTROLLED RELEASE SYSTEMS Drug Polymer Time = 0 Time = t Fig: Drug Release by Diffusion across the Insoluble Membrane of Reservoir Device

36. In such systems, the drug is encased in a partially soluble membrane. Pores are thus created due to dissolution of parts of membrane, that permits entry of aqueous medium. At the same time it allows diffusion of dissolved drug out of the system. E.g., such can be obtaining by using mixture of EC and PVP or MC. Later it dissolves in water which create pores in the insoluble EC membrane. DISSOLUTION AND DIFFUSION CONTROLLED RELEASE SYSTEMS

37. Rate controlling factor: Fraction of soluble polymer in the coat. DISSOLUTION AND DIFFUSION CONTROLLED RELEASE SYSTEMS Drug Drug diffusion Entry of dissolution fluid Insoluble membrane Fig: Dissolution and Diffusion Controlled Release System

38. It is based on the formation of drug resin complex formed when ionic solution is kept in contact with ionic resins. Provides CR of an ionic or ionizable drug for intra-gastric delivery. The drug release rely only on the ionic environment of the resin containing drug. Drug is less susceptible to environmental conditions, such as enzyme content and pH at the site of absorption. ION EXCHANGE RESIN DRUG COMPLEXES

39. Method of Preparation: Prepared by absorbing an ionized drug onto the ion-exchange resin granules, such as codeine base with amberlite , and filtering through an alcoholic medium. Then coating the drug resin complex granules with a water permeable polymer. Spray dry the coated granules to produce coated drug resin preparation. E.g., Noscapine , Phenylpropanolamine, Phentermine have been retarded by such an approach. ION EXCHANGE RESIN DRUG COMPLEXES

40. ION EXCHANGE RESIN DRUG COMPLEXES Drug-Ion Exchange Resin granules Polymer coating

41. Further Improvement of this system can be done by treating the granules with impregnating agent like PEG-4000 This will retard the rate of swelling in water and then coated by air suspension technique with water permeable polymer (EC). That will act as a rate controlling barrier to regulate the release of drug from the system. This further improvement of the system is known as pennkinetic system. ION EXCHANGE RESIN DRUG COMPLEXES

42. ION EXCHANGE RESIN DRUG COMPLEXES Drug-Ion Exchange Resin granules Ethyl Cellulose Coating PEG Treatment Fig: Pennkinetic System of Ion Exchange Resin

43. Mechanism of drug release from the dosage Form: Cationic drugs: A cationic drug forms a complex with an anionic ion-exchange resin. E.g., A resin with a SO 3 - group. In GIT, H + ion penetrates the system and activates the release of cationic drug form the drug-resin complex. Resin - - Drug + + Y + → Resin - - Y + +Drug + ION EXCHANGE RESIN DRUG COMPLEXES

44. Mechanism of drug release from the dosage Form: Anionic drugs: A anionic drug forms a complex with an cationic ion-exchange resin. E.g., A resin with a [N(CH 3 ) 3 + ]group. In GIT, Cl - ion penetrates the system and activates the release of anionic drug form the drug-resin complex. Resin + - Drug - + X - → Resin + - X - +Drug - ION EXCHANGE RESIN DRUG COMPLEXES

45. Advantages: The rate of drug release is not dependent upon the pH condition, enzyme, temperature and volume of GIT. The system is administered in the form of large number of particles which may eliminate the effect of gastric emptying. Can be formulated as a stable liquid suspension type of pharmaceutical dosage form. By combining different ratios of polymer coated and uncoated granules, in the formulation, a range of dissolution profile and blood levels can be achieved. ION EXCHANGE RESIN DRUG COMPLEXES