Diffusion controlled systems, solvent-activated system, chemically controlled system
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This document provides an overview of different controlled release polymer systems, including diffusion-controlled systems, solvent-activated systems, and chemically controlled systems. Diffusion-controlled systems use a reservoir or matrix to control the diffusion of a drug. Solvent-activated systems use osmotic pressure or polymer swelling to control drug release. Chemically controlled systems link drugs to polymers or use biodegradable polymers so the drug releases as the polymer breaks down. Magnetically controlled systems can also be used to selectively and controllably release drugs using magnetic fields.
Diffusion controlled systems, solvent-activated system, chemically controlled system
- 1. DIFFUSION-CONTROLLED SYSTEMS, SOLVENT-ACTIVATED SYSTEM, CHEMICALLY CONTROLLED SYSTEM PRESENTED BY-Biswajit Maity M.Sc. (POLYMER SCIENCE) 3/29/2017 1
- 2. CONTENTS • DIFFUSION CONTROLLED SYSTEM • What is diffusion controlled system • Reservoir and matrix • Problems with the reservoir system • Advantage & Disadvantage • SOLVENT-ACTIVATED SYSTEM • What is solvent-activated system • Classification • Osmotically controlled systems • Swelling-controlled systems • CHEMICALLY CONTROLLED SYSTEM • What is chemically controlled system • Classification • Pendant-chain system • Bio-erodible or biodegradable system • Major advantages of erodible systems • MAGNETICALLY CONTROLLED SYSTEMS • Reference 3/29/2017 2
- 3. CURRENTLYAVAILABLE POLYMERS FOR CONTROLLED RELEASE • Diffusion controlled systems • Solvent activated systems • Chemically controlled systems • Magnetically controlled systems 3/29/2017 3
- 4. DIFFUSION-CONTROLLED SYSTEM Reservoir type Shape spherical, cylindrical, disk-like Core, Powdered or liquid forms Properties of the drug and the polymer diffusion rate and release rate into the bloodstream. Problems - removal of the system, accidental rupture Matrix type Uniform distribution and uniform release rate No danger of drug dumping 3/29/2017 4
- 5. DIFFUSION LAYER MODEL • Also called ‘film theory’. • Formation of a thin film at the interface, called as stagnant layer. • 2 steps are involved: 1) Interaction of solvent with drug surface to form a saturated drug layer , called stagnant layer. 2) Diffusion of drug molecules from stagnant layer into bulk of the system. 3/29/2017 5
- 6. Diagram Representing Diffusion through the Stagnant Layer 3/29/2017 6
- 7. Noyes- Whitney’s equation: dC/dt = Dissolution rate of the drug, k = Dissolution rate constant, Cs = Concentration of drug in the stagnant layer, and Cb = Concentration of drug in the bulk of the solution at time t 3/29/2017 7
- 8. Modified Noyes-Whitney’s equation: • Where, • D = Diffusion coefficient (diffusivity) of the drug • A = Surface area of the dissolving solid • Kw/o = Water/oil partition coefficient of the drug. • V = Volume of dissolution medium • h = Thickness of the stagnant layer • (Cs – Cb)= Concentration gradient for diffusion of drug. 3/29/2017 8
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- 10. DIFFUSION-CONTROLLED SYSTEMS • Reservoir Devices 3/29/2017 10
- 11. CHARACTERISTICS OF A RESERVOIR DIFFUSIONAL SYSTEMS • Advantages • Zero-order delivery is possible • Release rate variable with polymer type • Disadvantages • Removal of system from implants • Bad for high-molecular weight compounds • Cost • Potential toxicity if system fails 3/29/2017 11
- 12. RESERVOIR DIFFUSIONAL PRODUCTS PRODUCT MANUFACTURER Nico-400 Jones Nitro-Bid Marion Nitrospan Rorer 3/29/2017 12
- 13. MATRIX DEVICES • Consists of drug dispersed homogeneously throughout a polymer matrix. • Drug in the outside layer is exposed to the bathing solution is dissolved and diffuses out of the matrix. • This process continues with the interface between bathing solution and the solid drug moving toward the interior. 3/29/2017 13
- 15. CHARACTERISTICS OF MATRIX DIFFUSION SYSTEMS • Advantages • Easier to produce than reservoir devices • Can deliver high molecular-weight compounds • Disadvantages • Cannot obtain zero-order release • Removal of remaining matrix is necessary for implanted systems 3/29/2017 15
- 16. MATRIX DIFFUSIONAL PRODUCTS Product Manufacturer Procan SR Parke-Davis Desoxyn-Gradumet Abbott Choledyl SA Parke-Davis 3/29/2017 16
- 17. DIFFUSION-CONTROLLED SYSTEMS INVOLVE RESERVOIR AND MATRIX • A reservoir is generally spherical, cylindrical, or disc-like in shape and consists of a drug core in powdered or liquid form. • A layer of non-bio-degradable polymeric material, through which the drug slowly diffuses, surrounds the core. • The properties of the drug and the polymer govern the diffusion rate of the drug and its release rate into the bloodstream. In order to maintain uniformity of drug delivery, • The thickness of the polymer must be consistent. 3/29/2017 17
- 18. PROBLEMS WITH THE RESERVOIR SYSTEM -One of the problems with the reservoir system is that such a system must be removed from the body after the drug is depleted because the polymer remains intact. -Another potential problem is that if the reservoir membrane accidentally ruptures, a large amount of drug may be suddenly released into the bloodstream (known as “drug dumping”). 3/29/2017 18
- 19. ADVANTAGE & DISADVANTAGE • Advantage:-In the matrix type of diffusion-control system, the drug is uniformly distributed throughout the polymer matrix and is released from the matrix at a uniform rate as drug particles dislodge from the polymer network. • In such a system, unlike the reservoir, there is no danger of drug dumping in case of an accidental rupture of the membrane. • Disadvantage:- Diffusion rate and release rate into the bloodstream Problems - removal of the system 3/29/2017 19
- 20. SOLVENT-ACTIVATED SYSTEM SOLVENT ACTIVATED SYSTEM Osmotically controlled system Semipermeable membrane Osmotic pressure decrease concentration gradient Inward movement of fluid, out of the device through a small orifice Swelling controlled system Hydrophilic macromolecules cross- linked to form a three-dimensional network Permeability for solute at a controlled rate as the polymer swells. • Solvent-activated systems are also of two types:- • Swelling-controlled systems • Osmotically controlled systems 3/29/2017 20
- 21. Swelling-controlled systems:- • In the swelling-controlled systems, the polymer holds a large quantity of water without dissolving. • The system consists of hydrophilic macromolecules cross-linked to form a three-dimensional network. • A characteristic of such systems is their permeability, for low molecular weight solutes, at a controlled rate as the polymer swells. 3/29/2017 21
- 22. Osmotically controlled systems:- In the osmotically controlled system, an external fluid containing a low concentration of a drug moves across a semipermeable membrane to a region inside the device, where the drug is in high concentration. Osmotic pressure tends to decrease the concentration gradient between one side of the membrane and the other. The inward movement of fluid forces the dissolved drug out of the device through a small orifice. 3/29/2017 22
- 23. OSMOTICALLY CONTROLLED SYSTEMS • Osmotic pressure provides the driving force to generate controlled release of drug. • Consider a semipermeable membrane that is permeable to water, but not to drug. When this device is exposed to water or any body fluid, water will flow into the tablet owing to the osmotic pressure difference. dV/dt= Ak/h(P) k=membrane permeability, A=area of the membrane, h=membrane thickness = osmotic pressure difference, P =hydrostatic pressure difference 3/29/2017 23
- 24. TYPES OF OSMOTICALLY CONTROLLED SYSTEMS Type A contains a osmotic core with drug Type B contains the drug solution in a flexible bag, with the osmotic core surrounding 3/29/2017 24
- 25. TYPES OF OSMOTICALLY CONTROLLED SYSTEMS 3/29/2017 25
- 26. IMMEDIATE RELEASE OXYBUTYNIN V/S CONTROLLED RELEASE DITROPAN XL 3/29/2017 26
- 27. CHARACTERISTICS OF OSMOTICALLY CONTROLLED DEVICES • Advantages • Zero-order release is obtainable • Reformulation is not required for different drugs • Release of drug is independent of environment of the system • Disadvantages • Systems can be very expensive • Quality control is more extensive 3/29/2017 27
- 28. EXAMPLES OF OSMOTIC PUMP SYSTEMS • Acutrim Appetite suppressant • Concerta ADHD • Procardia Hypertension/angina • Volmax Bronchiodilator • Ditropan Overactive bladder 3/29/2017 28
- 29. OSMOTIC PRESSURE ACTIVATED DDS Drug reservoir ( API + osmotic agent) Delivery Orifice Semi-permeable Membrane. (cellulose esters) 3/29/2017 29
- 30. Alzet Osmotic Pump 3/29/2017 30
- 31. MAJOR COMPANIES INVOLVED IN POLYMERIC DELIVERY TECHNOLOGY • Alza - DUROS, OROS • Alkermes Inc - Ring Caps • Nobex Corp. - Drug/Polymer Conjugates • Elan - MODAS, PRODAS • Andrx - SCOT, DPHS 3/29/2017 31
- 32. CHEMICALLY CONTROLLED SYSTEM CHEMICALLY CONTROLLED SYSTEMS Pendant-chain system Drug,chemically linked to the backbone Chemical hydrolysis or enzymatic cleavage Linked directly or via a spacer group Bioerodable or biodegradable system Drug: uniformly dispersed Slow released as the polymer disintegrates No removal from the body Irrespective of solubility of drug in water Chemically controlled systems also have two classes:- • The “pendant-chain” system and • The bio-erodible or biodegradable, system. 3/29/2017 32
- 33. • Pendant-chain system:- A “pendant chain system” is one in which the drug molecule is chemically linked to the backbone of the polymer. In the body, in the presence of enzymes and biological fluids, chemical hydrolysis, or enzymatic cleavage, occurs with concomitant release of the drug at a controlled rate. The drug may be linked directly to the polymer or via a “spacer group”. 3/29/2017 33
- 34. Bio-erodible or biodegradable, system:- In the bio-erodible system, the controlled release of the drug involves polymers that gradually decompose. The drug is dispersed uniformly throughout the polymer and is slowly released as the polymer disintegrates. 3/29/2017 34
- 35. TWO MAJOR ADVANTAGES OF ERODIBLE SYSTEMS ARE (1) Polymers do not have to be removed from the body after the drug supply is exhausted, (2) The drug does not have to be water-soluble .In fact, because of these factors, future use of bio-erodible polymers is likely to increase more than any other type of polymer in the future. 3/29/2017 35
- 36. BIOERODIBLE AND COMBINATION DIFFUSION AND DISSOLUTION SYSTEM • Strictly speaking, therapeutic systems will never be dependent on dissolution only or diffusion only. • Bioerodibile devices, however, constitute a group of systems for which mathematical descriptions of release is complex. • The complexity of the system arises from the fact that, as the polymer dissolves, the diffusion path length for the drug may change. this usually results in a moving-boundary diffusion system. • Zero-order release can occur only if surface erosion occurs and surface area does not change with time. • The inherent advantage of such a system is that the bioerodible property of the matrix does not result in a ghost matrix. 3/29/2017 36
- 37. Representation of a Bioerodible Matrix System Drug is dispersed in the matrix before release at time = 0. At time = t, partial release by drug diffusion or matrix erosion has occurred 3/29/2017 37
- 38. CHARACTERISTICS OF BIOERODIBLE MATRIX SYSTEMS • Advantages • All the advantages of matrix dissolution system • Removal from implant sites is not necessary • Disadvantages • Difficult to control kinetics owing to multiple processes of release • Potential toxicity of degraded polymer 3/29/2017 38
- 39. BIOERODIBLE AND BIODEGRADABLE CONTROLLED RELEASE POLYMERS These polymers are designed to degrade within the body • Polylactides (PLA) • Polyglycolides (PGA) • Polylactide-co-glycolides (PLGA) • Polyanhydrides • Polyorthoesters 3/29/2017 39
- 40. DEGRADATION OF BIODEGRADABLE POLYMERS These materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed • Bulk hydrolysis - the polymer degrades in a fairly uniform manner throughout the matrix • Surface Eroding - degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system 3/29/2017 40
- 41. BIODEGRADABLE POLYMERS Drug delivery from (a) Bulk-eroding (b) Surface-eroding biodegradable systems. 3/29/2017 41
- 42. BIODEGRADABLE (SURFACE ERODING) POLY-ORTHO- ESTER RODS AFTER (LEFT) 9 WEEKS AND (RIGHT) 16 WEEKS OF IMPLANTATION Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems. 3/29/2017 42
- 43. MAJOR COMPANIES INVOLVED IN POLYMERIC DELIVERY TECHNOLOGY • Alza - DUROS, OROS • Alkermes Inc - Ring Caps • Nobex Corp. - Drug/Polymer Conjugates • Elan - MODAS, PRODAS • Andrx - SCOT, DPHS 3/29/2017 43
- 44. MAGNETICALLY CONTROLLED SYSTEMS MAGNETICALLY CONTROLLED SYSTEMS Cancer chemotherapy Selective targeting of antitumor agents Minimizing toxicity Magnetically responsive drug carrier systems Albumin and magnetic microspheres High efficiency for in vivo targeting Controllable release of drug at the micro-vascular 3/29/2017 44
- 45. MAGNETICALLY ACTIVATED - DDS 3/29/2017 45
- 46. In this type, drug reservoir is a dispersion of peptide or protein powders in polymer matrix from which macromolecular drug can be delivered only at a relatively slow rate. Device is fabricated by positioning a tiny magnet ring in core of hemispherical drug dispersing polymer matrix. The external surface is coated with drug impermeable polymer (ethylene vinyl acetate or silicone elastomer) except one cavity at the centre of the flat surface. 3/29/2017 46
- 47. This delivery device used to deliver protein drugs such as bovine serum albumin, at a low basal rate, by a simple diffusion process under non triggering condition. As the magnet is activated to vibrate by an external electromagnetic field, the drug molecules are delivered at a much higher rate. 3/29/2017 47
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- 49. POLYMERS FOR CONTROLLED RELEASE These are some of the first materials selected for delivery systems bases on their intended non-biological physical properties: • Polyurethanes for elasticity • Polysiloxanes for insulating ability • Polymethyl methacrylate for physical strength and transparency • Polyvinyl alcohol for hydrophilicity and swelling • Polyvinyl pyrrolidone for suspension capabilities 3/29/2017 49
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- 51. REFERENCE • Drug delivery systems ( second edition) –Vasant V.Ranade, A.Mannfred Hollinger • http://www.purac.com/purac-biomaterials Leon lachman – The theory and practic of industrial pharmacy. Michael E Alton - Pharmaceutics The science of dosage form design. N.K. Jain – Controlled & novel drug delivery. S.P. Vyas & Khar – Controlled Drug delivery, Brahmankar – Text Book of Biopharmaceutics & Pharmacokinetics. Yie.W.Chein- Controlled & Novel Drug Delivery, CBS publishers.3/29/2017 51
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