ControlledDrugDeliverySystem

Controlled Drug Delivery System: 

Controlled Drug Delivery System Dr. Basavaraj K. Nanjwade KLE University’s College of Pharmacy BELGAUM- 590010, India E-mail: bknanjwade@yahoo.co.in Cell No: 0091 9742431000

“Ideal” Drug Delivery System: 

“Ideal” Drug Delivery System Inert Biocompatible Mechanically strong Comfortable for the patient Capable of achieving high drug loading Readily processable Safe from accidental release Simple to administer and remove Easy to fabricate and sterilize Free of leachable impurities 09/08/2010 2 KLE COP, NIpani

Modified Drug Release: 

Modified Drug Release Release can be: instantaneous (delayed-release) zero-order process (sustained release - mostly non-oral) first-order process (oral extended release) 09/08/2010 3 KLE COP, NIpani

Terminology: 

Terminology Sustained release: any dosage form that provides medication over an extended time timed release, prolonged release etc Controlled release: denotes that the system is able to provide some actual therapeutic control, whether this be of a temporal nature, spatial nature, or both 09/08/2010 4 KLE COP, NIpani

Traditional vs. Controlled Release Drug Dosing: 

Traditional vs. Controlled Release Drug Dosing 09/08/2010 5 KLE COP, NIpani

Traditional vs. Controlled Release: 

Traditional vs. Controlled Release With traditional administration, the drug active must remain between a maximum blood level value which may represent a toxic level and a minimum value below which the drug is no longer effective With controlled administration, the blood levels are constant between the desired maximum and minimum for an extended period of time 09/08/2010 6 KLE COP, NIpani

Controlled Drug Delivery: 

Controlled Drug Delivery Controlled drug delivery occurs when a polymer is combined with a drug or active agent such that the release from the bulk material is pre-designed. not all controlled systems are sustaining targeted drug delivery prodrugs, others 09/08/2010 7 KLE COP, NIpani

Advantages of Controlled Drug Delivery: 

Advantages of Controlled Drug Delivery Eliminate over or underdosing Maintain drug levels in desired range Need for less dosing Increased patient compliance Prevention of side effects 09/08/2010 8 KLE COP, NIpani

Design of Controlled Drug Delivery: 

Design of Controlled Drug Delivery Biopharmaceutic Characteristics of the Drug Molecular weight, Aqueous solubility, Partition coefficient, Drug Pka and Ionization, Route of administration, Drug stability etc Pharmacokinetic Characteristics of the Drug Absorption rate, Elimination Half-Life, Rate of metabolism etc. Pharmacodynamic Characteristics of the Drug Therapeutic Range, Therapeutic index, Plasma concentration response relatioship 09/08/2010 9 KLE COP, NIpani

Controlled Drug Delivery: 

Controlled Drug Delivery Depending on the formulation and the application, the time of release can be quite varied Procardia XL - 24 hours 09/08/2010 10 KLE COP, NIpani

Controlled Drug Delivery: 

Controlled Drug Delivery Lupron Depot - 1 month Norplant - 5 years 09/08/2010 11 KLE COP, NIpani

Polymers for Controlled Release: 

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 09/08/2010 12 KLE COP, NIpani

Current Polymers used in Controlled Drug Delivery: 

Current Polymers used in Controlled Drug Delivery These polymers became usable in controlled delivery due to their inert physical characteristics and being free of leachable impurities Poly 2-hydroxy ethyl methacrylate Poly N-vinyl pyrrolidone Polyvinyl alcohol Polyacrylic acid Polyethylene glycol Polymethacrylic acid 09/08/2010 13 KLE COP, NIpani

Oral Dosage Form: 

Oral Dosage Form Biological Factors Half-life Absorption active vs passive GI transit time floating systems bioadhesives penetration enhancers Metabolism 09/08/2010 14 KLE COP, NIpani

Oral Dosage Form: 

Oral Dosage Form Physicochemical Factors Dose Size (0.5-1.0 g) Ionization, pKa and aqueous solubility solubility less 0.01 mg/ml (digoxin, griseofulvin) Partition Coefficient Stability 09/08/2010 15 KLE COP, NIpani

Diffusion-Controlled Systems: 

Diffusion-Controlled Systems Reservoir Devices 09/08/2010 16 KLE COP, NIpani

Characteristics of a Reservoir Diffusional Systems: 

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 09/08/2010 17 KLE COP, NIpani

Reservoir Diffusional Products: 

Reservoir Diffusional Products 09/08/2010 18 KLE COP, NIpani

Matrix Devices: 

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. 09/08/2010 19 KLE COP, NIpani

Matrix Diffusional System: 

Matrix Diffusional System 09/08/2010 20 KLE COP, NIpani

Characteristics of Matrix Diffusion Systems : 

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 09/08/2010 21 KLE COP, NIpani

Matrix Diffusional Products: 

Matrix Diffusional Products 09/08/2010 22 KLE COP, NIpani

Dissolution-Controlled Systems: 

Dissolution-Controlled Systems alternating layers of rate-controlling coats group of beads with different coatings (Spansule, SmithKline Beecham) dC/dt = kd*A(Cs-C) = D/h*A(Cs-C) dC/dt=dissolution rate, kd=dissolution rate const D=diffusion coefficient, Cs=saturation solubility C=concentration of solute in bulk solution 09/08/2010 23 KLE COP, NIpani

Types of Dissolution Controlled Systems: 

Types of Dissolution Controlled Systems Two types of dissolution- controlled, pulsed delivery systems A: Single bead-type device with alternating drug and rate controlling layer B: Beads containing drug with differing thickness of dissolving coats 09/08/2010 24 KLE COP, NIpani

Encapsulated Dissolution Products: 

Encapsulated Dissolution Products 09/08/2010 25 KLE COP, NIpani

Matrix Dissolution Products: 

Matrix Dissolution Products 09/08/2010 26 KLE COP, NIpani

Bioerodible and Combination Diffusion and Dissolution System: 

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. 09/08/2010 27 KLE COP, NIpani

PowerPoint Presentation: 

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 09/08/2010 28 KLE COP, NIpani

Characteristics of Bioerodible Matrix Systems: 

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 09/08/2010 29 KLE COP, NIpani

Bioerodible and Biodegradable Controlled Release Polymers: 

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 09/08/2010 30 KLE COP, NIpani

Degradation of Biodegradable Polymers: 

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 09/08/2010 31 KLE COP, NIpani

Biodegradable Polymers: 

Biodegradable Polymers Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems . 09/08/2010 32 KLE COP, NIpani

Biodegradable (surface eroding) Polyorthoester rods after (left) 9 weeks and (right) 16 weeks of implantation: 

Biodegradable (surface eroding) Polyorthoester rods after (left) 9 weeks and (right) 16 weeks of implantation Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems . 09/08/2010 33 KLE COP, NIpani

Major Companies Involved in Polymeric Delivery Technology: 

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 09/08/2010 34 KLE COP, NIpani

Osmotically Controlled Systems: 

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 09/08/2010 35 KLE COP, NIpani

Types of Osmotically Controlled Systems: 

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 09/08/2010 36 KLE COP, NIpani

Types of Osmotically Controlled Systems: 

Types of Osmotically Controlled Systems 09/08/2010 37 KLE COP, NIpani

Immediate Release Oxybutynin V/s Controlled Release Ditropan XL: 

Immediate Release Oxybutynin V/s Controlled Release Ditropan XL 09/08/2010 38 KLE COP, NIpani

Characteristics of Osmotically Controlled Devices: 

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 09/08/2010 39 KLE COP, NIpani

Examples of Osmotic Pump Systems: 

Examples of Osmotic Pump Systems Acutrim Appetite suppressant Concerta ADHD Procardia Hypertension/angina Volmax Bronchiodilator Ditropan Overactive bladder 09/08/2010 40 KLE COP, NIpani

Hydrodynamic Pressure Controlled Systems: 

Hydrodynamic Pressure Controlled Systems Hydrodynamic pressure generated by swelling of a hydrophilic gum The device comprises of a rigid, shape retaining housing enclosing a collapsible, impermeable containing liquid drug The gun imbibes water in GIT through an opening at the lower side of external housing and swells creating an hydrodynamic pressure The pressure thus created squeeze the collapsible drug reservoir to release the medicament through the delivery orifice 09/08/2010 41 KLE COP, NIpani

Delayed Transit Release Systems: 

Delayed Transit Release Systems Altered Density Systems High Density Pellets Low Density Pellets Mucoadhesive Systems Cross linked Polyacrylic acid tablet Intestinal Release Systems Peyer’s patches – Proteins, Peptides, Antigens Colonic Release Systems pH sensitive bioerodiable polymer polymethacrylates Divinylbenzene cross linked polymers – azoreductase of colonic bacteria 09/08/2010 42 KLE COP, NIpani

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 09/08/2010 43 KLE COP, NIpani

Different Novel Drug Delivery Systems: 

Different Novel Drug Delivery Systems Microspheres, Liposomes, Niosomes Implants Pharmacosomes Nanoparticles Polymeric Films Local drug delivery systems, etc 09/08/2010 44 KLE COP, NIpani

Classes of Drugs for Novel Drug Delivery: 

Classes of Drugs for Novel Drug Delivery Anti-cancer agents Anti-hypertensive agents Anti-psychotic agents Non steroidal anti-inflammatory agents Anti infective agents Anti-diabetic agents Protein and peptide drugs Biotechnological products 09/08/2010 45 KLE COP, NIpani

Routes of Administration: 

Routes of Administration Peroral Route Parenteral Route Subdermal implants Buccal Administration Occular Delivery Transdermal delivery Pulmonary Drug Delivery Nasal delivery Colon drug delivery 09/08/2010 46 KLE COP, NIpani

Parenteral Controlled Release Systems: 

Parenteral Controlled Release Systems Injectables Solutions Dispersions Microspheres and Microcapsules Nanoparticles and Niosomes Liposomes and Pharmacosomes Resealed erythrocytes Implants Infusion Devices Osmotic Pumps (Alzet) Vapor Pressure Powered Pumps (Infusaid) Battery Powered Pumps 09/08/2010 47 KLE COP, NIpani

Infusaid Model 400 Implantable Pump : 

Infusaid Model 400 Implantable Pump 09/08/2010 48 KLE COP, NIpani

Bone Implants : 

Bone Implants 09/08/2010 49 KLE COP, NIpani

Administration of Implant to Rabbit Femur : 

Administration of Implant to Rabbit Femur 09/08/2010 50 KLE COP, NIpani

Transdermal Drug Delivery Systems: 

Transdermal Drug Delivery Systems Membrane permeation-controlled system Transderm – Scop (scopolamine; Ciba-Geigy) Adhesive dispersion-type system Deponit (nithroglycerin; Wyeth) Matrix diffusion-controlled system Nitrodur (nitroglycerin; Key) Microresevoir dissolution-controlled system Nitrodisc (Nitroglycerin; Searle) 09/08/2010 51 KLE COP, NIpani

Transdermal Device: 

Transdermal Device Monolithic Membrane 09/08/2010 52 KLE COP, NIpani

Transdermal Device: 

Transdermal Device Transdermal device for the delivery of scopolamine 09/08/2010 53 KLE COP, NIpani

Nasal and Pulmonary Drug Delivery Systems: 

Nasal and Pulmonary Drug Delivery Systems Dry Powder Inhalations Aerosols Nasal Gels Nasal Sprays Insuffulations 09/08/2010 54 KLE COP, NIpani

Buccal Delivery : 

Buccal Delivery Delivery protein and peptide like drugs Examples: Insulin , Oxytocin , Vasopressin analogues , Buserelin, Calcitonin, etc which cannot be given orally 09/08/2010 55 KLE COP, NIpani

Occular Drug Delivery Systems : 

Occular Drug Delivery Systems Liposomes and Niosomes as carriers for antibiotics and protein and peptides. Biodegradable matrix drug delivery to the anterior segment. Polymeric dispersion to prolong the delivery of Pilocarpine. Microemulsions, Self Emulsifying Drug Delivery Systems 09/08/2010 56 KLE COP, NIpani

Occular Delivery Systems : 

Occular Delivery Systems Ocusert intraocular device for release of pilocarpine 09/08/2010 57 KLE COP, NIpani

Dental Systems: 

Dental Systems Local administration of drugs to periodontal pocket using biodegradable polymers We are working on delivery of drugs to periodontal pocket using biodegradable in situ gels and matrix implants 09/08/2010 58 KLE COP, NIpani

Administration of Implant to Periodontal Pocket : 

Administration of Implant to Periodontal Pocket 09/08/2010 59 KLE COP, NIpani

Administration of In situ gel to Periodontal Pocket : 

Administration of In situ gel to Periodontal Pocket 09/08/2010 60 KLE COP, NIpani

Current and Future Trends in Polymer Drug Delivery Systems: 

Current and Future Trends in Polymer Drug Delivery Systems Hydrogels Ringcap Technology Pulsincap Technology Novel Drug Delivery for Insulin Oral Insulin Molecular Gates 09/08/2010 61 KLE COP, NIpani

Hydrogels: 

Hydrogels Hydrogels consist of polymers that swell without dissolving in an aqueous environment (water or other biological fluid) At equilibrium, the gels comprise 60-90% fluid and only 10-30% polymer Factors that affect release include pH, ionic strength, and temperature Polymers commonly used in Hydrogels include Poly-(N-isopropylacrylamide) Poly(methacrylic acid) Polyethylene Glycol 09/08/2010 62 KLE COP, NIpani

Ringcap Technology: 

Ringcap Technology Based on a tablet (usually film coated) Tablet is partially coated with a series of “rings” Rings can be made of any insoluble polymer that does not erode or degrade during the dispensing period The number of rings, the position of the rings, and the thickness of rings control the rate of release of drug in the final dosage form 09/08/2010 63 KLE COP, NIpani

Pulsincap: 

Pulsincap Water insoluble capsule body and a water soluble cap Capsule body contains drug and hydrogel polymer capable of rapidly expelling the drug at the predetermined time As the soluble cap erodes, the hydrogel swells and pushes out the drug The hydration rate depends on the hydrogel plug, the length of the plug and the fit ratio (plug diameter to body diameter) 09/08/2010 64 KLE COP, NIpani

Oral Protein Delivery: 

Oral Protein Delivery Nobex Corp. has designed a polymer that binds to specific sites on drug structure to form drug polymer conjugates and allows for oral delivery. Benefits include increased stability in the body, ability to retain normal biological actions, improved efficacy and safety, and increased patient compliance This technology is being used to develop many new products, one of which is oral insulin. 09/08/2010 65 KLE COP, NIpani

Synthesis of the Drug-Polymer Molecule: 

Synthesis of the Drug-Polymer Molecule The polymer blocks enzymes from attacking the protein 09/08/2010 66 KLE COP, NIpani

Molecular Gates: 

Molecular Gates A new gel has been developed that is used to make a “molecular gate” The gel expands at high pH and shrinks at low pH. The gel contains two polymers Polymethacrylic acid Polyethylene glycol 09/08/2010 67 KLE COP, NIpani

Molecular Gates: 

Molecular Gates Adding the enzyme glucose oxidase causes the gel to respond to changes in glucose levels because the glucose and enzyme chemically react to produce an acid. The gates would shrink or open at low pH to release insulin As the glucose levels drop, the pH rises causing the gates to expand and block the release of insulin 09/08/2010 68 KLE COP, NIpani

Questions?: 

Questions? 09/08/2010 69 KLE COP, NIpani

Thank You: 

Thank You 09/08/2010 70 KLE COP, NIpani E-mail: bknanjwade@yahoo.co.in Cell No: 0091 9742431000