OSMOTIC DRUG DELIVERY SYSTEM

1. OSMOTIC DRUG DELIVERY SYSTEM

2. LIST OF CONTENTS INTRODUCTION • 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 PUMP OSMOTIC 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 BELOW SATURATION • MISCELLANEOUS DEVICES • SPECIALIZED COATINGS PROCESSING AND PERFORMANCE IMPROVEMENT IN VITRO EVALUATION MARKET PRODUCTS REFERENCES

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 DRUG DELIVERY 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 in artificial gastric and intestinal fluid. The release profile for both media are similar and not affected by pH.

7. ADVANTAGES • Higher release rates are possible with osmotic systems compared with conventional diffusion-controlled drug delivery systems. • The release rate of osmotic systems is highly predictable and can be programmed by modulating the release control parameters. • A high degree of in vivo–in vitro correlation (IVIVC) is obtained in osmotic systems because the factors that are responsible for causing differences in release profile in vitro and in vivo (e.g., agitation, variable pH) affect these systems to a much lesser extent.

8. Figure shows the cummulative amount of nifidipine released from push pull osmotic pump (POPP) in vitro and in the GIT tract of dogs as 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 OSMOTIC DRUG 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 LIMITATIONS AND ADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM • During quality control of nifedipine GITS (Gastrointestinal therapeutic System) tablets, it was observed that several batches show different release patterns of the drug. It was found that non uniform coating around the tablet produced different membrane thicknesses, which was responsible for differences in release pattern among different patches. • Another case was reported for Osmosin (Indomethacin OROS), which was first introduced in UK in 1983. A few months after its introduction frequent incidences of gastointestinal reactions (hemorrhage and perforation)was observed by the Committee on the Safety of Medicines, and Osmosin was withdrawn from market.

12. PRINCIPLE OF OSMOSIS • Osmosis refers to the process of movement of solvent from lower concentration of solute towards higher concentration of solute across a semi permeable membrane. • Abbe Nollet first reported osmotic effect in 1748, but Pfeffer in 1877 had been the pioneer of quantitative measurement of osmotic effect. • Pfeffer measured the effect by utilizing a membrane which is selectively permeable to water but impermeable to sugar. The membrane separated sugar solution from pure water. Pfeffer observed a flow of water into the sugar solution that was halted when a pressure p was applied to the sugar solution. Pfeffer postulated that this pressure, the osmotic pressure π of the sugar solution is proportinal to the solution concentration and absolute temperature. • Van’t Hoff established the analogy between the Pfeffer results and the ideal gas laws by the expression π= n2RT----------------------(1) • Where n2 represents the molar concentration of sugar (or other solute) in the solution, R depicts the gas constant, and T the absolute temperatue. • This equation holds true for perfect semipermeable membranes and low solute concentrations.

13. Another method of obtaining a good approximation of osmotic pressure is by utilizing vapour pressure measurements and by using expression: π = RT ln (Po/P)/v -------- (2) • Where Po represents the vapour pressure of the pure solvent, P is the vapour pressure of the solution and v is the molar volume of the solvent. As vapour pressure can be measured with less effort than osmotic pressure this expression is frequently used.

14. Osmotic pressure for soluble solutes is extremely high. This high osmotic pressure is responsible for high water flow across semipermeable membrane. • The rate of water flow dictated by osmotic pressure can be given by following equation, dV/dt = A θ Δπ/l ----------------------- (3) • Where dV/dt represents the water flow across the membrane area A and thickness l with permeability θ. • Δπ depicts the difference in osmotic pressure between the two solutions on either side of the membrane. NOTE- This equation is strictly applicable for perfect semipermeable membrane, which is completely impermeable to solutes.

15. A number of osmotic pressure powered drug delivery system has been developed. The principle of their operation can be described by a basic model as outlined in following figure.

16. Schematic representation of the basic model of osmotic pressure powered drug delivery systems PUMP HOUSING SEMIPERMEABLE MEMBRANE Vs Vd DELIVERY ORIFICE MOVABLE 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 osmotic device of (volume per unit time) is defined by Q/t = Pw Sm [γm (πs- πe)-(ΔPd+ΔPc)] ------------ (4) • Pw is permeability of semi permeable membrane to water; • Sm is effective surface area of the membrane; • γm is osmotic reflection coefficient of the membrane; • πs and πe are the osmotic pressure of saturated solution of osmotic driving agent and of the environment where device is located, respectively; • ΔPd is elevation of internal pressure generated in the drug formulation compartment as the result of water influx into osmotic agent compartment; • ΔPc is pressure required to deform drug formulation compartment inward. • If the net osmotic pressure gradient [γm (πs- πe)] is constant and the hydrostatic pressure (ΔPd+ΔPc) is negligibly small, equation (4) can be simplified to: Q/t = Pw Sm (πs- πe) -------------- (5)

18. And a zero order rate of drug release from osmotic device can be achieved if following conditions are met: • The amount of osmotic driving agent used is sufficient to maintain a saturated solution in the osmotic agent compartment i.e. πs is constant. • The environmental osmotic activity is either constant or negligibly small i.e. (πs- πe) ≈ constant. • The osmotic reflection coefficient is constant and very close to unity i.e. γm≈1. 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 deformable partition should be used. So, ΔPd =ΔPc≈0.

19. BASIC COMPONENTS OF OSMOTIC PUMP 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.

20. OSMOGEN / OSMAGENT / OSMOTIC DRIVING AGENT • For the selection of osmogen, the two most critical properties to be considered are osmotic activity and aqueoussolubility. • 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 the preparation of osmotic pumps. • Some other polymers such as agar acetate, amylose triacetate, betaglucan acetate, 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 pump is that it permits only the passage of water into the unit, thereby effectively isolating the dissolution process from the gut environment.

22. HYDROPHILIC AND HYDROBHOBIC POLYMERS • These polymers are used in the formulation development of osmotic systems containing matrix core. • The selection of polymer is based on the solubility of drug as well as the amount and rate of drug to be released from the pump. • The highly water soluble compounds can be co-entrapped in hydrophobic matrices and moderately water soluble compounds can be co-entrapped in hydrophilic matrices to obtain more controlled release. • Examples of hydrophilic polymers are Hydroxy ethyl cellulose, carboxy methyl cellulose, hydroxyl propyl methyl cellulose, etc. • Examples of hydrophobic polymers are ethyl cellulose, wax materials, etc.

23. WICKING AGENTS • It is defined as a material with the ability to draw water into the porous network of a delivery device. • The function of the wicking agent is to draw water to surfaces inside the core of the tablet, thereby creating channels or a network of increased surface area. • Examples: colloidon silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide,sodium lauryl sulphate (SLS), low molecular 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 or otherwise act by complexation of drug (e.g., PVP, PEG, and cyclodextrins) • A high HLB micelle forming surfactant, particularly anionic surfactants (e.g., Tween 20, 60, 80, poly oxy ethylene or polyethylene containing surfactants and other long chain anionic surfactants such as SLS). • Citrate esters and their combinations with anionic surfactants (e.g., alkyl esters particularly triethyl citrate)

25. SURFACTANTS • They are added to wall forming agents. • The surfactants 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.

26. 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. • Examples: methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, cyclohexane, etc.

27. PLASTICIZERS • Permeability of membranes can be increased by adding plasticizer, which increases the water diffusion coefficient. • Examples: dialkyl pthalates, trioctyl phosphates, alkyl adipates, 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 flux decreasing agent are added to the wall forming material; it assist in regulating the fluid permeability through membrane. • Poly hydric alcohols such as poly alkylene glycols and low molecular weight glycols such as poly propylene, poly butylene and poly amylene,etc. can be added as flux regulators.

29. 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. 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 Chamber Drug Chamber Water Chamber Delivery orifice Rigid Semi permeable membrane Elastic Diaphragm

31. PHARMETRIX DEVICE • This device is composed of impermeable membrane placed between the semi permeable membrane and the water chamber. • These allows the storage of the pump in fully water loaded condition. The pump is activated when seal is broken. Water is then drawn by a wick to the membrane surface and pumping action begins. • This modification allows improved storage of the device, which on demand can be easily activated.

32. HIGUCHI LEEPER OSMOTIC PUMPS • It has no water chamber, and the activation of the device occurs after imbibition of the water from surrounding environment. • It has a rigid housing. • Widely employed for veterinary use. It is either swallowed or implanted in body 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 movable separator to separate drug and osmotic chamber. Rigid Housing Drug Chamber Satd. Sol. Of MgSO4 contg. Solid MgSO4 Movable Separator MgSO4 Semi-permeable Membrane Porous Membrane Support

33. HIGUCHI THEEUWES OSMOTIC PUMP • In this device, the rigid housing is consisted of a semi permeable membrane. The drug is loaded in the device only prior to its application, which extends advantage for storage of the device for longer duration. • The release of the drug from the device is governed by the salt used in the salt chamber and the permeability characteristics of outer membrane. • Diffusional loss of the drug from the device is minimized by making the delivery port in 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 compound Delivery port SPM Rigid Semi permeable Membrane Osmotic Agent layer Delivery port Squeezed Drug Core Wall of flexible collapsible material Swollen Osmogen layer

34. ALZET OSMOTIC PUMP • ALZET® Osmotic pumps are miniature, infusion pumps for the continuous dosing of laboratory animals as small as mice and young rats. These minipumps provide researchers with a convenient and reliable method for controlled agent delivery in vivo.

35. ALZET OSMOTIC PUMP ADVANTAGES • Ensure around-the-clock exposure to test agents at predictable levels. • Permit continuous administration of short half-life proteins and peptides. • 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 Operation • ALZET pumps have 3 concentric layers: • Rate-controlling, semi-permeable membrane • Osmotic layer • Impermeable drug reservoir • ALZET pumps work by osmotic displacement. Water enters the pump across the outer, semi-permeable membrane due to the presence of a high concentration of sodium chloride in the osmotic chamber. The entry of water causes the osmotic chamber to expand, thereby compressing the flexible reservoir and delivering the drug solution through 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 in the form of elementary osmotic pump(by Theeuwes,1975) which made osmotic delivery as a major method of achieving controlled drug release.

40. ELEMENTARY OSMOTIC PUMP (EOP) Delivery Orifice Core 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: • Sd is concentration in drug compartment • πf is osmotic pressure of the drug formulation • A is surface area • h is thickness • k is permeability of membrane • πe is osmotic pressure of the environment which is negligible • So zero order release rate can be expressed as,

42. PROBLEM • Area of semi permeable membrane of an elementary osmotic pump is 2.7 cm2, thickness is 0.031 cm, permeability coefficient is 2.1*10-6 cm2/atm*h and the osmotic pressure is 225 atm, calculate the rate of delivery of the solute under zero-order conditions if the concentration of saturated solution at 37°C is 290 mg/ cm3? dm/dt = (A/h)k(π) 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 membrane should be 200-300μm thick to withstand pressure with in the device. • 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 are suitable for highly water soluble drugs. • This problem can be overcome by using coating materials with high water permeabilities. For example, addition of plasticizers and water soluble additive to the cellulose acetate membranes, which increased the permeability of membrane up to ten fold.

44. MODIFICATIONS IN ELEMENTARY OSMOTIC PUMP • 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. Inner microporous membrane Drug chamber Delivery orifice Outer semi permeable membrane COMPOSITE MEMBRANE COATING USED TO DELIVER MODERATELY SOLUBLE DRUGS

45. x x x x x x x x x x x x x x DELIVERY OF INSOLUBLE DRUG Rigid SPM • Coating osmotic agent with elastic semi permeable film • Mixing of above particles with the insoluble drug • Resultant mixture is coated with the rigid semi permeable membrane Elastic SPM Insoluble Particles

46. MULTICHAMBER OSMOTIC PUMPS • Multiple chamber osmotic pumps can be divided into two major classes a) Tablets with a second expandable osmotic chamber b) Tablets with a non-expanding second chamber a) Tablets with a second expandable osmotic chamber • In the tablets with a second expandable osmotic chamber, the water is simultaneously drawn into both the chambers in proportion to their respective osmotic gradients, eventually causing an increase in volume of the chamber and subsequently forcing the drug out from the drug chamber. • The matrix should have sufficient osmotic pressure to draw water through the membrane into the drug chamber. Under hydrated conditions matrices should have to be fluid enough to be pushed easily through a small hole by the little pressure generated by the elastic 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. Drug delivery process of two chamber osmotic tablet Before operation During operation Delivery Orifice Delivery Orifice Osmotic Drug Core SPM Polymer push compartment Expanded push compartment

50. LIQUID OSMOTIC SYSTEM (L-OROS) • A liquid formulation is particularly well suited for delivering insoluble drugs and macromolecules such as polysaccharide and polypeptides. • Such molecules requie external liquid components to assist in solubilization, dispersion, protection from enzymatic degradation and promotion of gastrointestinal absorption. • Thus the L-OROS system was designed to provide continuous delivery of liquid drug formulation and improve bioavailability of drugs.