sasi pppt

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BY: GANTA.DARZINI SHIFT-02, ROLL NO-09 SRINIVASARAO COLEGE OF PHARMACY VISAKHAPATANAM

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Introduction Osmosis principle Osmotic Pressure Advantages n Disadvantages Factors affecting drug release rate Formulations Properties of Drugs Types of Osmotic Pumps Applications Evaluation Marketed Products Conclusion 2 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Osmosis can be defined as the net movement of water across a selectively permeable membrane driven by a difference in osmotic pressure across the membrane. Osmotic pressure is the pressure which, if applied to the more concentrated solution , would prevent transport of water across the semipermeable membrane. 3 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Solutions of different concentrations having the same solute and solvent system exhibit an osmotic pressure proportional to their concentrations. An osmotic delivery system that results in a constant zero order release rate of drug . Osmotic pressure is used as driving force for these systems to release the drug in controlled manner. These systems can be used for both route of administration i.e. oral and parenterals. Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS). Parenteral osmotic drug delivery includes implantable pumps . 5 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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It has no water chamber , and the device is activated by water imbibed from the surrounding environment. 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. Further simplified variant of Rose-Nelson pump was developed by Higuchi and Theeuwes. 6 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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About 75 years after discovery of osmosis principle Rose and Nelson, the Australian scientists, initiated the osmotic drug delivery system . They developed an implantable pump, which consisted of three chambers: a drug chamber, a salt chamber contains excess solid salt, and a water chamber. The design and mechanism of this pump is comparable to modern push-pull osmotic pump. 7 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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. 8 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Drug Release: : 

Drug Release: 9 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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 t he delivery orifice . 10 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Pfeffer showed that this pressure, the osmotic pressure π of the sugar solution is directly proportional to the solution concentration and the absolute temperature. π  = c t With in few years, Vant Hoff had shown the analogy between these results and ideal gas laws by the expression π  = Ф c r t 11 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Where, Ф is the osmotic coefficient of the solution, C is the molar concentration of sugar in the solution, r is the gas constant and t is the absolute temperature. Osmotic pressure for concentrated solution of   soluble solutes commonly used in controlled release formulation are extremely high ranging from 30 atm for sodium phosphate and up to 500 atm for a lactose-fructose mixture, as their osmotic pressure can produce high water flow across semi permeable membrane. 12 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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. The osmotic water flow through a membrane is given by the equation dv\dt   = A Q Δ π\ L Where, dv\dt is water flow across the membrane area A, thickness L, and the permeability Q in cm2 and Δ π is the osmotic pressure difference between the two solutions on either side of the membrane. This equation is strictly for completely perm selective membrane that is membrane permeable to water but completely impermeable to osmotic agent. 13 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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. 14 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Semi permeable membrane Osmosis … refers to the process of movement of solvent molecules from lower solute concentration to higher solute concentration across a semi permeable membrane.

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15 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 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.

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. 16 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI DELIVERY ORIFACE OSMOTIC PRESSURE MEMBRANE TYPE SOLUBILITY

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A. Solubility : Solubility should be in the desired range to get optimize drug release. The fraction of a drug release with zero order kinetic is given by F (z) = 1 – S Р Where, F (z) = fraction release by zero order S = drug solubility in g / cm 3 P = density of core tablet. 17 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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B . Osmotic pressure: The next release-controlling factor that must be optimized is the osmotic pressure , between inside the compartment and the external environment. To achieve a constant osmotic pressure is to maintain a saturated solution of osmotic agent in the compartment. 18 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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C . Size of delivery orifice: 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 Indentation (Modified punches) Use of leachable substances in the semi permeable coating e.g. controlled porosity osmotic pump. 19 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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D . Membrane type Entry of water in Osmotic Drug delievery depends on nature and type of membrane used for formulation. Example: Cellulose Ester, Cellulose Triacetate, Cellulose Propionate, Cellulose Acetate Butyrate, Ethyl Cellulose and Eudragits. E . Other level of pore formers incorporated into the wall the drug load in the core 20 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Oral osmotic pumps Implantable osmotic pumps 21 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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TWO CHAMBER SHOWING THE SEMIPERMEABLE OVER LAY 1-MICROPOROUS RIGID SHELL 2-DIVIDING WALL 3-ORIFICE 4-SEPERATING CHAMBER 5-CONTAINING OSMOTIC AGENTS 6-CONTAINING ACTIVE AGENTS OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 22

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IT IS A CROSS SECTION OF NOVEL DEVICE WITH THREE CHAMBERS 1- RELATIVELY PERMEABLE MEMBRANE 2 -MICROPOROUS CELL 3 -DIVIDING WALLS 4,5 -ORIFICES 6 -SEPERATING CHAMBER 7 -ABSORPTION CHAMBER 8 -CONTAINS OSMOTIC AGENT 9 -CONTAINING ACTIVE AGENT OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 23

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24 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Pump Modified version of Rose Nelson Pump Higuchi Leeper Higuchi-Leeper pump

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25 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Oral osmotic pumps

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The osmotic pump consists of three chambers. Water chamber Salt chamber Drug chamber Water Chamber OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 26 Elastic Diaphragm Salt Chamber Rigid Semi permeable membrane Drug Chamber Delivery orifice

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. OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 27 Elastic Diaphragm Salt Chamber Water Chamber Drug Chamber Delivery orifice Rigid Semi permeable membrane Rose and Nelson developed the first osmotic pump in 1955. The Osmotic pump was having three chamber. Water to be loaded prior to use was the drawbacks of rose nelson osmotic pump .

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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 . OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 28 Rigid housing Movable seperator Membrane Drug chamber salt chamber

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Rigid housing is divided in two chambers by a movable separator . It has a salt chamber containing saturated soln of Mgso 4 with excess Mgso4 and Drug chamber . Drug release OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 29 Rigid housing Movable seperator Membrane Drug chamber

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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. OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 26

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Delivery tube Drug concent. Osmogen Collapsible tube Rigid tube Cap Opening orifice . OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 31 In vivo

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. DRUG RELEASE. 32 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI In vivo

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Core Delivery Orifice Semi permeable membrane OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 34 3. Applicable mostly for water soluble drugs 2. Thick coatings lowers the water permeation rate 1. SPM should be 200-300 μ m thick to withstand pressure

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Rose Nelson pump was further simplified in the form of elementary osmotic pump by Theeuwes in 1975. It is fabricated as a tablet coated with SPM Normally EOP deliver 60 – 80 % of its content at constant rate. It has short lag time of 30 – 60 minute. OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 35 Core Delivery Orifice Semi permeable membrane

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EOP is the most basic device made up of a compressed tablet. The EOP consists of an osmotic core with the drug, surrounded by a semipermeable membrane . The semipermeable membrane is provided with a hole for the controlled delivery of the saturated solution of the drug formed as a result of imbibition of water whose rate is determined by the fluid permeability of the membrane and the osmotic pressure of the compressed tablet when the dosage form is placed in the aqueous environment. 36 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 37 Fig. : EOP Limitations: SPM should be 200-300 μ m thick to withstand pressure Thick coatings lowers the water permeation rate Applicable mostly for water soluble drugs

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38 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 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 gradiant and thereby controlling the release of drug.

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A controlled porosity wall can be described as having a sponge like appearance. Generally, materials producing from 5 to 95% pores with a pore size from 10A - 100µm can be used . The resulting membrane is substantially permeable to both water and dissolved solute. Water-soluble additives used for this purpose are dimethyl sulfone, saccharides, amino acids, sorbotil, etc. Core: API ± osmogents Coat: Semi permeable membrane with water soluble additives 39 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Core: API ± osmogents Coat: Semi permeable membrane without delivery orifice When placed in aqueous environment, water is imbibed and hydraulic pressure is built up inside the system, then wall ruptures and the contents are released. It is used for pulsated release. 40 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Core Tablet: Layer 1:  API ± osmogents Layer 2: Polymeric osmotic agents Coat: Semi permeable membrane with delivery orifice. It is a bilayer tablet coated with semi permeable membrane. The PPOP system consists of two compartments separated usually by an elastic diaphragm . The upper compartment contains the drug and is connected to the outside environment via a small delivery orifice. It is used for delivery of APIs having extremes of water solubility. Modifications can be done: - delayed push-pull - multi-layer push-pull - push-stick system 41 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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It is composed of polymeric push layer sandwiched between two drug layers with two delivery orifices . When placed in the aqueous environment the middle push layer containing the swelling agents, swells and the drug is released from the delivery orifices. Advantage : the drug is released from the two orifices situated on opposite sides of the tablet 44 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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. 48 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Composition: 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 & delivers insoluble drug out of orifice. 49 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Insoluble Drug Water Osmotic agent coated with elastic SPM For Insoluble Drugs

DRUG RELEASE: 

DRUG RELEASE 50 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Insoluble Drug Water Osmotic agent coated with elastic SPM For Insoluble Drugs

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They contain two or three compartment separated by elastic diaphragm. Upper compartment contain drug with or without osmogen (drug compartment nearly 60 – 80 %) and lower compartment (Push compartment) contain Osmogen at 20 – 40 %. Example : ProcardiaXL for Nifedipine 51 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

DRUG RELEASE: 

DRUG RELEASE . Upper compartment contain drug with or without osmogen (drug compartment nearly 60 – 80 %) and lower compartment (Push compartment) contain Osmogen at 20 – 40%. 52 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Selected asymmetric membrane capsule formulations Component Coating : Coating Quench Sealing Cellulose acetate 15.0 15.0 15.0 , Acetone 49.0 49.0 56.9 Ethyl alcohol 28.0 28.0 28.0, Glycerin 8.0 3.0 10.0 Triethylcitrate 5.0, Water 90.0, Dye 0.1 Polydimethylsioxane (Dow MDX4 Medical Grade Fluid) diluted in methylene chloride was used as the mold-pin lubricant. 53 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Components Coating Quench Sealing Cellulose acetate 15.0 15.0 15.0 acetone 49.0 49.0 56.9 Ethyl alcohol 28.0 28.0 28.0 glycerin 8.0 3.0 10.0 Tri ethyl citrate 5.0 5.0 5.0 dye 0.1 0.1 0.1 water 90.0 90.0 90.0

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A new type of membrane coating, has been developed for osmotic drug coatings used in conventional osmotic tablets. These new coatings have an asymmetric structure , similar to asymmetric membranes made for reverse osmosis or ultrafiltration, in that the coating consists of a porous substrate with a thin outer skin . These asymmetric-membrane coatings can be used to make osmotic drug-delivery formulations with several unique characteristics . 54 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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The permeability of the coating to water can be adjusted by controlling the membrane structure , thereby allowing control of the release kinetics without altering the coating material or significantly varying the coating thickness. In addition, the porosity of the skin can be controlled, minimizing the time lag before drug delivery begins and allowing the drug to be released from a large number of delivery ports. 56 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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non-disintegrating polymeric capsule. The capsule wall was made by phase inversion process in which the membrane structure was precipitated on stainless steel mold pins, By dipping the mold pins into a coating solution containing a polymer–solvent–non solvent system followed by dipping into a quench solution . The resulting asymmetric membrane wall was composed of a thin dense region supported on a thicker porous region. These can be filled with a blend of the active agent and excipients for use in osmotically modulated controlled drug delivery application. 57 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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A comprehensive model describing drug release from an AM dosage form consists of osmotic and diffusional contributions. The diffusional contribution is derived from the fact that the asymmetric membrane is not perfectly semipermeable, and therefore a portion of drug is released by diffusion, primarily through pores in the coating. The total mass of drug delivered per unit time, (dm / dt) t is modeled by: (dm/dt) t = (dm/dt) + (dm/dt) d 58 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Where, (dm/dt) t is the mass released by osmotic pumping (dm/dt) d is the mass released due to diffusion. The osmotic drug release component is described by Eq 2. (dm/dt) d = (AC/h)p w ∆∏ Here, A is the surface area of the device, h the membrane thickness, C the dissolved drug con­centration in the core fluid, P w the water permeability of the semipermeable membrane, and ∆∏ the osmotic pressure difference across the membrane. 59 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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The diffusional release component is de­pendent on the dissolved drug permeability in the membrane, P d , the device surface area, A, the drug concentration in the core, C, and the membrane thickness, h, as described in Eq. 3. (dm/dt) d =(P d AC)h The total drug release is described by Eq. 4. (dm/dt) t = (AC/h)p w ∆∏+(P d AC)/h The combination of both osmotic and diffusional release mechanisms has been addressed previously by Theeuwes for the simple osmotic pump and by Zenter et al for the controlled porosity osmotic pump. 60 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Colour                                    Any imperfection Texture and membrane size                         Height and radius Scanning electron microscopy                     Drug content Dissolution behavior                                 Stability studies 63 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Short biological Half-life (2- 6 hrs) High potency Required for prolonged treatment (e.g: Nifedipine, Glipizide, Verapamil and Chlorpromazine hydrochloride). 65 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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OSMOTIC AGENTS SEMIPERMEABLE MEMBRANE COATING MATERIAL POLYMERS WICKING AGENTS SOLUBILIZING AGENTS SURFACTANTS PLASTISICERS FLUX REGULATORS PORE FORMING AGENTS 66 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Polymeric osmogents are mainly used in the fabrication of osmotically controlled drug delivery systems Osmotic pressures for concentrated solution of soluble solutes commonly used in controlled release formulations are extremely high, ranging from 30 atm for sodium phosphate up to 500 atm for a lactose-fructose mixture. These osmotic pressures can produce high water flows across semipermeable membranes . 67 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Osmotic pressure of saturated solutions of commonly used pharmaceutical solutes: 

Osmotic pressure of saturated solutions of commonly used pharmaceutical solutes 68 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Osmotic pressure of saturated solutions of commonly used pharmaceutical solutes: 

Osmotic pressure of saturated solutions of commonly used pharmaceutical solutes 69 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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The membrane must possess certain performance criteria such as: Sufficient wet strength and water permeability Should be biocompatible Rigid and non-swelling Should be sufficient thick to withstand the pressure within the device. 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. 70 OSMOTIC DRUG DELIEVERY SYSTEM PPT by; GANTA.DARZINI

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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 Triethyl citrate Diethyl tartarate or Diacetin- for more permeable films 71 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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. 72 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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 are 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. 73 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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 Cyclodextrine) 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). 74 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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. 75 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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Permeability of membranes can be increased by adding plasticizer, which increases the water diffusion coefficient. Examples: dialkyl phthalates, trioctyl phosphates, alkyl adipates, triethyl citrate and other citrates, propionates, glycolates, glycerolates, myristates, benzoates, sulphonamides and halogenated phenyls. 76 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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. Examples : Polyhydric 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. 77 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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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. Examples: 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. 78 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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A-core b-membrane c-layer seperator d-osmotic chamber e-coating f-pressure due to osmosis g-drug : 

A-core b-membrane c-layer seperator d-osmotic chamber e-coating f-pressure due to osmosis g-drug 80 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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81 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Drug solution leaving via delivery portal Removable cap Flow moderator Semipermeable membrane Osmotic agent Flexible impermeable reservoir wall Reservoir

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DRYING CHAMBER DRYING RAILS QUENCH BATH AIR BLAST DIPING IN TO COATING SOLUTION LINE FEED OVER VIEW OF THE MANUFACTURING PROCESS. 99 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

drying chamber.: 

drying chamber. 100 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Drying rails.: 

Drying rails. 101 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Quench bath.: 

Quench bath. 102 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Air-blast to blow away excess moisture.: 

Air-blast to blow away excess moisture. 103 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

dipping into coating solution.: 

dipping into coating solution. 104 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Line feed.: 

Line feed. 105 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Overview of the robotic manufacturing process: 

Overview of the robotic manufacturing process 106 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 107: 

Swellable-core technology (SCT) formulations that used osmotic pressure and polymer swelling to deliver drugs to the GI tract in a reliable and reproducible manner were studied. The SCT formulations consisted of a core tablet containing the drug and a water-swellable component, and one or more delivery ports. The in vitro and in vivo performance of two model drugs, tenidap and sildenafil, formulated in four different SCT core configurations: 107 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 108: 

homogeneous-core (single layer), tablet-in-tablet (TNT), bilayer, and trilayer core, were evaluated. In vitro dissolution studies showed that the drug-release rate was relatively independent of the core configuration but the extent of release was somewhat lower for the homogeneous-core formulation, particularly under non-sink conditions . 108 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 109: 

The drug-release rate was slower with increasing coating thickness and decreasing coating permeability, and was relatively independent of the drug loading and the number and size of the delivery ports. The drug-release rates were similar for the two model drugs despite significant differences in their physicochemical properties. Tablet-recovery and pharmacokinetic studies conducted in beagle dogs showed that the in vivo release of drug from SCT formulations was comparable to the in vitro drug release. 109 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 110: 

A plastic micro drug delivery system has been successfully demonstrated by utilizing the principle of osmosis without any electrical power consumption. The system has an osmotic micro actuator and a poly dimethyl siloxane (PDMS) micro fluidic cover compartment consisting of a reservoir, a micro fluidic channel and a delivery port . 110 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 111: 

. The typical dimension of the microfluidic channel is 1 cm in length with a cross-sectional area of 30×100 μm 2 to minimize the diffusive drug flow while pressure drop remains moderate. Using oxygen plasma to activate the surfaces of polymers for bonding, the osmotic actuator is bonded with the PDMS cover while liquid drug can be encapsulated during the bonding process. Employing the net water flow induced by osmosis , the prototype drug delivery system has a measured constant delivery rate at 0.2 μL/h for 10 h with an accumulated delivery volume of 2 μL. 111 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 112: 

Both the delivery rate and volume could be altered by changing the design and process parameters for specific drug delivery applications up to a few years. Moreover, the induced osmotic pressure can be as high as 25 MPa to overcome possible blockages caused by cells or tissues during drug delivery operations. These are the few applications under the osmotic drug delievery systems which follows the principle of osmosis ,but by using different core active ingredients. 112 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Schematic osmotic pump: 

Schematic osmotic pump 113 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 114: 

114 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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115 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Duros osmotic pump: 

Duros osmotic pump Design : Implantable drug-dispensing osmotic pump, shaped as a small rod with titanium housing. Mechanism : Through osmosis, water from the body is slowly drawn through the semi-permeable membrane into the pump by osmotic agent residing in the engine compartment, which expands the osmotic agent and displaces a piston to dispense small amounts of drug formulation from the drug reservoir through the orifice. Application: Systemic or site-specific administration of a drug 116 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Duros osmotic pump: 

Duros osmotic pump 117 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

A miniature cylinder made from a titanium alloy, which protects & stabilizes the drug inside Water enters through a semipermeable membrane; the drug is delivered from a port at the other end of the cylinder at a controlled rate for up to one year.: 

A miniature cylinder made from a titanium alloy, which protects & stabilizes the drug inside Water enters through a semipermeable membrane; the drug is delivered from a port at the other end of the cylinder at a controlled rate for up to one year . 118 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

duros osmotic pump: 

OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 119 duros osmotic pump

Slide 120: 

120 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 121: 

DUROS Intrathecal Opioid Delivery System has a nominal volume-pumping rate of 10 l/day (0.42 l/hr). It demonstrates a constant volume-pumping rate from a DUROS system over 100 days. The in vitro pumping rate was determined by placing the systems in an aqueous buffer solution at 37^C , and by measuring the effluent from the systems at preset time intervals. 121 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

DUROS Intratumoral Delivery of Antineoplastic Agents Into The Brainstem: 

DUROS Intratumoral Delivery of Antineoplastic Agents Into The Brainstem 122 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 123: 

Figure 8 shows the DUROS system coupled with a nickel-titanium catheter. The catheter consisted of a 30-cm silicone-tubing proximal section (ID: 0.25 mm and OD: 1.22 mm), and a 2-cm Nickel Titanium Alloy (NiTi) distal section. The distal tip of the NiTi section was tapered and closed with a series of small holes (0.025-mm diameter) along the distal 3 mm of length. The NiTi tubing has an ID of 0.20 mm and an OD of 0.30 mm 123 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Figure 7 demonstrates a constant volume-pumping rate from a DUROS system over 100 days.: 

Figure 7 demonstrates a constant volume-pumping rate from a DUROS system over 100 days. 124 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 125: 

125 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

The rate of drug delivery from the DUROS system is described by the following equation: 

The rate of drug delivery from the DUROS system is described by the following equation 126 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Where: dm/dt = drug delivery rate (eg, mg/day) k = effective hydraulic permeability A = membrane surface area h = membrane thickness c = drug concentration in the drug reservoir For constant delivery rate applications, steady delivery results because: k is constant because the membrane has been shown not to foul or change permeability during delivery; A and h are constant by design; and c is constant for a stable drug formulation.

The equation for delivery from osmotic (Equation 2) to demonstrate the effect of backpressure on delivery rate: : 

The equation for delivery from osmotic (Equation 2) to demonstrate the effect of backpressure on delivery rate: 127 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Equation 2 assumes that the reflection coefficient is 1.0. 2,8 this equation, P is the pressure inside the DUROS system. For NaCl, DP is 350 atmospheres (5100 psi). Backpressures inside the DUROS system are generally at most several hundred psi. Hence, the impact of backpressure on the water imbibition rate is negligible. This characteristic also gives the DUROS technology the capability to deliver viscous suspension formulations

Slide 128: 

128 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 129: 

The CHRONOGESIC system is implanted in the inside of the upper arm using a specially designed sterile implanter (Figure 5). The Implanter is a trocar-like device that facilitates precise, efficient subcutaneous placement of the CHRONOGESIC implant. The implantation procedure involves administration of a local anesthetic followed by a small incision made with a scalpel. The Implant is loaded into the Implanter cannula via a special docking system in the vial that contains the Implant. 129 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 130: 

. The physician inserts the cannula of the Implanter through the incision. Then, while holding the Implanter steady, the physician withdraws the cannula using the actuator on the Implanter handle. A rod interior to the cannula holds the Implant in place. The Implanter is then withdrawn from the subcutaneous space, leaving the Implant properly placed subcutaneously . The incision is then closed with a bandage. The implantation procedure is quick (duration less than 5 minutes). To date, both the implantation and explantation procedures have been well tolerated in CHRONOGESIC clinical trials, mirroring the Viadur experience 130 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 131: 

131 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 132: 

Design: Empty reservoir within the core of the pump is filled with the drug or hormone solution to be delivered and is surrounded by salt chamber with impermeable layer between them. Mechanism: Water enters into the salt chamber through semipermeable membrane and causes compression of flexible reservoir and delivery of drug solution. Application: To deliver drugs, hormones, and other test agents continuously at controlled rates from one day to six weeks. 132 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 133: 

133 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 134: 

134 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 135: 

A chronotherapeutic drug delivery system may be classified as per the function of the dosage form into single pulse system and multiple pulse system. A single pulse system after a lag time releases majority of the drug in a specific part of the GIT, which may be distal part of the small intestine or the colon depending on the prearranged lag time. 135 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI SINGLE PULSE:

Multile pulse:: 

Multile pulse: A multiple pulse system delivers the drug in divided doses in concomitant pulses to provide advantages such as reduced dose. As in case of antibiotics better or improved accomplishment of the objective of effectively killing bacteria by not allowing them to develop biological tolerance by switching over to a dormant and more resistant state. 136 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 137: 

A multiple pulse system may be programmed to release fractions of drug in different parts of the GIT viz. stomach, distal jejunum and transverse colon as in case of a three pulse system. The barrier may prevent the drug release from occurring either by its slow erosion or slow dissolution or swelling or rupture due to osmosis or may be the mechanism can be based on pH dependent solubility of the polymer as in methylmethaacrylates (MMA) to provide the necessary lag time required. 137 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 138: 

138 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 139: 

139 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 140: 

140 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 141: 

An oral monolithic osmotic system for highly water-soluble pramipexole dihydrochloride monohydrate has been developed and characterized. Monolithic osmotic system was developed using controlled porosity membrane , this system delivers drug in controlled manner for prolonged period of time. Controlled porosity osmotic membrane consists of cellulose acetate as coating polymer and water-soluble pore formers , which forms an in-situ microporous membraneafter imbibing water, hence no laser drilling is required. 141 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 142: 

Pore formation was controlled by varying concentration of pore forming agents. Scanning electron microscopy was carried out to confirm the microporous structure. From in vitro release studies it was evident that drug release was independent of pH and agitation but highly dependent on concentration of pore forming agents used. Increasing concentration of cellulose acetate from 2 % - 5 % w/v drastically retarded drug release. 142 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 143: 

Osmotic pressure generated was determined using 3D Freezing point osmometer and was found to be linear with drug release. The developed formulation gave desired once a day release of pramipexole without using laser drilling technique making it more patient compliance and cost effective. Pramipexole has been investigated as a monotherapy in the treatment of PD [12-15] In advanced Parkinson’s disease . 143 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 144: 

Pramipexole dihydrochloride monohydrate . It is white crystalline powder with melting point of 290oC. Sodium bicarbonate, sodium chloride,mannitol, magnesium stearate, were used as osmogents, Lactose,microcrystalline cellulose , Hydroxypropyl methyl cellulose , Cellulose Acetate with 39.8 % acetyl content was used as semipermeable membrane. Polyethyleneglycol 400, dibutylphthalate were employed as pore formers. Titanium dioxide and talc ,Potassiumdihydrogen orthophosphate, sodium hydroxide , acetonitrile HPLC . 144 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 145: 

Formulation development Coating tablet core Drug content Invitro release HPLC analysis on drug release Effect of PH on drug release Effect of agitation intensity Effect of different concentrations of cellulose acetate Determination of osmotic pressure Scanning electron microscopy Stability studies. 145 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 146: 

Different Types of coating solution tried on formulation : Ingredients Coating Cellulose Acetate (% w/v) 2 PEG 400 (% w/w) 20 Acetone (%) 100 Dichloro methane:Methanol:Water - - 70:20:10 146 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 147: 

Monolithic osmotic tablets coated with cellulose acetate as a semi permeable membrane containing different channeling agents have been developed for Pramipexole. The desired zero order release profile was obtained by optimizing concentration of osmogent, polymer and pore formers. Drug release increased with the amount of osmogents due to the increased water uptake and increased driving force for drug release. The drug release was further retarted using proper pore former to achieve desired zero order release profile. 147 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 148: 

The developed formulation was found to be stable. And the system delivered Pramipexole at zero order rate for a period of 24 hrs independent of pH and agitational intensity. This system is simple to prepare and is cost effective, alternative to conventional osmotic delivery pump as the sophisticated laser drilling technique is not required. 148 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 149: 

The delivery rate of zero-order is achievable with osmotic systems. Delivery may be delayed or pulsed , if desired. 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. For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic conditions . The release from osmotic systems is minimally affected by the presence of food in gastrointestinal tract. A high degree of in vivo- in vitro correlation (IVIVC) is obtained in osmotic systems. 149 OSMOTIC DRUG DELIEVERY SYSTEM PPT by; GANTA.DARZINI

Slide 150: 

150 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Osmotic system

Slide 151: 

Theeuwes (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. 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 drug delivery (60%) at zero-order rates . 151 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 152: 

OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI 152 Vyas (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%).

Slide 153: 

153 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI WEIGHT VARIATION DISSOLUTION PORE DIAMETER THICKNESS HARDNESS Evaluation COATING THICKNESS IN VIVOEVALUATION

Slide 154: 

Osmotic system technology has been extended to allow rate-controlled, constant drug delivery . These systems made 4- and 3-times-a-day regimens obsolete. Instead they made once-a-day dosing practical for many agents. For these and other reasons, the future of osmotic technology in drug delivery is bright ! 154 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

Slide 155: 

Gupta Roop, Gupta Rakesh, Basniwal Pawan k, Rathore Garvendras, Osmotically controlled oral drug delivery systems: a review, int. J. Ph. Sci., 2009, 1(2), 269-275. Gohel M.C Parikh .R.K , Shah. N.Y Osmotic drug delivery- an update, pharmainfo.net, 2009, 7(2). Lachman L., Liberman H. A., Kanig J. L., The theory and practise of industrial pharmacy. 2 nd Edition 1991, Varghese publishing house, Pg. 455. Aulton M. E., pharmaceutics the science of dosage form design. 2 nd Edition 2002, Churchill livingstone, Pg. 38, 39, 74, 304, 417. Ajay Babu, M. Prasada Rao, Vijaya Ratna J, Controlled-porosity osmotic pump tablets-an overview, jprhc. Shailesh Sharma. Osmotic controlled drug delivery. Pharmainfo.net. 2008; 6(3). 155 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI

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156 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI Patent application title : ORAL OSMOTIC DRUG DELIVERY SYSTEM Inventors: Hasmukh B. Patel (Edison, NJ, US) Assignees: RELIANT PHARMACEUTICALS, INC. IPC8 Class : AA61K924FI USPC Class: 424472 Class name: Layered unitary dosage forms Publication date: 10/09/2008 Patent application number: 20080248114 Wright JC, Leonard ST, Stevenson CL, Beck JC, Chen G, Jao RM, Johnson PA, Leonard J, Skowronski RJ. An in vivo/in vitro comparison with a leuprolide osmotic implant for the treatment of prostate cancer. J Control Rel. 2001; 75:1-10. Eckenhoff B, Theeuwes F, Urquhart J. Osmotically actuated dosage forms for rate-controlled delivery. Pharm Tech. 1987;11:96-105. Theeuwes F. Elementary osmotic pump. J Pharm Sci. 1975;64:1987-1991. Theeuwes F, Yum SI. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations. Ann Biomed Eng. 1976;4:343-353.

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157 OSMOTIC DRUG DELIEVERY SYSTEM PPT by;GANTA.DARZINI