1. OSMOTIC DRUG DELIVERY SYSTEMBy:Mr. Kailash VilegaveAsst. Prof,Shivajirao S. Jhondhle college of PharmacyAsangaon .

2. LIST OF CONTENTSINTRODUCTION ADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM REPORTED CASES REGARDING LIMITATIONS AND ADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM PRINCIPLE OF OSMOSIS BASIC COMPONENTS OF OSMOTIC PUMPOSMOTIC PUMPS FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON OSMOTIC PUMP) PHARMETRIX DEVICE HIGUCHI LEEPER OSMOTIC PUMPS HIGUCHI THEEUWES OSMOTIC PUMP ELEMENTARY OSMOTIC PUMP MULTICHAMBER OSMOTIC PUMPS CONTROLLED PORSITY OSMOTIC PUMPS 3. ASYMMETRIC MEMBRANE COATED TABLETS PULSATILE DRUG DELIVERY OSMOTIC PUMPS DELAYED-DELIVERY OSMOTIC DEVICES VOLUME AMPLIFIER DELIVERY DEVICE OSMOTIC DEVICES THAT USE SOLUBILITY MODIFIERS OSMOTIC DEVICES FOR USE IN ORAL CAVITY OSMOTIC DEVICE THAT DELIVER DRUG BELOWSATURATION MISCELLANEOUS DEVICES SPECIALIZED COATINGSPROCESSING AND PERFORMANCE IMPROVEMENTIN VITRO EVALUATIONMARKET PRODUCTSREFERENCES 4. INTRODUCTION Osmotic drug delivery uses the osmotic pressure of drug or other solutes (osmogens or osmagents) for controlled delivery of drugs. Osmotic drug delivery has come a long way since Australian physiologists Rose and Nelson developed an implantable pump in 1955. 5. ADVANTAGES OF OSMOTIC DRUGDELIVERY SYSTEM The delivery rate of zero-order (which is most desirable) is achievable with osmotic systems. Delivery may be delayed or pulsed, if desired. For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic conditions which is mainly attributed to the unique properties of semipermeable membrane (SPM) employed in coating of osmotic formulations. 6. Graph shows nifedipine release from push pull osmotic pump inartificial gastric and intestinal fluid. The release profile for bothmedia are similar and not affected by pH. 7. ADVANTAGESHigher release rates are possible with osmotic systems comparedwith conventional diffusion-controlled drug delivery systems.The release rate of osmotic systems is highly predictable and canbe programmed by modulating the release control parameters.A high degree of in vivoin vitro correlation (IVIVC) isobtained in osmotic systems because the factors that areresponsible for causing differences in release profile in vitro andin vivo (e.g., agitation, variable pH) affect these systems to amuch lesser extent. 8. Figure shows the cummulative amount of nifidipine released frompush pull osmotic pump (POPP) in vitro and in the GIT tract of dogsas a function of time. 9. ADVANTAGES The release from osmotic systems is minimally affected by the presence of food in the gastrointestinal tract (GIT). This advantage is attributed to design of osmotic systems. Environmental contents do not gain access to the drug until the drug has been delivered out of the device. Production scale up is easy. 10. DISADVANTAGES OF OSMOTICDRUG DELIVERY SYSTEM Toxicity due to dose dumping. Rapid development of tolerance. Additional patient education and counseling is required. Hypersensitvity reaction may occur after implantation. 11. REPORTED CASES REGARDING LIMITATIONSAND ADVERSE EFFECTS OF OSMOTIC DRUGDELIVERY SYSTEM During quality control of nifedipine GITS (Gastrointestinaltherapeutic System) tablets, it was observed that several batches showdifferent release patterns of the drug. It was found that non uniformcoating around the tablet produced different membrane thicknesses,which was responsible for differences in release pattern amongdifferent patches. Another case was reported for Osmosin (Indomethacin OROS), whichwas first introduced in UK in 1983. A few months after itsintroduction frequent incidences of gastointestinal reactions(hemorrhage and perforation)was observed by the Committee on theSafety of Medicines, and Osmosin was withdrawn from market. 12. PRINCIPLE OF OSMOSIS Osmosis refers to the process of movement of solvent from lowerconcentration of solute towards higher concentration of solute across asemi permeable membrane. Abbe Nollet first reported osmotic effect in 1748, but Pfeffer in 1877 hadbeen the pioneer of quantitative measurement of osmotic effect. Pfeffer measured the effect by utilizing a membrane which is selectivelypermeable to water but impermeable to sugar. The membrane separatedsugar solution from pure water. Pfeffer observed a flow of water into thesugar solution that was halted when a pressure p was applied to the sugarsolution. Pfeffer postulated that this pressure, the osmotic pressure of thesugar solution is proportinal to the solution concentration and absolutetemperature. Vant Hoff established the analogy between the Pfeffer results and theideal gas laws by the expression = n2RT----------------------(1) Where n2 represents the molar concentration of sugar (or other solute) inthe solution, R depicts the gas constant, and T the absolute temperatue. This equation holds true for perfect semipermeable membranes and lowsolute concentrations. 13. Another method of obtaining a good approximation of osmoticpressure is by utilizing vapour pressure measurements and byusing expression: = RT ln (Po/P)/v -------- (2) Where Po represents the vapour pressure of the pure solvent, Pis the vapour pressure of the solution and v is the molarvolume of the solvent. As vapour pressure can be measuredwith less effort than osmotic pressure this expression isfrequently used. 14. Osmotic pressure for soluble solutes is extremely high. Thishigh osmotic pressure is responsible for high water flow acrosssemipermeable membrane. The rate of water flow dictated by osmotic pressure can begiven by following equation, dV/dt = A /l ----------------------- (3) Where dV/dt represents the water flow across the membranearea A and thickness l with permeability . depicts the difference in osmotic pressure between thetwo solutions on either side of the membrane.NOTE- This equation is strictly applicable for perfectsemipermeable membrane, which is completely impermeableto solutes. 15. A number of osmotic pressure powered drugdelivery system has been developed. Theprinciple of their operation can be described bya basic model as outlined in following figure. 16. Schematic representation of the basic model ofosmotic pressure powered drug delivery systems PUMPSEMIPERMEABLEHOUSINGMEMBRANE VsVdDELIVERY MOVABLEORIFICE PARTITION Vs is volume of osmotic agent compartment Vd is volume of drug compartment 17. When a single osmotic driving agent is used, the pumping rate of the osmoticdevice of (volume per unit time) is defined byQ/t = Pw Sm [m (s- e)-(Pd+Pc)] ------------ (4) Pw is permeability of semi permeable membrane to water; Sm is effective surface area of the membrane; m is osmotic reflection coefficient of the membrane; s and e are the osmotic pressure of saturated solution of osmotic drivingagent and of the environment where device is located, respectively; Pd is elevation of internal pressure generated in the drug formulationcompartment as the result of water influx into osmotic agent compartment; Pc is pressure required to deform drug formulation compartment inward. If the net osmotic pressure gradient [m (s- e)] is constant and the hydrostaticpressure (Pd+Pc) is negligibly small, equation (4) can be simplified to:Q/t = Pw Sm (s- e) -------------- (5) 18. And a zero order rate of drug release from osmoticdevice can be achieved if following conditions aremet: The amount of osmotic driving agent used is sufficient tomaintain a saturated solution in the osmotic agent compartmenti.e. s is constant. The environmental osmotic activity is either constant ornegligibly small i.e. (s- e) constant. The osmotic reflection coefficient is constant and very close tounity i.e. m1. That means ideal semi permeable membrane,selectively permeable to water but not to osmotic drug agent,should be used. A sufficiently large delivery orifice and a highly deformablepartition should be used. So, Pd =Pc0. 19. BASIC COMPONENTS OF OSMOTICPUMPDRUG Drug itself may act as an osmogen and showsgood aqueous solubility (e.g., potassium chloridepumps). But if the drug does not possess an osmogenicproperty, osmogenic salt and other sugars can beincorporated in the formulation. 20. OSMOGEN / OSMAGENT / OSMOTICDRIVING AGENT For the selection of osmogen, the two mostcritical properties to be considered areosmotic activity and aqueous solubility. Osmotic agents are classified as, Inorganic water soluble osmogens:Magnesium sulphate, Sodium chloride, Sodium sulpahte, Potassium chloride, Sodium bicarbonate,etc. Organic polymeric osmogens:Na CMC, HPMC, HEMC, etc. Organic water soluble osmogens:Sorbitol,Mannitol,etc. 21. SEMIPERMEABLE MEMBRANE Semipermeable membrane must possess certain performance criteia: It must have sufficient wet strength and water permeability. It should be selectively permeable to water and biocompatible. Cellulose acetate is a commonly employed semipermeable membrane for thepreparation of osmotic pumps. Some other polymers such as agar acetate, amylose triacetate, betaglucanacetate, poly (vinylmethyl) ether copolymers, poly (orthoesters), poly acetals,poly (glycolic acid) and poly (lactic acid) derivatives. The unique feature of semipermeable membrane utilized for an osmotic pumpis that it permits only the passage of water into the unit, thereby effectivelyisolating the dissolution process from the gut environment. 22. HYDROPHILIC AND HYDROBHOBICPOLYMERS These polymers are used in the formulation development ofosmotic systems containing matrix core. The selection of polymer is based on the solubility of drug aswell as the amount and rate of drug to be released from thepump. The highly water soluble compounds can be co-entrapped inhydrophobic matrices and moderately water solublecompounds can be co-entrapped in hydrophilic matrices toobtain more controlled release. Examples of hydrophilic polymers are Hydroxy ethylcellulose, carboxy methyl cellulose, hydroxyl propyl methylcellulose, etc. Examples of hydrophobic polymers are ethyl cellulose, waxmaterials, etc. 23. WICKING AGENTS It is defined as a material with the ability to draw water into theporous network of a delivery device. The function of the wicking agent is to draw water to surfacesinside the core of the tablet, thereby creating channels or anetwork of increased surface area. Examples: colloidon silicon dioxide, kaolin, titanium dioxide,alumina, niacinamide,sodium lauryl sulphate (SLS), lowmolecular weight polyvinyl pyrrolidone (PVP), bentonite,magnesium aluminium silicate, polyester and polyethylene,etc. 24. SOLUBILIZING AGENTS Non swellable solubilizing agents are classified into three groups: Agents that inhibits crystal formation of the drugs orotherwise act by complexation of drug (e.g., PVP, PEG,and cyclodextrins) A high HLB micelle forming surfactant, particularlyanionic surfactants (e.g., Tween 20, 60, 80, poly oxyethylene or polyethylene containing surfactants and otherlong chain anionic surfactants such as SLS). Citrate esters and their combinations with anionicsurfactants (e.g., alkyl esters particularly triethyl citrate) 25. SURFACTANTS They are added to wall forming agents. The surfactants act by regulating the surface energy ofmaterials to improve their blending in to the compositeand maintain their integrity in the environment of useduring the drug release period. Examples: polyoxyethylenated glyceryl recinoleate,polyoxyethylenated castor oil having ethylene oxide,glyceryl laurates, etc. 26. COATING SOLVENTS Solvents suitable for making polymeric solution that isused for manufacturing the wall of the osmotic deviceinclude inert inorganic and organic solvents. Examples: methylene chloride, acetone, methanol,ethanol, isopropyl alcohol, ethyl acetate, cyclohexane,etc. 27. PLASTICIZERS Permeability of membranes can be increased by addingplasticizer, which increases the water diffusion coefficient. Examples: dialkyl pthalates, trioctyl phosphates, alkyladipates, triethyl citrate and other citrates, propionates,glycolates, glycerolates, myristates, benzoates,sulphonamides and halogenated phenyls. 28. FLUX REGULATORS Flux regulating agents or flux enhancing agent or fluxdecreasing agent are added to the wall forming material;it assist in regulating the fluid permeability throughmembrane. Poly hydric alcohols such as poly alkylene glycols andlow molecular weight glycols such as poly propylene,poly butylene and poly amylene,etc. can be added asflux regulators. 29. PORE FORMING AGENTSThese agents are particularly used in the pumps developed for poorly water soluble drug and in the development of controlled porosity or multiparticulate osmotic pumps. The pore formers can be inorganic or organic and solid or liquid in nature.For example Alkaline metal salts such as sodium chloride, sodium bromide, potassium chloride, etc. Alkaline earth metals such as calcium chloride and calcium nitrate Carbohydrates such as glucose, fructose, mannose,etc. 30. FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON OSMOTIC PUMP)Salt ChamberWater Chamber Drug Chamber Delivery orificeRigid Semi permeable membraneElastic Diaphragm 31. PHARMETRIX DEVICE This device is composed of impermeablemembrane placed between the semipermeable membrane and the waterchamber. These allows the storage of the pump infully water loaded condition. The pump isactivated when seal is broken. Water isthen drawn by a wick to the membranesurface and pumping action begins. This modification allows improved storageof the device, which on demand can beeasily activated. 32. HIGUCHI LEEPER OSMOTIC PUMPS It has no water chamber, and the activation of the device occurs afterimbibition of the water from surrounding environment. It has a rigid housing. Widely employed for veterinary use. It is either swallowed or implanted inbody of an animal for delivery of antibiotics or growth hormones to animal. Modification: A layer of low melting waxy solid, is used in place of movableseparator to separate drug and osmotic chamber.Rigid Housing Drug ChamberSatd. Sol. OfMgSO4 contg. Movable SeparatorSolid MgSO4 MgSO4Semi-permeableMembrane Porous Membrane Support 33. HIGUCHI THEEUWES OSMOTIC PUMP In this device, the rigid housing is consisted of a semi permeable membrane. Thedrug is loaded in the device only prior to its application, which extends advantagefor storage of the device for longer duration. The release of the drug from the device is governed by the salt used in the saltchamber and the permeability characteristics of outer membrane. Diffusional loss of the drug from the device is minimized by making the delivery portin shape of a long thin tube. Small osmotic pumps of this form are available under the trade name Alzet.Fluid to be pumped Coating contg. Solid Osmotic compoundSPM Delivery portRigidSemi permeableMembraneOsmotic Agent layerDelivery port Wall of flexible Squeezed collapsible material Drug Core Swollen Osmogen layer 34. ALZET OSMOTIC PUMP ALZET Osmotic pumps areminiature, infusion pumps for thecontinuous dosing of laboratoryanimals as small as mice andyoung rats. These minipumpsprovide researchers with aconvenient and reliable methodfor controlled agent delivery invivo. 35. ALZET OSMOTIC PUMP ADVANTAGES Ensure around-the-clock exposure to test agents at predictablelevels. Permit continuous administration of short half-life proteins andpeptides. Convenient method for chronic dosing of laboratory animals. Minimize unwanted experimental variables and ensure reproducible,consistent results. Eliminate the need for nighttime or weekend dosing. Reduce handling and stress to laboratory animals. Small enough for use in mice or very young rats. Allow for targeted delivery of agents to virtually any tissue. Cost-effective research tool. 36. Principle of OperationALZET pumps have 3 concentric layers: Rate-controlling, semi-permeablemembrane Osmotic layer Impermeable drug reservoirALZET pumps work by osmoticdisplacement. Water enters the pumpacross the outer, semi-permeablemembrane due to the presence of a highconcentration of sodium chloride in theosmotic chamber. The entry of watercauses the osmotic chamber to expand,thereby compressing the flexiblereservoir and delivering the drug solutionthrough the delivery portal. 37. ALZET Osmotic Pumps are available in three sizes 38. ALZET BRAIN INFUSION KITS 39. ELEMENTARY OSMOTIC PUMP Rose Nelson pump was further simplified inthe form of elementary osmotic pump(byTheeuwes,1975) which made osmoticdelivery as a major method of achievingcontrolled drug release. 40. ELEMENTARY OSMOTIC PUMP (EOP) Delivery OrificeCore containing agent Semi permeable membrane It essentially contains an active agent having a suitable osmotic pressure. It is fabricated as a tablet coated with semi permeable membrane, usually cellulose acetate. A small orifice is drilled through the membrane coating. This pump eliminates the separate salt chamber unlike others. When this coated tablet is exposed to an aqueous environment, the osmotic pressure of the soluble drug inside the tablet draws water through the semi permeable coating and a saturated aqueous solution of drug is formed inside the device. The membrane is non-extensible and the increase in volume due to imbibition of water raises the hydrostatic pressure inside the tablet, eventually leading to flow of saturated solution of active agent out of the device through the small orifice. The process continues at a constant rate till the entire solid drug inside the tablet is eliminated leaving only solution filled shell. This residual dissolved drug is delivered at a slower rate to attain equilibrium between external and internal drug solution. 41. RELEASE PROFILES The mass delivery rate from the pump can be written as:dmA kSd dt z h f e Sd is concentration in drug compartment f is osmotic pressure of the drug formulation A is surface area h is thickness k is permeability of membrane e is osmotic pressure of the environment which is negligible So zero order release rate can be expressed as,Z dmA k Sddtz h f 42. PROBLEM Area of semi permeable membrane of an elementary osmotic pump is2.7 cm2, thickness is 0.031 cm, permeability coefficient is 2.1*10-6cm2/atm*h and the osmotic pressure is 225 atm, calculate the rate ofdelivery of the solute under zero-order conditions if the concentrationof saturated solution at 37C is 290 mg/ cm3?dm/dt = (A/h)k() Cs= 2.7 cm2 / 0.031 cm 2.1*10-6 cm2/atm*h 225 atm 290 mg/ cm3= 11.93 mg/h 43. LIMITATION OF EOP Generally in osmotic pumps the semi permeable membraneshould be 200-300m thick to withstand pressure with in thedevice. These thick coatings lower the water permeation rate,particularly for moderate and poorly soluble drugs. In general we can predict that these thick coating devices aresuitable for highly water soluble drugs. This problem can be overcome by using coating materials withhigh water permeabilities. For example, addition of plasticizersand water soluble additive to the cellulose acetatemembranes, which increased the permeability of membraneup to ten fold. 44. MODIFICATIONS IN ELEMENTARY OSMOTIC PUMP The first layer is made up of thick micro porous film that provides thestrength required to withstand the internal pressure, while second layer iscomposed of thin semi permeable membrane that produces the osmoticflux. The support layer is formed by: Cellulose acetate coating containing 40 to 60% of pore forming agentsuch as sorbitol.Inner microporousDrug chambermembrane Delivery orificeOuter semi permeable COMPOSITE MEMBRANE COATING USED TOmembrane DELIVER MODERATELY SOLUBLE DRUGS 45. DELIVERY OF INSOLUBLE DRUG Rigid SPMxx xx xx x x xx xx xx Elastic SPMInsoluble Particles Coating osmotic agent with elastic semi permeable film Mixing of above particles with the insoluble drug Resultant mixture is coated with the rigid semi permeablemembrane 46. MULTICHAMBER OSMOTIC PUMPS Multiple chamber osmotic pumps can bedivided into two major classesa) Tablets with a second expandable osmoticchamberb) Tablets with a non-expanding secondchambera) Tablets with a second expandable osmoticchamber In the tablets with a second expandableosmotic chamber, the water issimultaneously drawn into both thechambers in proportion to theirrespective osmotic gradients, eventuallycausing an increase in volume of thechamber and subsequently forcing thedrug out from the drug chamber. The matrix should have sufficientosmotic pressure to draw water throughthe membrane into the drug chamber.Under hydrated conditions matricesshould have to be fluid enough to bepushed easily through a small hole bythe little pressure generated by theelastic diaphragm. 47. OROS ORAL DRUG DELIVERY TECHNOLOGY OROS technology employs osmosis to provide precise, controlled drug delivery for up to 24 hours and can be used with a range of compounds, including poorly soluble or highly soluble drugs. 48. Before operationDuring operationDelivery Orifice Delivery Orifice Osmotic Drug Core SPMPolymer push compartmentExpanded push compartmentDrug delivery process of two chamber osmotic tablet 49. LIQUID OSMOTIC SYSTEM (L-OROS) A liquid formulation isparticularly well suited fordelivering insoluble drugs andmacromolecules such aspolysaccharide andpolypeptides. Such molecules requieexternal liquid components toassist in solubilization,dispersion, protection fromenzymatic degradation andpromotion of gastrointestinalabsorption. Thus the L-OROS system wasdesigned to providecontinuous delivery of liquiddrug formulation and improvebioavailability of drugs. 50. Another type of L-OROS system consists of a hard gelatincapsule containing a liquid drug layer, a barrier layer and apush layer surrounded by a semipermeable membrane. TheL-OROS hardcap system was designed to accommodate moreviscous suspensions with higher drug loading than would bepossible using softcap design.Delivery orificeBarrier layerRate controlling membranePush layerInnerCompartment Inner Capsule 51. LIQUID DRUG DELIVERY OTHER THAN L-OROSUSE OF POROUS PARTICLES The controlled release of liquid active agent formulations is provided by dispersing porous particles that contain the liquid active agent formulation in osmotic push-layer dosage forms. The liquid active agent formulations may be absorbed into the interior pores of the material in significant amounts and delivered to the site of administration in the liquid state. Microcrystalline cellulose, porous sodium carboxymethyl cellulose, porous soya bean fiber and silicon dioxideall of which have high surface area and good absorption properties and can be used indosage form described here in. 52. OROS TRI-LAYER 53. DUROS DUROS implants are designed to bring the benefit ofcontinuous therapy for up to one year. The non-biodegradable, osmotically driven system is intended toenable delivery of small drugs, peptides, proteins, DNA andother bioactive macromolecules for systemic or tissue-specific therapy. Viadur (leuprolide acetate implant), the first marketedproduct to incorporate DUROS, is indicated for thepalliative treatment of advanced prostate cancer.ADVANTAGES Can deliver highly concentrated and viscous formulations. Improved patient compliance Titanium protects the drug from enzymatic degradation. The system can be engineered to deliver a drug at a desireddosing rate with high degree of precision. 54. DUROS SYSTEM 55. Affecting factors Compositions of osmotic agent Thickness of semipermeable membrane Surface area 56. b) DEVICES WITH A NON-EXPANDINGSECOND CHAMBER: This group can be subdivided intotwo subgroups depending upon thefunction of the second chamber. In one group the second chamberserves for the dilution of the drugsolution leaving the device. This isimportant in cases where drugscauses irritation of GIT. Before the drug can exit from thedevice, it must pass through asecond chamber. Water is alsodrawn osmotically into this chambereither due to osmotic pressure ofthe drug solution or because thesecond chamber that bears water-soluble diluents such as sodiumchloride. 57. Exit Orifice WallFirstDrug in diluted soln.Compartment Interior Orifice Second Compartment Interior wall Drug 58. The second group of non-expanding multichamber devices essentiallycontains two separate simple OROS tablets formed into a singletablet. Two chambers contain two separate drugs both are deliveredsimultaneously. This system is also known as sandwiched osmotictablet system (SOTS). A more sophisticated version of this device consists of two rigidchambers, one contains biologically inert osmotic agent such as sugaror NaCl, and the second chamber contains the drug. When exposed toaqueous environment, water is drawn into both chambers across thesemi permeable membrane. The solution of osmotic agent then passesinto the drug chamber through the connecting hole where it mixeswith the drug solution before escaping through the micro porousmembrane that forms part of the wall around the drug chamber.Relatively insoluble drugs can be delivered using this device. Osmotic agent Semi permeable containing chambermembrane orifice Drug containing chamberMicroporous membrane 59. CONTROLLED PORSITY OSMOTICPUMPS They are not having any aperture for release of drugs. Thedrug release is achieved by the pores, which are formed inthe semi permeable wall in situ during the operation. The semi permeable coating membrane contains water-soluble pore forming agents. This membrane after formationof pores becomes permeable for both water and solutes.AqueousEnvironmentPore Formation and SubsequentCoating Containing Pore Drug ReleaseForming Agents 60. SPECIFICATIONS FOR CONTROLLEDPOROSITY OSMOTIC PUMPSMaterials SpecificationsPlasticizers and flux regulating 0 to 50, preferably 0.001 to 50agents parts per 100 parts of wall materialSurfactants0 to 40, preferably 0.001 to 40 parts per 100 parts of wall materialWall Thickness 1 to 1000, preferably 20 to 500mMicro porous nature5 to 95% pores between 10 to 100mPore forming additives 0.1 to 60%, preferably 0.1 to 50%, by weight, based on the total weight of pore forming additive and polymer pH insensitive pore forming additive (solid or liquid) preferably 0.1 to 40% by weight 61. SPECIFICATIONS FOR CORE OFCONTROLLED POROSITY OSMOTIC PUMPS Property SpecificationsCore loading (size) 0.05ng to 5g or more (includedosage forms for humans andanimals)Osmotic pressure developed by a 8 to 500atm typically, withsolution of corecommonly encountered watersoluble drugs and excipientsCore solubility To get continuous, uniformrelease of 90% or greater of theinitially loaded core masssolubility, S, to the core massdensity, , that is S/, must be0.1 or lower. Typically this occurswhen 10% of the initially loadedcore mass saturates a volume ofexternal fluid equal to the totalvolume of the initial core mass 62. ASYMMETRIC MEMBRANE COATEDTABLETS Here, the coatings have an asymmetric structure, similarto asymmetric membranes made for reverse osmosis orultra filtration, in that the coating consists of a poroussubstrate with a thin outer membrane. Asymmetric tablet coating possesses some uniquecharacteristics, which are more useful in development ofosmotic devices they are as follows: High water fluxes can be achieved. The permeability of the coating to water can be adjustedby controlling the membrane structure. The porosity of the membrane can be controlled tominimize the time lag before drug delivery begins andallowing the drug to be released from large number ofdelivery ports. 63. PULSATILE DRUG DELIVERY Delivering a drug in one or more pulses issometimes beneficial, from the requiredpharmacological action point of view. Mechanical and drug solubilitymodifyingtechniques have been implemented toachieve the pulsed delivery of drugs with anosmotic system. 64. SOLUBILITY MODULATION FORPULSED RELEASE The composition described in the patents comprised the drugsalbutamol sulfate and modulating agent sodium chloride. Pulsed delivery is based on drug solubility. Salbutamolssolubility is 275 mg/mL in water and 16 mg/mL in a saturatedsolution of sodium chloride. Sodium chlorides solubility is 321mg/mL in water and 320 mg/mL in a saturated solution. Thesevalues show that the solubility of the drug is a function of themodulator concentration, whereas the modulators solubility islargely independent of the drug concentration. The tablet is similar to elementary osmotic pump, with a mixtureof salbutamol and sodium chloride in the tablet core. The release profile of the device is constant for salbutamol untilthe sodium chloride becomes exhausted, afterwards theremaining drug is delivered as a large pulse. This rlease pattern is exploited for nocturnal asthma in whichpulsatile delivery of salbutamol is desirable. 65. PULSATILE DELIVERY BASED ONAN EXPANDABLE ORIFICE. The system is in the form ofa capsule from which thedrug is delivered by the Tiny orifice opened upon stretches under thecapsules osmotic infusion Osmotic pressureof moisture from the body. The delivery orifice opensElastic Capintermittently to achieve aDrug Solutionpulsatile delivery effect.The orifice forms in thecapsule wall, which isconstructed of an elasticmaterial.Movable piston As the osmotic infusionSeparating Barrierprogresses, pressure rises Semi permeablewithin the capsule, causing Osmogen Membranethe wall to stretch. Elastomers such as styrene-butadiene copolymer can beused. 66. PORT SYSTEMThe Port System (Port Systems,LLC) consists of a gelatin capsulecoated with a semipermeablemembrane (eg, cellulose acetate)housing an insoluble plug (eg,lipidic) and an osmotically activeagent along with the drugformulation.When in contact with the aqueousmedium, water diffuses across thesemipermeable membrane, resultingin increased inner pressure thatejects the plug after a lag time. Thelag time is controlled by coatingthickness. The system showed goodcorrelation in lag times of in-vitroand in-vivo experiments in humans. 67. DELAYED-DELIVERY OSMOTICDEVICES Because of their semipermeable walls, osmoticdevices inherently show a lag time before drugdelivery begins. Although this characteristic isusually cited as a disadvantage, it can be usedadvantageously. The delayed release of certain drugs (e.g., drugs forearly morning asthma or arthritis) may be beneficial.The following slides describes other means tofurther delay drug release. 68. TELESCOPIC CAPSULES FORDELAYED RELEASE The dispenser comprises a housing that has first- and second-wall sections in aslideable telescoping arrangement. The housing maintains integrity in its environment of use.The device consists of two chambers; the first contains the drug and an exit port,and the second contains an osmotic engine. A layer of wax-like material separatesthe two sections. To assemble the delivery device, the desired active agent is placed into one of thesections by manual- or automated-fill mechanisms. The bilayer tablet with the osmotic engine is placed into a completed cap part of thecapsule with the convex osmotic layer pointed into the closed end of the cap and thebarrier layer exposed toward the cap opening. The open end of the filled vessel isfitted inside the open end of the cap, and the two pieces are compressed togetheruntil the cap, osmotic bilayer tablet, and vessel fit together tightly. As fluid is imbibed through the housing of the dispensing device, the osmotic engineexpands and exerts pressure on the slideable connected first and second wallsections. During the delay period, the volume of the reservoir containing the active agent iskept constant; therefore, a negligible pressure gradient exists between theenvironment of use and the interior of the reservoir. As a result, the net flow ofenvironmental fluid driven by the pressure to enter the reservoir is minimal, andconsequently no agent is delivered for the period. 69. Push plates Second WallFirst wall sectionsectionPush means Drug Internal CompartmentA delayed release telescopic capsule release contents afterexpansion. 70. DELAYED-RELEASE DELIVERY BASEDON MULTIPLE COATINGS The osmotically driven pump can be miniaturized to a size suited for swallowingor implanting. The pump may be used to administer a drug in a fluid form after aninitial activation period during which essentially no drug is administered.The basic components of the pump are semi permeable membrane (SPM) thatencapsulates an osmotically effective solute and drug and a discharge port throughwhich the drug is dispensed. A micro porous outer cover surrounds the SPM andprotects it from an external aqueous environment.A water-swellable composition is positioned between the end of the SPM and theouter cover.As the pump is placed in an aqueous environment, water from the environmentpasses through the micro porous portion of the outer cover into the water swellablecomposition. The water swellable composition absorbs water, expands, and inpiston-like fashion displaces the outer cover, thereby exposing the SPM to theaqueous environment and activating the osmotic pump. The time required for the water-swellable composition to absorb water, expand,and displace the outer cover provides an initial activation period during whichessentially no drug is delivered by the pump. By suitably adjusting the membrane composition and structure, a predeterminedactivation period in the range of 318 h is achieved. 71. ENTERIC AND COLON TARGETEDOSMOTIC DOSAGE FORMS Use of osmotic systems for the pH triggered burst of theactive agent is disclosed. The devices are designed for oral administration, either in theform of tablets or capsules. If used in tablets, the core consists of the drug, osmagent,diluents, and superdisintegrants. The tablets are coated firstby SPM walls of insufficient thickness and then overcoatedwith the pH-triggered coating solution. The pH-triggered solution contains polymers such ascellulose acetate phthalate, pH-sensitive Eudragit grades, andinsoluble polymers. The patent claims that using only pH-sensitive materials to achieve site-specific delivery is difficultbecause the drug often leaks out of the dosage form before itreaches the release site or desired delivery time. 72. VOLUME AMPLIFIER DELIVERYDEVICE One of the limitations with osmotic devices, is theincomplete release of the drug. Here we will see the use of volume amplifiers to deliver theentire drug contained in the system. The device consists of a core, an SPM, and a deliveryorifice. In addition to the drug and the osmagent, thecompartment contains a volume amplifier to increase theamount of agent delivered from the system. The amplifier consists of a membrane surrounding a gas-generating couple with the membrane formed of anexpandable material that is permeable to fluid andimpermeable to the couple. 73. Gas generatingcouple Gas Volume Amplifier 74. EFFERVESCENT ACTIVITY-BASEDSYSTEMS The osmotic device comprises a semi permeable wall that surrounds acompartment housing a drug that exhibits limited solubility under neutraland acid conditions and a compound capable of releasing carbon dioxide inthe presence of an acid. As fluid is imbibed through the wall into the compartment at a ratedetermined by the walls permeability and the osmotic pressure gradientacross the wall, a basic solution containing drug and compound is formed,which is delivered from the compartment through the passageway. The released compound reacts with the acid in the environment at thedeviceenvironment interface and evolves carbon dioxide, therebyproviding an effervescent suspension that delivers the drug to theenvironment in a finely dispersed form over time. Thus the agent isdelivered in a form that is rapidly absorbed and does not block the orificeof the delivery device. 75. Drugs that can be delivered by such a system are those thatexhibit a propensity for rapid precipitation in an environmentthat has a pH less than 7 (e.g., the stomach). A few examplesare the anti-inflammatory arylcarboxylicacids such asindomethacin, aspirin, diclofenac, fenoprofen, flufenamic acidand prioxicam. The osmotic device without the compound releases the drugin the presence of an artificial gastric fluid containinghydrochloric acid; however, the drug precipitates onto thewall of the device and the exit port of the passageway and istherefore not observed in the fluid of the environment. Thisproblem is rectified with the use of an effervescent system. 76. OSMOTIC DEVICES THAT USESOLUBILITY MODIFIERSFor slightly soluble drug carbamazepine System consists of a core, crystal habit modifierand osmotic driving agent. Crystal habit modifying agent is useful onlywhen drug exists in more than one crystallineform and when desired form of the drug is notthe most stable form. Crystal modifying agent modifies the solubilityof the drug. The change in solubility should be significant. 77. For slightly soluble drug The core consists of a drug with limitedsolubility in water or physiologicalenvironments, a nonswelling solubilizingagent to enhance the solubility of the drug,and an osmagent. In addition, a nonswelling wicking agent isdispersed throughout the composition. Adelivery system for nifedipine used colloidalsilicon dioxide, polyvinylpyrrolidone, andsodium lauryl sulfate as nonswellingwicking agents. 78. For sparingly soluble drug The core consists of an active ingredient that is sparinglysoluble in water, a hydrophilic polymeric swelling agentcomposed of a mixture of a vinylpyrrolidonevinyl acetatecopolymer with an ethylene oxide homopolymer, and a water-soluble substance for inducing osmosis. This mixture has the surprising advantage that pressureproduced during swelling does not cause the system to ruptureand that the swelling speed is uniform, which allows almostconstant amounts of active ingredient to be released from thesystem. Theophylline, aspirin, carbamazepine and nifedipinehave been delivered by this system. 79. Use of Vitamin E tocopheryl polyethylene glycol succinate(TPGS) Vitamin E tocopheryl polyethylene glycol succinate (TPGS)drug compositions to obviate the need for surfactants ornonevaporated cosolvents. The advantage of using a TPGSdrug solid solution is that insoluble drugs can be consideredsoluble for the purpose of getting the drug out of the osmoticdevice. Cyclosporine has been cited as an example in patent. 80. OSMOTIC DEVICES FOR USE INORAL CAVITYUnique advantage of nicotine delivery by an oral osmoticdevice. The system consists of a nicotine salt and an optional alkalinesalt, which is capable of reacting with the nicotine salt in thepresence of water to form a nicotine base. The conversion ofnicotine salt to a nicotine base may take place within oroutside the device and in the patients mouth. The nicotinebase or salt is delivered from the compartment through apassageway in the wall. The advantage is that nicotine salt exhibits good stability anda long shelf life, and the nicotine base exhibits excellentabsorption through oral mucosal membranes. 81. OSMOTIC DEVICE THAT DELIVER DRUGBELOW SATURATION These types of delivery devices areuseful for dispensing drugs that areirritants to mucosal and GIT tissue suchas potassium chloride, aspirin, andindomethacin. The system comprises a first wall of asemi permeable material that surroundsa compartment containing a drugformulation and has a passagewaythrough the wall for releasing agentfrom the compartment. A second wallis positioned away from the first walland is constructed of a micro porous orhydrogel material. Because of thedistance between the two walls, adistribution zone interposed betweenthe first and second walls exists 82. MISCELLANEOUS DEVICES The device has a centrally located expandable core that is completelysurrounded by an active substance-containing layer, which is completelysurrounded by a membrane. The core consists of an expandable hydrophilic polymer and an optionalosmagent. The composition immediately surrounding the core comprisesan active substance, an osmagent, and an osmopolymer. The membrane ismicro porous in nature and may have a delivery orifice. The device is capable of delivering insoluble, slightly soluble, sparinglysoluble, and very soluble active substances to the environment.Exit Orifice Microporous membrane Active Agent Core layer 83. SPECIALIZED COATINGS The wall in this case is formed of a semipermeable hydrophobicmembrane that has pores in the wall. The pores are substantially filled witha gas phase. The hydrophobic membrane is permeable to water in thevapor phase and is impermeable to an aqueous medium at pressures lessthan 100 Pa. The drug is released by osmotic pumping or osmotic burstingupon the imbibition of sufficient water vapor into the device core. These devices minimize incompatibilities between the drug and the ions(such as hydrogen or hydroxyl) or other dissolved or suspended materialsin the aqueous medium because contact between the drug and the aqueousmedium does not occur until after the drug is released, which results fromthe SPMs selective permeability for water vapor. 84. FACTORS AFFECTING THE PERFORMANCE OFOSMOTIC DRUG DELIVERY SYSTEMPhysico-chemical properties of the drug Solubility Solid or liquid Viscosity (Liquids) Rheological propertiesProperties of osmotic agent Osmotic pressure difference generated by the agent which ultimately will decide the water influx and in turn the delivery of active.Membrane type and characteristics Wet strength Water permeabilitySize of delivery orificeCharacteristics of the polymer used (e.g. Hydration, Swelling etc.) 85. PROCESSING AND PERFORMANCEIMPROVEMENT Improvement of adhesion between core and semipermeable membrane. The tablet core containing the drug and other required components isevenly coated with a discrete layer of a water-soluble (or water-dispersible)and water-permeable non osmotically active solid polymeric binder to alevel of less than10%. The SPM is then coated on the tablet. Enhancing the startup and performance of osmotic drug deliverysystems. The osmotic delivery system should include a liquid or gel additive thatsurrounds the osmotic agent to enhance startup and lubricate the osmoticagent. The liquid or gel additive is an incompressible lubricating fluid that fillsany air gaps between the osmotic agent and the walls of a chamber andsubstantially reduces startup delays. 86. IN VITRO EVALUATION The in vitro release of drugs from oral osmotic systems hasbeen evaluated by the conventional USP paddle and baskettype apparatus. The dissolution medium is generally distilled water as wellas simulated gastric fluid (for first 2-4 h) and intestinal fluids(for subsequent hours) have been used. The standard specifications, which are followed for the oralcontrolled drug delivery systems are equivalently applicablefor oral osmotic pumps. In vivo evaluation of oral osmotic systems has been carriedout mostly in dogs. Monkeys can also be used but in most ofthe studies the dogs are preferred. 87. MARKET PRODUCTS Products Incorporating ALZAs OROS TechnologyAlpress LP (prazosin) once-daily extended-release tablet sold in France for the treatment ofhypertension.Cardura XL (doxazosin mesylate) sold in Germany for the treatment of hypertension.Concerta (methylphenidate HCl) CII once-daily extended-release tablet for the treatment ofAttention Deficit Hyperactivity Disorder (ADHD) in patients age six and older.Covera-HS (verapamil) a Controlled Onset Extended Release (COER-24) system for themanagement of hypertension and angina pectoris.Ditropan XL (oxybutynin chloride) extended-release tablet for the once-a-day treatment ofoveractive bladder characterized by symptoms of urge urinary incontinence, urgency andfrequency.DynaCirc CR (isradipine) once-daily, extended-release tablet for the treatment ofhypertension. 88. Efidac 24 (chlorpheniramine) over-the-counter, extended- release tablet providing 24-hour relief from allergy symptoms and nasal congestion. Glucotrol XL (glipizide) extended-release tablet used as an adjunct to diet for the control of hyperglycemia in patients with non-insulin-dependent diabetes. Sudafed 24 Hour (pseudoephedrine) over-the-counter nasal decongestant for 24-hour relief of colds, sinusitis, hay fever and other respiratory allergies. Procardia XL (nifedipine) extended-release tablet for the treatment of angina and hypertension. Volmax (albuterol) extended-release tablet for relief of bronchospasm in patients with reversible obstructive airway disease.Products Incorporating ALZAs DUROS ImplantTechnologyViadur (leuprolide acetate implant) delivers leuprolidecontinuously for 12 months as a palliative treatment for advancedprostate cancer. 89. Verma R., Mishra B. and Garg S., Osmoticallycontrolled oral drug delivery; Drug Development andIndustrial Pharmacy, 26(7), 695-708 (2000) Kaushal M.and Garg S., An Update on Osmotic DrugDelivery Patents; Pharmaceutical Technology, August2003 38-45. Theeuwes F.,Elementary Osmotic Pump, Journal ofPharmaceutical Science;64(12):1987-1991(1975). Theeuwes F., Journal of PharmaceuticalScience;72:253(1983). Chein Y., Novel Drug Delivery Systems:398-407 90. Wong P.,Gupta S. and Stewart B. Modified ReleaseDrug Delivery Technology: Osmotically controlledtablets:101-114 Fara J. and and Ray N.; Drug Delivery Devices,Fundamentals and Applications, :137-175 Santus G., and Baker R., Osmotic Drug Delivery: AReview of the Patent Literature, J. Controlled Release35, 121 (1995). Swarbrick J. and Boylan J, Encyclopedia ofPharmaceutical Technology, Vol. 3: 297-300 www.fda.gov/ohrms/dockets/ ac/04/slides/2004-4078S1_13_Khan.ppt cooklab.rutgers.edu/Intro_Lect_webct.ppt 91. http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=15 http://www.alzet.com/ http://www.alza.com/ www.glue.umd.edu/~nsw/enpm808b/he-b.ppt www.dissolution.com/vbulletin/ archive/index.php?t-523.html - 5k http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=115