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osmotic drug delivery

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detailed presentation regarding novel drug delivery, that is osmotic drug delivery

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osmotic drug delivery

  1. 1. OSMOTIC PRESSURE CONTROLLED PUMPS - AASHU GUPTA
  2. 2. WHAT SHOULD BE CHOSEN ???? CONVENTIONAL DRUG THERAPY OR CONTROLLED RELEASE DRUG THERAPY
  3. 3. PROBLEMS WITH CONVENTIONAL DRUG THERAPY  If the dosing interval is not proper according to the biological half life of the drug, then large peak &valleys are formed in the drug blood level.Thus, the drugs with short biological half lives require frequent dosing to maintain constant blood level.  The drug level may not be within the defined therapeutic range, hence problems associated in certain diseased conditions where early effect is not obtained.  Patient non compliance due to mutiple dosing can lead to failure in the therapy.
  4. 4. SPECIFICATIONS WITH CONTROLLED RELEASE DRUG THERAPY  SUSTAINED DRUG ACTION - by maintaining relatively constant & effective drug level in the body ith minimization of the side effects.  LOCALIZED DRUG ACTION - by placing the controlled release system adjacent to the diseased tissue or the organ.  TARGETED DRUG ACTION - by using carriers or chemical derivatives to deliver drug to particular target cell type.  PROVIDE A THERAPEUTICALLY BASED DRUG RELEASE SYSTEM - rate & amount of the drug release is according to the therapeutic needs of the body.
  5. 5. • Controlled release dosage form are actually designed to release drug in-vivo according to predictable rate that can be verified by in-vitro measurement. • Potential development and new approaches to oral controlled release dosage form includes - 1. Hydrodynamic pressure controlled system 2. Intragastric floating tablet 3. Transmucosal tablet 4. Microporous membrane coated tablet • Osmotic drug delivery has come a long way since Australian physiologists Rose and Nelson developed an implantable pump in 1955. Osmotic drug delivery uses the osmotic pressure for controlled delivery of drugs by using osmogens (for upto10 – 16 hrs). It is the most upcoming & popular controlled release system which can be used nowadays.
  6. 6. CLASSIFICATION OF CONTROLLED DDS 1. Rate-programmed drug delivery systems  Polymer membrane permeation-controlled drug delivery systems  Polymer matrix diffusion-controlled drug delivery systems  Microreservoir partition- controlled drug delivery systems 2. Activation-modulated drug delivery systems-  Osmotic Pressure- activated drug delivery systems  Hydrodynamic pressure- activated drug delivery systems  Vapor pressure- activated drug delivery systems  Mechanically activated drug delivery systems  Magnetically activated drug delivery systems  Sonophoresis –activated drug delivery systems  Iontophoresis-activated drug delivery systems  Hydration-activated drug delivery systems
  7. 7.  pH–activated drug delivery systems  Ion-activated drug delivery systems  Hydrolysis-activated drug delivery systems  Enzyme-activated drug delivery systems  Bio chemical-activated drug delivery system 3. Feedback- regulated drug delivery systems  Bioerosion- regulated drug delivery system  Bio responsive drug delivery systems  Self-regulating drug delivery systems 4. Site targeting drug delivery systems
  8. 8. OSMOTICALLY CONTROLLED DRUG DELIVERY SYSTEM
  9. 9. TOPICS COVERED 1. INTRODUCTION TO OSMOTIC DRUG DELIVERY SYSTEM 2. ADVANTAGES 3. DISADVANTAGES 4. NEED OF FORMULATING ODDS 5. MECHANISM OF ODDS 6. PARAMETERS AFFECTING ODDS 7. FORMULATION OF ODDS 8. PREPARATION OF ODDS 9. CLASSIFICATION & DETAIL OF EACH OSMOTIC PUMP 10.NEWER TECHNOLOGY IN ODDS 11.EVALUATION 12.MARKET FORMULATIONS
  10. 10. WHAT IS OSMOTIC PRESSURE???  Osmotic pressure is a most important colligative property according to pharma point of view. Colligative property means that the concentration of solution is independent of the solute property.  Osmotic pressure of a solution is the external pressure that must be applied to the solution in order to prevent it being diluted by the entry of solvent via a process known as Osmosis. Such membrane is only permeable to solvent molecule. Because only solvent can pass through the semi permeable membrane, the driving force for the osmosis arises from the inequity of the chemical potentials of the solvent on opposing side of the membrane.  It is used in the pharma field in the - 1. in the ajustment of the tonicity 2. in the development of the osmotic drug delivery 3. in oral drug deliveries
  11. 11. INTRODUCTION TO OSMOTICALLY CONTROLLED DRUG DELIVERY SYSTEM  Osmotically controlled drug delivery system, deliver the drug in a large extent and the delivery nature is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agents .  Among the controlled release devices, osmotically controlled hold a stable place because of its reliability to deliver the API at predetermined zero order rate for prolonged period of time so these are used as the standard dosage forms for the constant delivery of contents.  Osmotic Pump Controlled Release Preparation is a novel drug delivery system with eternally drug delivery rate as characteristic and controlled with the osmotic pressure difference between inside and outside of the semipermeable membrane as drug delivery power.
  12. 12.  Recently, osmotic tablets have been developed in which once the tablet comes in contact with the aqueous environment, the water-soluble component dissolves, and an osmotic pumping system results. Subsequently, water diffuses into the core through the microporous membrane, setting up an osmoticgradient and thereby controlling the release of drug.  The first osmotic effect was reported by Abbe Nollet in 1748. Later in 1877, Pfeffer performed an experiment using semi-permeable membrane to separate sugar solution from pure water. He showed that the osmotic pressure of the sugar solution is directly proportional to the solution concentration and the absolute temperature. In 1886, Vant Hoff identified an underlying proportionality between osmotic pressure, concentration and temperature. He revealed that osmotic pressure is proportional to concentration and temperature and the relationship can be described by following equation – π = n2RT where, π = osmotic coefficient n2 = molar concentration of solute in the solution R = gas constant T = Absolute temperature
  13. 13. ADVANTAGES OF OSMOTIC DDS ZERO ORDER DELIVERY POSSIBLE DRUG RELEASE INDEPENDENT OF GASTRIC pH , MOTILITY & PRESENCE OF FOOD DELIVERY MAY BE DELAYED OR PULSED HIGHER RELEASE RATES NO EFFECT OF ANY AGITATION RELATED PROBLEMS HIGH DEGREE OF IVIVC PRODUCTION SCALE UP IS EASY RELEASE RATE IS PREDICTABLE
  14. 14. DISADVANTAGES OF OSMOTIC DDS RAPID DEVELOPMENT OF TOLERANCE CHANCES OF TOXICITY DUE TO DOSE DUMPING HYPERSENSI- TIVITY REACTION CAN OCCUR VARIATION IN COMPOSITION OF MEMBRANE CAUSES ERROR. THICKNESS OF MEMBRANE & ITS SURFACE AREAAFFECTS THE RESULT. INTEGRITY & CONSISTENCY DIFFICULT TO MAINTAIN EXPENSIVE RELEASE CAN BE VARIED DUE TO THE SIZE OF HOLE
  15. 15. Osmotic Pump Systems for the Poorly Water-soluble Drugs Although push-pull osmotic pump executes an approximately constant release for the poorly water-soluble drugs, its applications are highly limited by the complexity of preparation. Therefore, a relative simple push-pull osmotic pump system is developed based on the application of polymers. In this system, special polymers (such as Arabic gum, PEO) are employed as the osmagent instead of salt. When the water is imbibed by the osmotic pressure, the polymers swell up, change into a suspension containing drugs, and then are extruded through the orifice along with the drug. CONTINUE….
  16. 16. WHY DO WE GO FOR THIS DRUG DELIVERY ??? 1. In order to reduce the dose 2. To decreases dose related side effect 3. To minimizes rate of administration 4. To provide controlled release and 5. To increase patient compliance
  17. 17. MECHANISM OF OSMOTIC DDS  Core contain water soluble osmotically active agent and blended with water soluble or insoluble drug, additives and coating has been carried out which functions as semi permeable membrane.  Since barrier is only permeable to water, initial penetration of water dissolves the critical part of the core, resulting in development of an osmotic pressure difference across the membrane.  The device delivers a saturated volume equal to the volume of water uptake through the membrane. Initial lag time (per hour) during which delivery rate increases to its maximum value, drug release is zero order, until all solid material is dissolved.
  18. 18. PARAMETERS AFFECTING THE OSMOTIC DDS  Orifice size  To achieve an optimal zero-order delivery profile, the cross-sectional area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice. Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure buildup in the system. Otherwise, the hydrostatic pressure can deform the membrane and affect the zero-order delivery rate. Therefore, the cross- sectional area of the orifice should be maintained between the minimum and maximum values.  Methods to create a delivery orifice in the osmotic tablet coating are: 1. Mechanical drill 2. Laser drill - This technology is well established for producing sub- millimeter size hole in tablets. Normally, CO2 laser beam (with output wavelength of 10.6μ) is used for drilling purpose, which offers excellent reliability characteristics at low costs.
  19. 19. 3. Indentation: that is not covered during the coating process: Indentation is made is core tablets by using modified punches having needle on upper punch. This indentation is not covered during coating process which acts as a path for drug release in osmotic system. 4. Use of leachable substances in the semipermeable coating  SOLUBILITY • The release rate depends on the solubility of the solute inside the drug delivery system. Therefore, drugs should have sufficient solubility to be delivered by osmotic delivery. In the case of lowsolubility compounds, several alternate strategies may be employed. Broadly, the approaches can be divided into two categories. First, swellable polymers can be added that result in the delivery of poorly soluble drugs in the form of a suspension .Second, the drug solubility can be modified employing different methods such as co compression of the drug with other excipients,which improve the solubility. For example, cyclodextrin can be included in the formulation to enhance drug solubility . Additionally, alternative salt forms of the drug can be employed to modulate solubility to a reasonable level. In one case, the solubility of oxprenolol is decreased by preparing its succinate salt so that a reduced saturation concentration is maintained.
  20. 20. • Solubility of drug is one of the most important factors since kinetic of osmotic release is directly related to the drug solubility. The fraction of a drug release with zero order kinetic is given by F (z) = 1 – 𝑺 𝑷 where F (z) = fraction release by zero order S = drug solubility in g / cm3 P = density of core tablet. • Drug with density of unity and solubility less than 0.05 g / cm3 would release greater than or equals to 95 % by zero order kinetics. Drug with density > 0.3 g / cm3 solubility would demonstrate with higher release rate > 70 % by zero order.  SEMI-PERMEABLE MEMBRANE • Since the semipermeable membrane is permeable to water and not to ions, the release rate is essentially independent of the pH of the environment. Additionally, the drug dissolution process takes place inside the delivery system, completely separated from the environment. Drug release from osmotic system is largly independent of pH and agitational intensity of GIT. • Example are: Cellulose Ester, Cellulose Triacetate, Cellulose Propionate, Cellulose Acetate Butyrate, Ester, Ethyl Cellulose and Eudragits.
  21. 21. • Among above Cellulose Acetate Butyrate is most commanly used as – 1. High water permeability, 2. Permeability can be adjusted by varying the degree of acetylation of polymer and also by increasing plastisizer concentration, 3. Flux enhancer and, 4. Superior drying property so advantageneous to thermolabile drugs. • However asymmetric membrane capsule are new type of coating which can be fully utilized for osmotic drug delivery system and offers significant advantage over membrane coating used in conventional Osmotic DDS which devoid of coating defects and they are having higher rate of water influx which allow the release of drug with lower or no osmotic pressure or lower solubility. SPM WVTR (g/100m2/24hr/mmthick) PVA 100 Methyl cellulose 70 Cellulose acetate 40-75 Ethyl cellulose 75 Ethylene vinyl acetate 1-3 Cellophane >1.2
  22. 22.  OSMOTIC PRESSURE • The osmotic pressure π directly affects the release rate. To achieve a zero- order release rate, it is essential to keep π constant by maintaining a saturated solute solution. Many times, the osmotic pressure generated by the saturated drug solution may not be sufficient to achieve the required driving force. In this case, other osmotic agents are added that enhance osmotic pressure. For example, addition of bicarbonate salt not only provides the necessary osmotic gradient but also prevents clogging of the orifice by precipitated drug by producing an effervescent action in acidic media. • Rate of drug release from an Osmotic system is directly proportional to osmotic Pressure of the core formulation. In order to achieve optimized and constant Osmotic Pressure in compartment Osmotic agent must be added to tablet. 𝒅𝑴 𝒅𝒕 = 𝑨𝒌𝝅𝑪 𝒉 • Thus, osmogens needed to be added either as a single component or in a combined form. • These can be either organic or inorganic or a combination of both.
  23. 23. Osmotic pressures of saturated solution of commonly used osmogents COMPOUNDS OF MIXTURE OSMOTIC PRESSURE ( atm ) Lactose-fructose 500 Dextrose-fructose 450 Sucrose-fructose 430 Mannitol-fructose 415 Sodium chloride 356 Fructose 335 Lactose-dextrose 225 Mannitol-dextrose 225 Dextrose-sucrose 190 Mannitol-sucrose 170 Sucrose 150 Mannitol-lactose 130 Sodium phosphate tribasic 36 Sodium phosphate dibasic 31
  24. 24. FORMULATION OF OSMOTIC DDS  DRUG - Drug itself may act as an osmogen and shows good aqueous solubility (e.g., potassium chloride pumps). But if the drug does not possess an osmogenic property, osmogenic salt and other sugars can be incorporated in the formulation. Various drug candidates such as Diltiazem HCl, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide etc are formulated as osmotic delivery.  SEMI-PERMEABLE MEMBRANE - An important part of the osmotic drug delivery system is the semipermeable membrane housing. Therefore, the polymeric membrane selection is key to the osmotic delivery formulation. The membrane should possess certain characteristics, such as impermeability to the passage of drug and other ingredients present in the compartments. The membrane should be inert and maintain its dimensional integrity to provide a constant osmotic driving force during drug delivery. Any polymer that is permeable to water but impermeable to solute can be used as a coating material in osmotic devices. e.g. Cellulose esters like cellulose acetate, cellulose acetate butyrate, cellulose triacetate and ethyl cellulose and Eudragits. Polymers are agar acetate, amylase triacetate,betaglucan, acetate, poly (vinylmethyl)ether copolymers, poly(orthoessters)poly acetals and selectively permeable poly(glycolic acid) and poly (lactic acid)derivatives can be used as semipermeable film forming materials.
  25. 25. • OSMOGENT - Osmotic agents maintain a concentration gradient across the membrane. They also generate a driving force for the uptake of water and assist in maintaining drug uniformity in the hydrated formulation. Osmotic components usually are ionic compounds consisting of either inorganic salts or hydrophilic polymers. Osmotic agents can be any salt such as sodium chloride, potassium chloride, or sulfates of sodium or potassium and lithium. Additionally, sugars such as glucose, sorbitol, or sucrose or inorganic salts of carbohydrates can act as osmotic agents. The polymers may be formulated along with poly(cellulose), osmotic solutes, or colorants such as ferric oxide. Swellable polymers such as poly(alkylene oxide), poly(ethylene oxide), and poly (alkalicarboxymethylcellulose) are also included in the push layer of certain osmotic systems. Further, hydrogels such as Carbopol (acidic carboxypolymer),Cyanamer (polyacrylamides), and Aqua-Keeps (acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polygluran) may be used. • HYDROPHILIC & HYDROPHOBIC POLYMERS -These polymers are used in the formulation development of osmotic system for making drug containg matrix convection.The highly water soluble compounds can be coentrappedcoentrapped in hydrophobic matrices and moderately water soluble compounds can be co-entrapped hydrophilic matrices to obtain more controlled release.The non-swellable polymers are used in caseof highly water-soluble drugs. Ionic hydrogels such as sodium carboxymethyl cellouse are preferably used because of their osmogenic nature. Hydrophilic polymers such as hydroxy ethyl cellulose ,carboxy methylcellulose, hydroxy propyl MC, high m.wt poly (vinyl pynolidone) and hydrophobic polymers such as EC and wax materials used for this purpose.
  26. 26. • WICKING AGENTS - A wicking agent is defined as a material with the ability to draw water into the porous network of a delivery device. A wicking agent is of either swellable or non-swellable nature. They are characterized by having the ability to undergo physisorption with water. The function of the wicking agent is to carry water to surfaces inside the core of the tablet, there by creating channels or a network of increased surface area. Materials, which suitably for act as wicking agents include colloidal silicon dioxide, kaolin, titanium dioxide, etc. • SOLUBILIZING AGENTS - These are classified under three groups- 1. Agents that inhibit crystal formation of the drugs or otherwise act by complexation with the drugs. Eg PVP, poly (ethylene glycol)(PEG 8000) and alpha, beta gammacyclodextrins. 2. A high HLB micelle- forming surfactant, particularly anionic surfactants (eg tween 20, 60 and 80 , poly oxy ethylene or polyethylene containing surfactants and other long chain anionic surfactants such as SLS). 3. Citrate esters and their combinations with anionic surfactants. eg alkyl esters particularly tri ethyl citrate. • SURFACTANTS - They are added to wall forming agents. They act by regulating the surface energy of materials to improve their blending in to the composite and maintain their integrity in the environment of use during the drug release period. Examples: polyoxyethylenated glyceryl recinoleate, polyoxyethylenated castor oil having ethylene oxide, glyceryl laurates, etc.
  27. 27. • COATING SOLVENTS - Solvents suitable for making polymeric solution that is used for manufacturing the wall of the osmotic device include inert inorganic and organic solvents that do not adversely harm the core, wall and other materials. The typical solvents include methylene chloride, acetone, methanol, ethanol, isopropyl alcohal, butyl alcohal, ethyl acetate, cyclohexane, carbon tetrachloride, water etc. The mixtures of solvents such as acetone-methanol (80:20), acetone-ethanol (80:20), acetone-water (90:10), methylene chloride-methanol (79:21), methylene chloride-methanol-water (75:22:3) etc. can be used. • PLASTICIZERS - Different types and amount of plasticizers used in coating membrane also have a significant importance in the formulation of osmotic systems. They can change visco-elastic behavior of polymers and these changes may affect the permeability of the polymeric films. Some of the plasticizers used are Polyethylene glycols, Ethylene glycol monoacetate; and diacetate- for low permeability films. • FLUX REGULATORS - Delivery systems can be designed to regulate the permeability of the fluid by incorporating fluxregulating agents in the layer. Hydrophilic substances such as polyethethylene glycols (300 to 6000 Da), polyhydric alcohols, polyalkylene glycols, and the like improve the flux, whereas hydrophobic materials such as phthalates substituted with an alkyl or alkoxy (e.g., diethyl phthalate or dimethoxy ethylphthalate) tend to decrease the flux. Insoluble salts or insoluble oxides, which are substantially water- impermeable materials, also can be used for this purpose.
  28. 28. • PORE FORMING AGENTS - These 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. Like alkaline metal salts such as sodium chloride, sodium bromide, potassium chloride, etc. or alkaline earth metals such as calcium chloride and calcium nitrate & Carbohydrates such as glucose, fructose, mannose, etc. These agents are particularly used in the pumps developed for poorly water soluble drug and in the development of controlled porosity or multiparticulate osmotic pumps. These poreforming agents cause the formation of microporous membrane. The microporous wall may be formed in situ by a pore-former by its leaching during the operation of the system. 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, potassium sulphate, potassium phosphate etc., alkaline earth metals such as calcium chloride and calcium nitrate, carbohydrates such as sucrose, glucose, fructose, mannose, lactose, sorbitol, mannitol and, diols and polyols such as poly hyric alcohols and polyvinyl pyrrolidone can be used as pore forming agents.
  29. 29. PREPARATION OF OSMOTIC DDS • One method is to utilize an osmotic mechanism to provide pre-programmed, controlled drug delivery to the gastro intestinal tract. The technology comprises a polymer membrane with one or more laserdrilled holes surrounding a core containing the drug or drugs, with or without osmotic or other agents. • Another oral technology uses a multiple dose system containing a large number of micro particles, on the order of 5,000 to 40,000 micro particles per capsule or tablet,depending on the specific formulation.Microparticle operates as a miniature delivery system, releasing the drug at an adjustable rate and over an extended period of time by means of osmotic pressure. • A third technology was developed as simple monolithic matrix systems. These approaches use conventional tableting technologies to form swellable, erodible matrix tablets, caplets, or capsules that can potentially yield first-order drug release profiles up to 24 hours. • In addition, any combination of soluble, highly soluble, insoluble, low drug dose, high drug load, and combinations can be easily formulated with these technologies.
  30. 30. CLASSIFICATION OF OSMOTIC DDS  These can be particularly divided into two types – 1. IMPLANTABLE OSMOTIC PUMPS 2. ORAL OSMOTIC PUMPS IMPLANTABLE OSMOTIC PUMP ROSE NELSON PUMP HIGUCHI- LEEPER PUMP MINI OSMOTIC PUMP HIGUCHI- THEEUWES PUMP
  31. 31. ORAL OSMOTIC PUMPS ELEMEN- TARY CONTROLLED POROSITY MULTICHA- MBER MODI- FIED MULTI - PARTICUL ATE RELEASE MONO- LITHIC NON EXPANDABLE EXPANDABLE FOR SOLID FOR LIQUID BILAYER TRILAYER
  32. 32. IMPLANTABLE PUMPS ROSE-NELSON PUMP - In, 1955, two Australian physiologists reported the first osmotic pump. They were interested in delivery of drug to the gut of sheep and cattle. The pump consisted of three chambers a drug chamber with an orifice, a salt chamber with elastic diaphragm containing excess solid salt, and a water chamber. A semipermiable membrane separates the drug and water chamber. The difference in osmotic pressure across the membrane moves water from the water chamber in to the salt chamber. The volume of chamber increases because of this water flow, which distends the latex diaphragm separating the salt and drug chambers, thereby pumping drug out of the device.
  33. 33.  HIGUCHI – THEEUWES PUMP - In the early 1970s, Higuchi and Theeuwes developed another, even simpler variant of the Rose-Nelson pump. As with the Higuchi- Leeper pump, water to activate the osmotic action of the pump is obtained from the surrounding environment. In the Higuchi-Theeuwes device, however, the rigid housing is dispensed with and the membrane acts as the outer casing of the pump. This membrane is quite sturdy and is strong enough to withstand the pumping pressure developed inside the device. The device is loaded with the desired drug prior to use. When the device is placed in an aqueous environment, release of the drug follows a time course set by the salt used in the salt chamber and the permeability of the outer membrane casing. Most of the Higuchi-Theeuwes pumps use a dispersion of solid salt in a suitable carrier for the salt chamber of the device. Small osmotic pumps of this form are available under the trade name Alzet®.Delivery of DNA by agarose hydrogel implant facilitates genetic immunization in cattle by using Alzet osmotic pumps.
  34. 34. HIGUCHI-LEEPER PUMP - Higuchi Leeper pump is widely swallowed or implanted in the body of animal for delivery of antibiotic or growth hormones. Higuchi Leeper pump consist of rigid housing and semi permeable membrane. A layer of low melting waxy solid, such as microcrystalline paraffin wax is used in place of elastic diaphragm to separate the drug and osmotic chamber. Recent modification in Higuchi-Leeper pump accommodated pulsatile drug delivery. The pulsatile release was achieved by the production of a critical pressure at which the delivery orifice opens and releases the drug.Pulsatile delivery could be achieved by using Higuchi Leeper pump; such modifications are described and illustrated in Figure. The Pulsatile release of drug is achieved by drilling the orifice in elastic material that stretches under the osmotic pressure. Pulse release of drug is obtained after attaining a certain critical pressure, which causes the orifice to open. The pressure then reduces to cause orifice closing and the cycle repeats to provide drug delivery in a pulsatile fashion. The orifice should be small enough to be substantially closed when the threshold level of osmotic pressure is not present.
  35. 35. MINI OSMOTIC PUMP - Implantable Mini osmotic pump is composed of three concentric layers-the drug reservoir, the osmotic sleeves and the rate controlling semi permeable membrane. The additional component called flow moderator is inserted into the body of the osmotic. The inner most compartment of drug reservoir which is surrounded by an osmotic sleeve, a cylinder containing high concentration of osmotic agent. The osmotic sleeve is covered by a semi permeable membrane when the system is placed in aqueous environment water enters the sleeve through semi permeable membrane, compresses the flexible drug reservoir and displaces the drug solution through the flow moderator. These pumps are available with variety of delivery rates between 0.25 to 10ml per hour and delivery duration between one day and four weeks. ALZET® MINI OSMOTIC PUMP
  36. 36. ORAL PUMPS  ELEMENTARY OSMOTIC PUMP - Elementary osmotic pump was invented by Theeuwes in 1974 and 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. Small orifice is drilled through the membrane coating. When this coated tablet is exposed to an aqueous environment, the osmotic pressure of the soluble drug inside the tablet draws water through the semipermeable 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 inhibition of water raises the hydrostatic pressure inside the tablet, eventually leading to flow of saturated solution of active agent out of the device through a small orifice. The pump initially releases the drug at a rate given by equation - dMt/dt = (dV/dt). Cs where, dV/dt depicts the water flow into the tablet Cs is the solubility of the agent inside the tablet.
  37. 37. • ADVANTAGES – 1. The system can contain the agent in solid form at loading higher than 90% of the total volume, and the agent can be delivered at rates several orders of magnitude higher than can be achieved by solution diffusion through polymeric membranes. 2. The delivery rate, the fraction of total content is delivered at zero order, and the system's delivery portal size can be calculated for delivery of a single compound. 3. Normally EOP deliver 60 – 80 % of its content at constant rate. 4. It has short lag time of 30 – 60 minute. • DISADVANTAGES – 1. SPM should be 200-300μm thick to withstand pressure. 2. Thick coatings lowers the water permeation rate. 3. Applicable mostly for water soluble drugs.
  38. 38. MODIFIED OSMOTIC PUMP – FOR MODERATELY SOLUBLE DRUGS -Semi permeable membrane must be 200-300 microns thick to withstand the pressure generated within the device. These thick membranes lowers water permeation rate, which is not desirable for moderately soluble drugs. This problem can be overcome by using coating materials with high water permeability. For example, addition of plasticizers and water soluble additive to the cellulose acetate membranes, this increased the permeability of membrane up to ten fold. Composite structured semi permeable membrane is used for moderately soluble drugs. The first layer is made up of thick micro porous film that provides the strength required to withstand the internal pressure, while second layer is composed of thin semi permeable membrane that produces the osmotic flux. The support layer is formed by, Cellulose acetate coating containing 40 to 60% of pore forming agent such as Sorbitol. • ADVANTAGE – overcomes the major disadvantage of the elementary pump as it can be used only for the water sioluble drugs.
  39. 39. FOR INSOLUBE DRUGS - Osmotic agents are coated with an elastic semi permeable membrane film in fluid bed coater and this particle are then mixed with insoluble drugs and compressed to form tablet which is coated with SPM and orifice is created in membrane. After coming in contact with aqueous environment, water is drawn through the two membranes into the osmotic agent particle which swells and hydrostatically pushes the insoluble drug via the orifice. • ADVANTAGE – Majiority of the pharmaceutical drugs are hydrophobic in nature , hence these types of pump can be used. Value Proposition of these pumps - •Controlled release maintains appropriate therapeutic level of active agent for several days •pH sensitive membrane with coitus trigger •Improved drug administration for the patient •Greater drug release efficiency and delivery duration •Ideal for delivery of contraceptives •Potential neutralizer for other infectious diseases such as HIV which one could contract during sexual intercourse
  40. 40.  CONTROLLED POROSITY PUMP -A controlled porosity osmotic pump-based drug delivery system Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The CPOP contains water soluble additives in coating membrane, which after coming in contact with water; dissolve resulting in an in-situ formation of a microporous membrane. Then the resulting membrane is substantially permeable to both water and dissolved solutes and the mechanism of drug release from these system was found to be primarily osmotic, with simple diffusion playing a minor role. Drug delivery from asymmetric membrane capsule is principally controlled by the osmotic pressure of the core formation. In-situ formed delivery orifice in the asymmetric membrane in mainly responsible for the solubilization in the core for a drug with poor water solubility. It is laser or micro driven orifice. When Controlled Porosity Osmotic Pump is placed in aqueous environment the water soluble component of coating dissolves and forms micropores in membrane and water diffuses inside the core through microporous membrane, setting up an osmotic gradint and thereby controlling the release of drug. The rate of release from controlled porosity osmotic pump is dependent on- 1) Level of soluble component in coating 2) Coating thickness 3) Osmotic pressure across the membrane 4) Solubility of drug in tablet core
  41. 41. Drug release from the whole surface of device rather than from a single hole which may reduce stomach irritation problem. Hole is produce by the coating procedure hence complicated laser drilling is not required. Citric acid is use as pore forming agent in Chitosan based colon specific pumps. MUTIPARTICULATE DELAYED RELEASE SYSTEM – Pellets containing drug with or without osmotic agent are coated with semi permeable membrane which on contact with aqueous environment results in penetration of water in core and forms a saturated solution of soluble component. The osmotic pressure difference results in rapid expansion of membrane, which leads to the formation of pores. For controlled release drug is located at first orifice and for fast release drug layer located adjacent to second orifice. Push layer is located in between controlled and fast release layer.
  42. 42. The dispenser comprises a housing that has first- and second-wall sections in a slideable 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 waxlike material separates the two sections. To assemble the delivery device, the desired active agent is placed into one of the sections by manual- or automated-fill mechanisms. The Bilayer tablet with the osmotic engine is placed into a completed cap part of the capsule with the convex osmotic layer pointed into the closed end of the cap and the barrier layer exposed toward the cap opening. The open end of the filled vessel is fitted inside the open end of the cap, and the two pieces are compressed together until the cap, osmotic Bilayer tablet, and vessel fit together tightly. As fluid is imbibed through the housing of the dispensing device, the osmotic engine expands and exerts pressure on the slideable connected first and second wall sections. During the delay period, the volume of the reservoir containing the active agent is kept constant; therefore, a negligible pressure gradient exists between the environment of use and the interior of the reservoir. As a result, the net flow of environmental fluid driven by the pressure to enter the reservoir is minimal, and consequently no agent is delivered for the period.
  43. 43.  MONOLITHIC OSMOTIC PUMPS - Dispersion of water soluble drug is made in a polymeric matrix and compressed as tablet. Tablet is then coated with semi permeable membrane or drilled on both side of tablet. When MOS comes in contact with aqueous environment, the water penetrates in the core and forms a saturated solution of component which will generate osmotic pressure which results in the rupturing of membrane of polymeric matrix surrounding the agent. Thus liberating drug to move outside the environment. MOS is simple to prepare but the system fails if more then 20 – 30 % volume of active agent is incorporated in device because above this level significant contribution is form leaching of substance Ketoprofen Monolithic Osmotic Pump Control Release Tablet made up of PEG 6000, NaCl, CMC-Na and Polyvinyl pyrrolidone which releases drug at 93.51 % for 24 hrs.
  44. 44.  MULTI CHAMBER OSMOTIC PUMP - Although EOP is simple to design and well suited for drug with intermediate water solubility there are many drugs with either poor or high water solubility. This problem has led to development of MOP. There are two type of MOP – 1. EXPANDABLE – a. FOR SOLIDS - Push pull osmotic pump is a modified EOP. Through, which it is possible to deliver both poorly water-soluble and highly water soluble drugs at a constant rate. This system resembles a standard bilayer coated tablet. One layer (depict as the upper layer) contains drug in a formulation of polymeric, osmotic agent and other tablet excipients. This polymeric osmotic agent has the ability to form a suspension of drug in situ. When this tablet later imbibes water, the other layer contains osmotic and colouring agents, polymer and tablet excipients. These layers are formed and bonded together by tablet compression to form a single bilayer core. The tablet core is then coated with semi permeable membrane. After the coating has been applied, a small hole is drilled through the membrane by a laser or mechanical drill on the drug layer side of the tablet. When the system is placed in aqueous environment water is attracted into the tablet by an osmotic agent in both the layers. The osmotic attraction in the drug layer pulls water into the compartment to form in situ a suspension of drug. The osmotic agent in the non-drug layer simultaneously attract water into that compartment, causing it to expand volumetrically and the expansion of non drug layer pushes the drug suspension out of the delivery orifice.
  45. 45. b. FOR LIQUIDS - OROS-CT is used as a once or twice a day formulation for targeted delivery of drugs to the colon. The OROS-CT can be a single osmotic agent or it can be comprised of as many as five to six push pull osmotic unit filled in a hard gelatin capsule. After coming in contact with the gastric fluids, gelatin capsule dissolved and the enteric coating prevents entry of fluids from stomach to the system as the system enters into the small intestine the enteric coating dissolves and water is imbibed into the core thereby causing the push compartment to swell. At the same time flowable gel is formed in the drug compartment, which is pushed out of the orifice at a rate, which is precisely controlled, by the rate of water transport across the semi permeable membrane. One type of L-Oros system consists of a soft gelatin capsule (softcap™) surrounded by a barrier layer, an osmotic push layer, and a semipermeable membrane. As with other Oros system, drug is released through a delivery orifice in the semipermeable membrane. Another type of L-Oros system consists of a hard gelatin capsule (Hardcap™) containing a liquid drug layer, a barrier layer, and a push layer surrounded by a semipermeable membrane.
  46. 46. SoftCap™ HardCap™ 2. NON-EXPANDABLE - Non expandable osmotic pump maintains the volume throughout the period of operation means the rigid one. Depending on function of second chamber non-expandable osmotic pump are divided into two subtypes – • Drug solution gets diluted in second chamber before leaving device. Such is useful when saturated solution of drug irritate GIT. • Two separate EOP tablet formed in single tablet. Here one chamber contains osmogen and second chamber contain drug. When such system comes in contact with aqueous environment, solution of osmotic agent formed in first chamber is delivered to drug chamber via the concentric hole, where it mixes with drug solution before coming out of the micro porous membrane that forms the pores of SPM surrounding the drug chamber useful for insoluble drug delivery.
  47. 47. NEWER TECHNOLOGY IN ODDS  Osmodex® Technology - The Osmodex® family of proprietary technologies combines laser drilled tablet technology with variety of single active and multiple active drug delivery devices. Osmodex® systems simplify dosing and aid in patient compliance.It includes – 1. Osmodex® ID delivery for insoluble drugs - This platform provides flexible delivery options for insoluble drugs. It can accommodate first order, zero order or delayed release options while assuring full release over the targeted timeframe. This technology has been used to solve multiple challenging insoluble drug delivery problems (Example – Osmotica Nifedipine Extended release Tablets). 2. Osmodex® SD delivery for soluble drugs - This platform technology can be used to resolve delivery challenges of soluble low-bioavailability drugs or drugs requiring targeted delivery. 3. Osmodex® Double CR combination - This dual controlled release platform allows delivery of two drugs from a single osmotic tablet where each drug release pattern can be independently tailored to the desired release profile.
  48. 48. 4. Osmodex® Triple combination tablet -This delivery system incorporates compressed druglayers around an osmotic core. This combination provides the benefits of immediate release and controlled release delivery, along with the unique benefits of an osmotic controlled release to achieve three different release rates in the same tablet • Duros Technology - DUROS pharmaceutical systems are miniature osmotic implants that deliver drugs for 3 months to 1 year with precise zero-order delivery kinetics. The technology is suited for potent drugs and can deliver up to 500 mg of drug from a single implant with a 1- cc drug reservoir. Formulation technology has been developed that maximizes drug payload, stabilizes drugs chemically and physically for extended periods at body temperature, and involves the use of aqueous and non- aqueous vehicles. Advanced applications of the DUROS technology are in clinical and preclinical testing and include the CHRONOGESIC system, delivering sufentanil systemically for chronic pain. The DUROS technology is a miniature drugdispensing system that operates like a miniature syringe and releases minute quantities of concentrated drug formulations in a continuous, consistent flow over months or years. The system is implanted under the skin and can be as small as 4 mm OD X 44 mm L or smaller. The drug formulation is contained in the drug reservoir compartment. The drug formulation may be either a solution or suspension. Duros system was chosen for their biocompatibility and suitability for implant use. The drug-contacting materials are also screened for compatibility with the drug and the specific drug formulation excipients.
  49. 49. Duros Advanced Applications of Duros Technology - 1. CHRONOGESIC™(sufentanil) Pain Therapy System - Chronic pain, defined as pain lasting 6 months or longer, is a significant problem associated with chronic diseases, including cancer and various neurological and skeletal disorders. To The CHRONOGESIC system is implanted in the inside of the upper arm using a specially designed sterile implanter The Implanter is a trocar-like device that facilitates precise, efficient subcutaneous placement of the CHRONOGESIC implant. 2. Targeted Drug Delivery with Catheterized Osmotic Pumps - Catheters of different designs can be attached to the exit port of an osmotic pump for targeted drug delivery. A number of organs and tissues have been evaluated as target sites in various animal models using ALZET Osmotic Pumps, which have been the devices of choice in numerous scientific research activities involving laboratory animals. Catheters should be flexible, compatible with targeted tissues/organs, and non-reactive with and nonabsorptive toward drug solutions. The most commonly used materials for catheters include silicone elastomers and polyolefin polymers, such as low-density polyethylene. Pharmacological agents for targeted delivery include various small-molecularweight drugs as well as peptides and proteins. The most common catheter material for site-specific drug delivery using ALZET with a catheter has been a low-density polyethylene tubing.
  50. 50. 3. Specific Drug Delivery Using Duros with a Precision Miniature Catheter – To deliver drug to a specific target site, DURECT is developing proprietary miniaturized catheter technology that can be attached to the DUROS system to direct the flow of drug directly to the target organ or tissue. Site-specific delivery enables a therapeutic concentration of a drug to be present at the desired target without exposing the entire body of the patient to a similar dose. The precision, miniature size, and performance characteristics of the DUROS system will allow for continuous site-specific delivery to a variety of precise locations within the body. 4. DUROS Intratumoral Delivery of Antineoplastic Agents Into The Brainstem - Local or site-specific delivery of chemotherapeutic agents increases drug concentration at the tumor target, decreases systemic exposure and toxicities, and increases the duration of exposure of the tumor to the drug. Experimental and clinical studies have demonstrated statistically significant increases in survival associated with local therapy for brain tumors. Drugs have been delivered via controlledrelease biodegradable matrices and infusion pumps.The brainstem continuously monitors and regulates cardiovascular, respiratory, and other autonomic functions, and hence, attempts to target chemotherapy directly into this brain area has always been met with extreme caution. One approach being tested, to maximize the effectiveness of chemotherapeutic agents in this sensitive brain region, is insertion of a catheter into the pons of the brainstem for intratumoral chemotherapy.
  51. 51. EVALUATION OF OSMOTIC ODDS 1. Characterization of dosage form 2. Effect of osmotic agents 3. Swelling properties 4. Membrane stability and thickness 5. Orifice diameter and drug release 6. Weight variation 7. Hardness 8. Friability 9. In vitro evaluation-The in vitro release of drugs from oral osmotic systems has been evaluated by the conventional USP paddle and basket type apparatus. The dissolution medium is generally distilled water as well as 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 oral controlled drug delivery systems are equivalently applicable for oral osmotic pumps
  52. 52. 11. In vivo evaluation –In vivo evaluation of oral osmotic systems has been carried out mostly in dogs. As the environment in the intestinal tract of the dog is very similar to that of human beings terms of both pH and motility, dogs have been used widely for in vivo delivery rate measurement of drugs from osmotically controlled oral drug delivery systems and also to establish in vitro in vivo correlation. Monkeys can also be used but in most of the studies the dogs are preferred. 12. Effect of pH - These are done to see the effect of pH on developed formulations, so a in-vitro study is carried out in different medias. 13. Effect of agitational intensity - Dissolution apparatus with different rotational spped are used to chech its effect on the in-vitro profile. 14. Effect of osmotic pressure - Release mechanism study is carried out at different osmotic pressure to see its effect on the formulation. 15. Kinetics of drug release - By using different time intervals & statistics , we can see its effect on the given formulation. Weigh the empty pump & then fill it using a syringe. Hold it in a upright position & insert the filling tube through opening at the top of the pump until it can go no further. This places the tip of the tube near the bottom of the pump reservoir. Push the plunger of the syringe slowly & when solution appears at the outlet , stop this process & remove the tube. Wipe of the excess solution & weigh the filled pump.
  53. 53. MARKETED FORMULATIONS TRADE NAME API DESIGN DOSE USE ALPRESS LP PRAZOSCIN PUSH PULL 2.5- 5mg HYPERTENSION ACUTRIM PHENYLPROPAN- OLAMINE ELEMENT- ARY PUMP 75mg AlLLERGIES CARDURA DOXAZOSCIN PUSH PULL 4-8mg HYPERTENSION COVERA VERAPAMIL PUSH PULL 180mg ANGINA DITROPAN XL OXYBUTININ PUSH PULL 5mg URINARY PROBLEMS INVEGA PALIPERIDONE PUSH PULL 3-9mg SCHIZOPHRENIA GLUCOTROL XL GLIPIZIDE PUSH PULL 5mg HYPERGLYCEMIA MINIPRESS PRAZOSCIN ELEMENT- ARY PUMP 2.5- 5mg HYPERTENSION PROCARDIA XL NIFEDIPINE PUSH PULL 30mg ANGINA
  54. 54. REFERENCES  Gennaro,Alfonso R.,Remigton:The Science & practice of pharmacy, Vol-I &II, Lipincott Williams & Wilkins, New York. Page No. 903-915  B. P. Gupta, N. Thakur, N. P. Jain, J. Banweer, and S. Jain, “Osmotically Controlled Drug Delivery System with Associated Drugs,” vol. 13, no. 3, pp. 571–588, 2010.  T. Sanitorium, “A Review on Osmotic Drug Delivery System,” vol. 4, no. 3, pp. 810–821, 2013.  K. Singh, M. Walia, and S. L. Harikumar, “REVIEWARTICLE OSMOTIC PUMP DRUG DELIVERY SYSTEM : A NOVALAPPROACH,” vol. 3, no. 5, pp. 156– 162, 2013.  Controlled & novel drug delivery by N.K.Jain, CBS publishers & distributors. Page No. 15-20  Drug Delivery principles & applications by Binghe Wang, Teruna Siahaan & Richard A. Soltero, Wiley publications. Page No.105-110  Novel drug delivery systems by Dr.Dheeraj T. Bhavsar & Dr.Dinesh K. Jain, Nirali prakashan. Page No.115-118  Controlled drug delivery, Fundamentals & applications, second edition, by Joseph R. Robinson & Vincent H. Lee, Williams publications & press. Page No.89-96
  55. 55. THANK YOU

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