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Osmotic system : 

Guided by” Mrs. Manisha Patel Presented by” Hitesh chaudhari Osmotic system Department of Pharmaceutics Sarsawati Institute of Pharmaceutical Sciences

Outline : 

Outline Osmotic systems: an introduction Basic principle: osmosis, osmotic pressure Basic components of osmotic pumps Factors affecting drug release from osmotic pumps Osmotic drug delivery devices Marketed products Advantages Limitations Evaluation conclusion

OSMOTIC SYSTEMS : 

OSMOTIC SYSTEMS Osmotic drug delivery systems are new approach for a controlled release dosage form. ODDS is useful for poorly soluble drug, for pulsatile drug release, zero order release. Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract. These systems can be utilized for systemic as well as targeted delivery of drugs.

Cont.. : 

Cont.. The release of drug(s) from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core component(s), size of the delivery orifice, and nature of the rate-controlling membrane. By optimizing formulation and processing factors, it is possible to develop osmotic systems to deliver drugs of diverse nature at a pre-programmed rate.

Some Explanations : 

Some Explanations Controlled Release?? Time release technology, also known as sustained-release (SR), sustained-action (SA), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), modified release (MR), or continuous-release (CR or Contin.), is a mechanism used in pill tablets or capsules to dissolve slowly and release a drug over time.

Pulsatile Release?? : 

Pulsatile Release?? There are certain conditions for which it is required that the drug should not be released at all during the initial phase of dosage form administration. Such a release pattern is known as pulsatile release. The conditions that demand such release include: Many body functions that follow circadian rhythm Diseases like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, and hypertension display time dependence

Pulsatile Release?? : 

Pulsatile Release?? Drugs that produce biological tolerance demand for a system that will prevent their continuous presence at the biophase as this tends to reduce their therapeutic effect The lag time is essential for the drugs that undergo degradation in gastric acidic medium (e.g, peptide drugs) irritate the gastric mucosa or induce nausea and vomiting. These conditions can be satisfactorily handled by enteric coating,and in this sense, enteric coating can be considered as a pulsatile drug delivery system. Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon requires that the drug release is prevented in the upper two-third portion of the GIT. The drugs that undergo extensive first-pass metabolism (B-blockers)

Slide 8: 

All of these conditions demand for a time-programmed therapeutic scheme releasing the right amount of drug at the right time. This requirement is fulfilled by Pulsatile Drug Delivery Systems. A pulsatile drug delivery system is characterized by a lag time that is an interval of no drug release followed by rapid drug release

Zero-order Release?? : 

Zero-order Release?? The ability to deliver a drug at a rate which is independent of time and the concentration of drug within a pharmaceutical dosage form. Zero order mechanism ensures that a steady amount of drug is released over time, minimizing potential peak/trough fluctuations and side effects, while maximizing the amount of time the drug concentrations remain within the therapeutic window (efficacy). This is particularly important for 24 hour delivery of drugs with a narrow therapeutic index. Osmotic tablet formulations, coated tablet matrices, and the use of polymer combinations in hydrophilic matrices can be utilized to provide zero order drug release profiles. Pharmaceutical Technology

OSMOSIS : 

OSMOSIS Osmosis refers to the process of movement of solvent molecules from lower solute concentration to higher solute concentration across a semi permeable membrane. Osmosis is the phenomenon that makes controlled drug delivery a reality. Osmotic pressure created due to imbibitions of fluid from external environment into the dosage form regulates the delivery of drug from osmotic device. Rate of drug delivery from osmotic pump is directly proportional to the osmotic pressure developed due to imbibitions of fluids by osmogent. Pharmaceutical Technology

Fig: : 

Fig: water or dilute solution concentrated solution membrane More water passes from dilute to concentrated ... level rises level falls

OSMOTIC PRESSURE : 

OSMOTIC PRESSURE The force per unit area, or pressure, required to prevent the passage of water through a selectively permeable membrane and into a solution of greater concentration is equivalent to the osmotic pressure of the solution. The osmotic pressure of the particles in a solute depends on the relative concentrations of the solutions on either side of the membrane, and on the area of the membrane. The osmotic pressure exerted by the non diffusible particles in a solution is determined by the numbers of particles (colligative property) in a unit of fluid and not by the mass of the particles.

Vant Hoff and Morse equation: : 

Vant Hoff and Morse equation: Osmotic pressure can be calculated using Vant Hoff eq. that describes that osmotic pressure is proportional to conc. & temp. πV = nRT Where π = osmotic pressure (atm) V = vol. of soln. (liters) n = no. of moles of solute R = gas constant. (0.082 lit. atm/mole deg) T =absolute temp.

Slide 14: 

These osmotic pressures can produce high water flows across semipermeable membranes. The osmotic water flow across a membrane is given by this eq. dv /dt = A/h Lp (σΔπ-ΔP) Where dv/dt is the water flow across the membrane of area A, thickness h; Δπ & ΔP are the osmotic and hydrostatic pressure differences, respectively, on either side of membrane; Lp is mechanical permeability; σ is the reflection coefficient ( leakage of solute through membrane ) In terms of membrane performance & predictability, it is important to select a material whose reflection coefficient is close to 1. Water permeabilities of membranes can vary over a wide range but most osmotic devices generally use relatively water permeable materials. Cellulosic materials, particularly cellulose acetate are widely used.

Basic Components Of Osmotic Pumps : 

Basic Components Of Osmotic Pumps 1. Drug 2. Osmotic agent 3. Semi permeable membrane 4. Plasticizers

1. Drugs : 

1. Drugs Short biological half-life {2-6h} Highly potent drug Required for prolonged treatment e.g. nifedipine glipizide verapamil

2. Osmotic agents : 

2. Osmotic agents Osmogents used for fabrication of osmotic dispensing device are inorganic or organic in nature. A water soluble drug by it self can serve the purpose of an osmogent Inorganic water-soluble osmogents                     Magnesium sulphate                     Sodium chloride                     Sodium sulphate                     Potassium chloride                     Sodium bicarbonate

Conti. : 

Conti. Organic polymer osmogents                      Sodium carboxymethyl cellulose                      Hydroxypropylmethyl cellulose                      Hydroxyethylmethylcellulose                      Methylcellulose s                      Polyethylene oxide                            Polyvinyl pyrollidine

Slide 19: 

Osmotic pressures for concentrated solutions of soluble solutes commonly used in controlled formulations are extremely high, ranging from 28 atm for sodium phosphate upto 500 atm for lactose: fructose mixture. Some commonly used osmotic agents are given in the table.

3. Semi Permeable Membrane : 

3. Semi Permeable Membrane Ideal Property of Semi Permeable Membrane The semi permeable membrane should be stable both to the outer inner environment of the device. The membrane must be sufficiently rigid so as to retain its dimensional integrity during the operational lifetime of the device. The membrane should also be relatively impermeable to the contents of dispenser so that osmogent is not lost by diffusion across the membrane finally, the membrane must be biocompatible The Semi Permeable Membrane must meet some performance criteria 1. The material must posses sufficient wet strength (~10 raise to power 5 psi) and wet modulus (~10 raise to power 5 psi ) so as to retain its dimensional integrity during the operational lifetime of the device. 2. The membrane exhibit sufficient water permeability so as to retain water flux rate in the desired range. The water vapor transmission rates can be used to estimate water flux rates 3. The reflection coefficient and leakiness of the osmotic agent should approach the limiting value of unity. Unfortunately, polymer membranes that are more permeable to water are also, in general more permeable to the osmotic agent.

4. Plasticizers: : 

4. 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 as below: Polyethylene glycols Ethylene glycol monoacetate; and diacetate- for low permeability Tri ethyl citrate Diethyl tartarate or Diacetin- for more permeable films

Factors affecting drug release rate : 

Factors affecting drug release rate Solubility: osmotic delivery system should have water solubility in the desired range to get optimize drug release. However, by modulating the solubility of these drugs within the core, effective release patterns may be obtained for the drugs, which might otherwise appear to be poor candidate for osmotic delivery. Solubility-modifying approaches: Use of swellable polymers: vinyl acetate copolymer, polyethylene oxide have uniform swelling rate which causes drug release at constant rate. Use of effervescent mixtures: Mixture of citric acid and sodium bicarbonate which creates pressures in the osmotic system and ultimately controls the release rate.

Slide 23: 

Use of cyclodextrin derivatives: They are known to increase solubility of poorly soluble drugs. The same phenomenon can also be used for the osmotic systems. Use of alternative salt form: Change in salt form of may change solubility.

2. Osmotic pressure: : 

2. Osmotic pressure: The next release-controlling factor that must be optimized is the osmotic pressure gradient between inside the compartment and the external environment. The simplest and most predictable way to achieve a constant osmotic pressure is to maintain a saturated solution of osmotic agent in the compartment.

3. Size of delivery orifice: : 

3. Size of delivery orifice: 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 build up in the system. The typical orifice size in osmotic pumps ranges from 600µ to 1 mm. Methods to create a delivery orifice in the osmotic tablet coating are: Mechanical drill 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. Indentation that is not covered during the coating process: Indentation is made in 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. Use of leachable substances in the semipermeable coating : e.g. controlled porosity osmotic pump

Osmotic Drug Delivery Devices : 

Osmotic Drug Delivery Devices 1. Implantable I. The Rose-Nelson Pump II. Higuchi-Leeper Pump III. Higuchi-Theeuwes pump IV. Implantable Miniosmotic pump 2. Oral osmotic Pump i. Single chamber osmotic pump Elementary osmotic pump ii. Multi chamber osmotic pump Push-pull osmotic pump Osmotic pump with non expanding second chamber

Cont…… : 

Cont…… iii. Specific types Controlled porosity osmotic pump Osmotic bursting osmotic pump Liquid OROS Delayed Delivery Osmotic device ·Telescopic capsule ·Oros ct (colon targeting) Sandwiched oral therapeutic system Osmotic pump for insoluble drugs Monolithic osmotic systems OSMAT

Implantable Osmotic Pumps : 

Implantable Osmotic Pumps ROSE NELSON PUMP In 1955, two Australian physiologists, Rose and Nelson, developed an implantable osmotic pump. They were interested in delivery of drugs to the gut of sheep & cattle. Composition: A drug chamber with orifice A salt chamber containing solid salt and elastic diaphragm A water chamber Drug Release: Difference in osmotic pressure across membrane moves water from water chamber into the salt chamber. Vol. of the salt chamber increases because of this water flow which distends the diaphragm separating the salt & drug chambers, thereby pumping drug out of the device.

Slide 29: 

Pumping rate of this pump is given by the equation: dm/dt = dv/dt × c where, dm/dt = drug release rate dv/dt = vol of flow of water into salt chamber c = conc. of drug in drug chambers

Fig: : 

Fig: Drug chamber Salt chamber Water chamber orifice

2. HIGUCHI-LEEPER PUMP : 

2. HIGUCHI-LEEPER PUMP It represents the first simplified version of Rose-Nelson pump. It contains a rigid housing and the semi permeable membrane, which is supported on a perforated frame. Rigid housing is divided in two chambers by a movable separator.

Drug release: : 

Drug release: The pump is activated when it is swallowed or implanted in the body. This pump consists of a rigid housing, and the semipermeable membrane is supported on a perforated frame. It has a salt chamber containing a fluid solution with excess solid salt. 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.

Slide 33: 

The benefit over Rose-Nelson pump is that it does not have water chamber, and the device is activated by water imbibed from the surrounding environment. This means the pump can be prepared loaded with drug and then stored for weeks or months prior to use.

3. HIGUCHI-THEEUWES PUMP : 

3. HIGUCHI-THEEUWES PUMP In early 1970s, Higuchi and Theeuwes developed a simpler form of Rose-Nelson Pump. Semi permeable wall itself acts as a rigid outer casing of the pump. The device is loaded with drug prior to use. When the device is placed in 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.

Fig: : 

Fig: Pharmaceutical Technology

IMPLANTABLE MINIOSMOTIC PUMP ORALZET OSMOTIC PUMP : 

IMPLANTABLE MINIOSMOTIC PUMP ORALZET OSMOTIC PUMP This is most advanced version in the category of implantable pumps developed by ALZA Corporation. It is composed of three concentric layers - the drug reservoir, the osmotic sleeve and the rate controlling semi permeable membrane. The additional component called flow moderator is inserted into the body of the osmotic pump after filling. The inner most compartment is drug reservoir which is surrounded by a osmotic sleeve, a cylinder containing high concentration of osmotic agent. The osmotic sleeve is covered by a semi permeable membrane.

Slide 37: 

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 10 ml per hour and delivery duration between 1 day and 4 weeks.

Advantages: : 

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

Fig: Brain infusion kit : 

Fig: Brain infusion kit

Applications: : 

Applications: ALZET osmotic pumps are miniature, implantable pumps used for research in mice, rats, and other laboratory animals. ALZET pumps can be used for systemic administration when implanted subcutaneously or intraperitoneally. ALZET pumps have been used successfully to deliver hundreds of different compounds including antibodies, chemotherapeutic drugs, cytokines, growth factors, hormones, and peptides.

DUROS® OSMOTIC PUMP : 

DUROS® OSMOTIC PUMP More recently, osmotic principles have been applied to human parenteral therapy, resulting in the development of the DUROS® technology. Implantable drug-dispensing osmotic pump, shaped as a small rod with titanium housing. DUROS® delivery technology consists of sterile, nonbiodegradable, single-use devices for continuous, subcutaneous administration of therapeutic molecules at steady rates. DUROS delivery technology is capable of delivering a wide range of therapeutic molecules for durations ranging from 3 to 12 months.

Drug Release: : 

Drug Release: The DUROS device releases a therapeutic agent at a predetermined rate based on the principle of osmosis. Extracellular fluid enters the DUROS device through a semipermeable membrane directly into a salt engine that expands to drive the piston at a slow and even delivery rate. Movement of the piston forces the drug formulation to be released through the orifice or exit port. The devices can be designed to provide an additional 10 to 14 days of continuous delivery of drug to allow scheduling flexibility for patients while avoiding interruption in drug delivery.

Slide 44: 

With a titanium outer cylinder, the DUROS device is designed to be removed quickly and safely. With calculated yield pressures of nearly 30,000 psi (based on a yield strength of 132,000 psi for the titanium alloy used), the device can withstand high pressures without structural failure. Successful start-up and continuous delivery of drug from the devices have been demonstrated in multiple animal studies and in in vitro models. All materials used in the manufacture of components for the DUROS device have a prior history of use in long-term human implants and have passed United States Pharmacopeia 23 Class VI 50°C and/or International Organization for Standardization 10993 biocompatibility tests. All of the inactive excipients have been used in prior pharmaceutical and parenteral drug products and are compellable grade. The excipients have been shown to be compatible with the drug as well as with the components of the DUROS device

Applications: : 

Applications: 1. Systemic & Site-specific Administration These technologies allow drug delivery for site-specific as well as systemic use for delivery periods of days to 1 year. To deliver drug systemically, the DUROS® system is placed just under the skin e.g., in the upper arm, in an out-patient procedure that is completed in just a few minutes using local anesthetic. Removal or replacement of the product is also a simple and quick procedure completed in doctor's office. To deliver a drug to a specific site, DURECT is a developing proprietary miniaturized catheter technology. Catheter can be attached to a DUROS® system to direct the flow of drug to the target organ, tissue or synthetic medical structure such as a graft.

Slide 46: 

The Viadur delivery system (the commercial device employing the DUROS delivery technology) is designed to deliver the therapeutic peptide leuprolide acetate for 12 months. New extensions of the DUROS drug delivery concept have been developed with different therapeutic agents and different delivery rates. The Viadur delivery system contains a solution formulation of leuprolide acetate dissolved in solvent, and the DUROS drug delivery platform has been expanded to include suspension formulations. These extensions make the DUROS device an even more versatile platform for delivering treatment to patients.

Oral Osmotic Pumps : 

Oral Osmotic Pumps As oral route is the most popular route of administration, most of the osmotic systems are developed as oral drug delivery. It is possible to deliver drugs at zero-order release rate, independent of gastric pH and hydrodynamic conditions with these osmotically controlled drug delivery systems. These systems can be further classified in Single chamber osmotic system: Elementary osmotic pump Multi-chamber osmotic systems: Tablets with second expandable osmotic chamber: push-pull osmotic pump Tablets with second non-expandable osmotic chamber: Two systems falls in this class i.e. 1) Drug solution gets diluted in the second chamber before leaving device and 2) Two separate EOP tablet  formed in a single tablet Miscellaneous: Controlled porosity osmotic pumps, multiparticulate osmotic pump10, osmotic bursting osmotic pump11, Effervescent activity-based osmotic systems12, Lipid osmotic pump.

ELEMENTARY OSMOTIC PUMP : 

ELEMENTARY OSMOTIC PUMP Composition: Osmotic core containing drug ( may or may not contain osmogent depending on osmotic activity of drug) Semipermeable membrane (usually of cellulose acetate) Delivery orifice Drug Release: The water penetrates inside the dosage form at the rate determined by the fluid permeability of the membrane and osmotic pressure of core formulation. This will result in formation of saturated solution of drug within the core, which is dispensed at a controlled rate from the delivery orifice in the membrane.

Slide 50: 

Release rate from EOP is based on zero order release rate from t=0 to t=z at which all of drug has dissolved and is described as (dm/dt)z = A/H k ΠS Where, dm/dt = drug release rate A = area of membrane H = thickness of membrane S = solubility Π = osmotic pressure (atm) k = Lpσ (membrane permeability) Normally EOP delivers 60-80% of its contents at a constant rate. It is used for moderately soluble drugs EOP is simplest possible form of osmotic pump because it works on same mechanism as implantable and does not need any equipment or technology and can be produced using ordinary tabletting & coating machine & facility to drill an orifice.

Construction of an EOP : 

Construction of an EOP

Combination of Effervescent Agents with the Drug : 

Combination of Effervescent Agents with the Drug This is a commercially important variation of elementary osmotic pump. Drugs, which are poorly soluble at low pH, may precipitate at the pH of gastric fluid, when such drug (indomethacin) is delivered through osmotic pump it may precipitate on the orifice affecting its functioning. An effervescent compound such as potassium bicarbonate can be incorporated to overcome this problem. When delivered from the pump With the drug solution, the bicarbonate reacts with acid in the exterior environment generating carbon dioxide. The expansion of gas dispenses the precipitated drug, allowing for rapid absorption of the drug and preventing blockage of the orifice.

PUSH-PULL OSMOTIC PUMP : 

PUSH-PULL OSMOTIC PUMP 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. Composition: 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 layer are formed and bonded together by tablet compression to form a single bilayer core. The tablet core is then coated with semipermeable 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. Fig: two-layer osmotic push-pull tab.

Drug Release: : 

Drug Release: 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.

OSMOTIC BURSTING OSMOTIC PUMP : 

OSMOTIC BURSTING OSMOTIC PUMP This system is similar to an EOP except delivery orifice is absent and size may be smaller. Drug Release: When it is placed in an aqueous environment, water is imbibed and hydraulic pressure is built up inside until the wall rupture and the contents are released to the environment. Varying the thickness as well as the area, the semipermeable membrane can control release of drug. This system is useful to provide pulsated release.

CONTROLLED POROSITY OSMOTIC PUMP (CPOP) : 

CONTROLLED POROSITY OSMOTIC PUMP (CPOP) The pump can be made with single or multicompartment dosage form, in either form, the delivery system comprises a core with the drug surrounded by a membrane which has an asymmetric structure, i.e. comprises a thin dense skin layer supported by a porous substructure. The membrane is formed by phase inversion process controlled by the evaporation of a mixed solvent system. Membrane is permeable to water but impermeable to solute and insensitive pore forming additive dispersed through out the wall.

Process for manufacturing asymmetric membrane: : 

Process for manufacturing asymmetric membrane: The asymmetric membrane capsule was made by a phase inversion process in which the membrane structure was precipitated on a stainless steel mold pin by dipping the mold pin a coating solution followed by quenching in an aqueous solution. as shown in Fig. The coating solution was a multi component polymer-solvent-non-solvent system containing a film forming polymer, cellulose acetate. The solvent non-solvent mixtures were formulated with acetone, water and glycerol. The ratio of solvents / non-solvents in the coating solution was selected so that on evaporation, phase inversion was immediately initiated. This assured the formation of an asymmetric as opposed to a dense membrane structure.

Drug Release: : 

Drug Release: When exposed to water, low levels of water-soluble additive are leached from polymer materials that were permeable to water yet remained insoluble. Then resulting sponge like structure formed the controlled porosity walls of interest and was substantially permeable to both water and dissolved drug agents. Rate of drug delivery depends upon the factors are water permeability of the semi permeable membrane and the osmotic pressure of the core formulation, thickness and total surface area of coating. All of these variable are under the control of the designer and do not vary under physiological condition, leading to the robust performance allued to above. The rate of flow dv/dt of water into the device can be represented as dv / dt = Ak / h (Dp-DR) Where   k  =  Membrane permeability  A   = Area of the membrane Dp  = Osmotic pressure difference  DR =  Hydrostatic pressure difference

Fig: : 

Fig:

Advantages: : 

Advantages: Porosity is easily controlled with selection of pore-former type & conc. Higher water flux & permeability of symmetric membranes allows greater flexibility in designing faster release rates or incorporating lower solubility drug substances into the dosage form. Another advantage is ability to fabricate asymmetric membrane (AM) dosage forms in conventional pharmaceutical process equipment without additional manufacturing complexities. Finally the physical design of an AM dosage form is flexible & it is possible to adapt the technology to fabricate coatings on tablets or on small particles, or to fabricate osmotic capsules directly from the asymmetric polymer membrane.

OSMOTIC PUMPS FOR INSOLUBLE DRUGS : 

OSMOTIC PUMPS FOR INSOLUBLE DRUGS Composition: In this system, particles of osmotic agents are coated with an elastic semipermeable membrane. These coated particles are then mixed with insoluble drug & tabletted & coated with rigid semipermeable membrane in usual way. Drug Release: When this system is placed in water it imbibes into the osmotic agent w/h swells & hydrostatic force delivers insoluble drug out of orifice.

SANDWITCHED OSMOTIC TABLETS (SOTs) : 

SANDWITCHED OSMOTIC TABLETS (SOTs) Composition: It is composed of polymeric push layer sandwiched between two drug layers with two delivery orifices. Drug Release: When placed in the aqueous environment the middle push layer containing the swelling agents swells and the drug is released from the two orifices situated on opposite sides of the tablet and thus SOTS can be suitable for drugs prone to cause local irritation of the gastric mucosa.

MONOLITHIC OSMOTIC SYSTEM : 

MONOLITHIC OSMOTIC SYSTEM Composition: It constitutes a simple dispersion of water-soluble agent in polymer matrix. Drug Release: When the system comes in contact with the aqueous environment, Water imbibtion by the active agents takes place rupturing the polymer matrix capsule surrounding the drug; thus liberating it to the outside environment. Initially this process occurs at the outer environment of the polymeric matrix, but gradually proceeds towards the interior of matrix in a serial fashion. However this system fails if more then 20 –30 volume per liter of the active agents is incorporated in to the device as above this level, significant contribution from the simple leaching of the substance take place.

PELLETED DELAYED RELEASE : 

PELLETED DELAYED RELEASE Composition: This system is composed of pellets of drug, with or without osmogents, coated with semipermaeble membrane. Drug Release: On coming in contact with water, membrane expands & causes pore formation & release drug. High flux rates and thus having higher release rates for poorly water soluble drugs.

LIQUID ORAL OSMOTIC SYSTEM (L-OROS) : 

LIQUID ORAL OSMOTIC SYSTEM (L-OROS) Liquid OROS are designed to deliver drugs as liquid formulations and combine the benefits of extended release with high bioavailability. They are of following types: L OROS hard cap L OROS soft cap Composition: Liq. Drug formulation is present in a soft gelatin capsule w/h is surrounded with the barrier layer, the osmotic layer, and the release rate controlling membrane. A delivery orifice is formed through these layers

Slide 69: 

Drug Release: When the system comes in contact with aqueous environment, water permeates across the rate controlling membrane and activates the osmotic layer. The expansion of the osmotic layer results in the development of hydrostatic pressure inside the system, thereby forcing the liquid formulation to break through the hydrated gelatin capsule shell at the delivery orifice.

Applications: : 

Applications: To deliver drugs as liquid formulations and combine the benefits of extended release with high bioavailability. Suitable for controlled delivery of lipophilic drugs.

OROS-CT (colon targeting) : 

OROS-CT (colon targeting) The colonic region of the GIT has become an increasingly important site for drug delivery and absorption. 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 comprise of as many as five to six push pull osmotic unit filled in a hard gelatin capsule.

Drug Release: : 

Drug Release: After coming in contact with the gastric fluids, gelatin capsule dissolves 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.

Fig: : 

Fig:

example : 

example The effects of two oxprenolol oral osmotic (OROS) delivery systems on heart rate and blood pressure before and during recovery from exercise at a predetermined load were examined in twelve patients with hypertension previously responding to beta-blocker monotherapy. Haemodynamic responses were attenuated during the 24 h after single and repeated (15 days') once daily administrations of 10/170 and 16/260 oxprenolol OROS. At 24 h after repeated doses, compared to placebo there were significant reductions in resting blood pressure and in heart rate immediately following exercise. Attenuation of heart rate after exercise was dose related but differences between the systems with respect to resting heart rate and blood pressure were inconsistent. Antihypertensive responses after repeated doses were greater than those after single doses.

Slide 75: 

However, reductions in resting and exercise heart rates were consistently less on chronic therapy. This may reflect enhanced expression of the partial agonist activity of oxprenolol due to altered receptor sensitivity after prolonged beta-blockade. The plasma oxprenolol profiles after both systems indicated slow absorption and substantial concentrations were apparent 24 h after drug administration. These observations suggest that both oxprenolol OROS systems display sustained drug release and on once daily dosing provide 24 h beta-blockade and control of blood pressure at rest and following exercise.

OSMAT: : 

OSMAT: It is a novel osmotically driven matrix system, which utilizes the hydrophilic polymers to swell, and gel in aqueous medium forming a semipermiable membrane in-situ releases from such a matrix system containing an osmogen could, therefore be modulated by the osmotic phenomenon. Osmat thus judiciously combines both matrix osmotic characteristics resulting in a quantum improvement in drug delivery from swellable matrix system. Osmat produces controlled drug release with adequate delivery rates in an agitation independent manner. Thus osmat represents simple, versatile, and easy to fabricate osmotically driven controlled drug delivery system based upon low cost technology.

Marketed Products : 

Marketed Products

Osmotic pumps as drug delivery devices: Advantages : 

Osmotic pumps as drug delivery devices: Advantages Apart from reduced dosing frequency, reduced systemic side effects and improved patient compliance, other unique advantages of osmotic pump are as follows: It delivers drugs at zero-order release kinetics. Constant delivery rate is an important specification for chronic treatment. The delivery rate is significantly greater than that attainable with diffusion based system(s) of comparable size. This is particularly vital when large doses of drug have to be administered. In vitro delivery rate can be accurately predicted using mathematical equations, which in turn, bears high degree of correlation with in vivo delivery rate. Delivery rate is independent of pH variations in the environment, including those in the gastrointestinal tract (GIT)

Slide 79: 

Delivery rate is independent of agitation outside, including GI motility. Delivery of drug takes place in the solution form ready for absorption, with osmotic pump simulating as a liquid dosage form prepared in-situ. Delivery rate is almost independent of delivery orifice size within limits. Drugs with widely varying solubilities can be incorporated. Isolation of yet to be delivered solid drugs from gut contents and GI mucosa is advantageous in case of drugs prone to hydrolysis in GIT and those which may cause irritation to the mucosa. The device is relatively simple to fabricate using conventional pharmaceutical manufacturing equipment. Due to its zero order release profile it is used in very early stages of drug research, such as drug screening, animal toxicology and pharmacology and initial clinical testing.

Limitations : 

Limitations Special equipment is required for making an orifice in the system. Residence time of the system in the body varies with the gastric motility and food intake. It may cause irritation or ulcer due to release of saturated solution of drug.

Applications of ODDS: : 

Applications of ODDS: Theeuwes et al (1985) developed elementary osmotic pump for metoprolol and oxprenolol for once daily administration. For the desired solubility succinate salt of oxprenolol and fumarate salt of metoprolol were used along with sodium bicarbonate as osmotic agent. Highly efficient method of laser drilling was used with rate of failure less than one in million. The systems were found to be stable after storage period of 2, 1, and 1 years at 23°, 37° and 51°C, respectively. In vitro release study was conducted using differential method apparatus, which indicated substantial drug delivery (60%) at zero-order rates.

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Vyas et al (1995) designed elementary osmotic pump, push-pull osmotic pump and diffusion pump of ciprofloxacin HCI using empty gelatin capsule shell. Elementary osmotic pump and push-pull osmotic pumps were coated with solution of cellulose acetate and diffusion pump was coated with emulsion of cellulose acetate solution and dextran solution (99:1). In case of push-pull osmotic pump, a swellable polymer was added in 1/3 part of capsule and separated drug and polymer layers with a septum. The extent of drug release was found in the decreasing order of push-pull osmotic pump (80%), elementary osmotic pump (60%) and diffusion pump (45%). This was explained on the basis of extra mechanical forces that developed inside the push-pull osmotic pump and elementary osmotic pump.

In Vitro Evaluation: : 

In Vitro Evaluation: 1. In vitro Dissolution: The in vitro release of drug from oral osmotic system has been evaluated by the conventional USP paddle and basket type apparatus. US patent described the use of commercial vankel standard dissolution apparatus. The dissolution media is generally distilled water as well as stimulated gastric fluid (for first 2-4 hr) and stimulated intestinal fluids (for subsequent hours) have been used. The standard specification, which are followed for the oral controlled drug delivery systems are equivalently applied for oral osmotic pump.

2 Scanning Electron MicroscopyCoating membranes of formulation obtained before and after complete dissolution of core contents can be examined for their porous morphology by scanning electron microscope.3Effect of pHTo study the effect of pH and to assure a reliable performance of the developed formulations independent of pH, in vitro release studies can be conducted in media of different pH.4 Effect of Agitational IntensityIn order to study the effect of agitational intensity of the release media, release studies were performed in dissolution apparatus at various rotational speeds. : 

2 Scanning Electron MicroscopyCoating membranes of formulation obtained before and after complete dissolution of core contents can be examined for their porous morphology by scanning electron microscope.3Effect of pHTo study the effect of pH and to assure a reliable performance of the developed formulations independent of pH, in vitro release studies can be conducted in media of different pH.4 Effect of Agitational IntensityIn order to study the effect of agitational intensity of the release media, release studies were performed in dissolution apparatus at various rotational speeds.

5 Effect of Osmotic PressureTo confirm the major mechanism of drug release, release studies of the optimized formulation can be conducted in media of different osmotic pressure. To increase the osmotic pressure of the release media (pre-equilibrated to 37°C ± 1°C), mannitol (osmotically effective solute) can be added.6 Kinetics of Drug Release the data obtained can be fitted in different models at different time intervals and by using satistics we can know kinetics of drug release. : 

5 Effect of Osmotic PressureTo confirm the major mechanism of drug release, release studies of the optimized formulation can be conducted in media of different osmotic pressure. To increase the osmotic pressure of the release media (pre-equilibrated to 37°C ± 1°C), mannitol (osmotically effective solute) can be added.6 Kinetics of Drug Release the data obtained can be fitted in different models at different time intervals and by using satistics we can know kinetics of drug release.

Conclusion : 

Conclusion Osmotic system technology has been extended to allow rate-controlled, constant drug delivery over a wide range of water solubility. Delivery rates & duration can be designed to limits imposed by GI transit time & absorption capacity. In general, these systems made 4- and 3-times-a-day regimens obsolete. Instead they made once-a-day dosing practical for many agents, including some with short half-lives. For these and other reasons, the future of osmotic technology in drug delivery will be excellent!

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