osmotic drug delivery system

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JAIPUR NATIONAL UNIVERSITY School of Pharmaceutical science:

JAIPUR NATIONAL UNIVERSITY School of Pharmaceutical science OSMOTIC DRUG DELIVRY SYSTEM SUPERVISED BY SUBMITTED BY Mr.Ajay tiwari Ankit Mittal Professor, M.Pharma, 2 nd Sem(P.ceutics) School of Pharmaceutical Sciences, Enrol.No: jnu-jpr/0801081476 Jaipur National University, Jaipur. JNU, Jaipur

Osmotic Drug delivery:

Osmotic Drug delivery New approach Utilise osmotic pressure Can be utilise for systemic as well as targeted delivery of drug. used for both oral and parental route also known as gastro intestinal therapeutic system

Osmosis:

Osmosis Movement of solvent molecule from lower solute conc. To higher solute conc. across semipermeable membrane.

Osmotic pressure:

Osmotic pressure pressure required to prevent the passage of water through a selective permeable membrane and into solution of greater concentration .

Advantages:

Advantages Ease of administration Greater effectiveness in the treatment of chronic conditions Greater patient convenience due to simlified dosing shedule Consistent blood level wihthin the therapeutic window Enhance bioavailability

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Reduced inter patient variability Decreased dosing frequency Improove patient compliance Reduced side effect

Disadvantages:

Disadvantages Expensive Rapid development of tolerance Chance of toxicity due to dose dumping

Principle:

Principle Abbe Nollet first reported osmotic effect in 1748, but Pfeffer in 1877 had been the pioneer of quantitative measurement of osmotic effect. Utilize a membrane permeable to water but impermeable to sugar is used to separate sugar solution from pure water. A flow of water takes place in to sugar solution that can not be stopped untill a pressure π is applied to sugar solution .

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This osmotic pressure π of sugar solution is directly proportional to solution concentration absolute temperature π = θ cRT ……… (1) π =osmotic pressure θ = osmotic cofficient c = molar concentration R = gas constant T = absolute temperature

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Van’t Hoff established the analogy between the Pfeffer results and the ideal gas laws π = n 2 RT……. (2) n 2 =the molar concentration of sugar (or other solute) in the solution R = the gas constant T =absolute temperature This equation holds true for perfect semipermeable membranes and low solute concentrations.

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Measurement of osmotic pressure by utilizing vapour pressure measurements π = RT ln (Po/P)/v……. (3) P o = the vapour pressure of the pure solvent P = the vapour pressure of the solution v = the molar volume of the solvent Osmotic pressure for soluble solutes is extremely high. This high osmotic pressure is responsible for high water flow across semipermeable membrane.

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The rate of water flow dV/dt = A θ Δ π /l……. (4) dV/dt = the water flow across the membrane area A and thickness l with permeability θ Δ π = the difference in osmotic pressure between the two solutions on either side of the membrane.

Schematic representation of the basic model of osmotic pressure powered drug delivery systems:

Schematic representation of the basic model of osmotic pressure powered drug delivery systems V s V d PUMP HOUSING DELIVERY ORIFICE MOVABLE PARTITION SEMIPERMEABLE MEMBRANE V s is volume of osmotic agent compartment V d is volume of drug compartment

Basic component of osmotic pump:

Basic component of osmotic pump Drug Osmotic agent Semipermeable agent Plasticizers Wicking agent Solubilising agent Surfactant Coating solvent Flux regulator Pore forming agent Hydrophilic and hydrophobic polymers

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Drugs Short biological half life Highly potent drug Required for prolong treatment Eg. Nifedipine , virapamil

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Osmotic agent/osmogen/osmagent Inorganic or organic in nature water soluble drug by itself can serve the the purpose of osmogent. Criteria for the selection of osmogen Osmotic activity Aquous solubility Inorganic water soluble osmogents MgSo 4 NaCl KCl NaHCo 3

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Organic polymer osmogents CMC ( sodium carboxy methylcellulose) HPMC (Hydroxy propyl methyl cellulose) MC (Methyl cellulose) Polyethylene oxide PVP (Polyvinyl pyrollidine) Organic water soluble osmogen Sorbitol Mannitol

Semipermeable membrane:

Semipermeable membrane Should stable both outside and inside enviourment of device. Sufficiently rigid and retain its dimensional integrity during the operational life time of device. Exhibit sufficient water permeability so as to retain water flux rate in desired range.

Semipermeable membrane forming polymer:

Semipermeable membrane forming polymer Cellulose polymer Cellulose acetate(common) Acetyl content 32% and 38% Degree of substitution(ds) Up to 1 - AC - 21% Ex. Cellulose diacetate DS=1-2, AC -21-35% Cellulose triacetate DS – 2-3 ,AC- 35-44.8%

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Other polymers Agar acetate Amylose triacetate Betaglucan acetate Polyacetals Polyether coplymer

Plasticizers:

Plasticizers Increase flexibility ,permeability of the fluid,polymers Examples PEG (Polyethylene glycol) Ethylene glycol monoacetate and diacetate -for low permeability Triethylene citrate Diehtyl tartarate or diacetine -for more permeable films Myristates , benzoates

Wicking agent :

Wicking agent Material which has ability to draw water into the porous network of 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) polyvinyl pyrrolidone (PVP) bentonite magnesium aluminium silicate polyester polyethylene,etc.

SOLUBILIZING AGENTS:

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 anionic surfactants such as SLS). Citrate esters and their combinations with anionic surfactants (e.g., alkyl esters particularly triethyl citrate)

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Combination of complexing agent and anionic surfactant PVP with SLS Polyethylene glycol with SLS

SURFACTANTS:

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

COATING SOLVENTS:

COATING SOLVENTS 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

FLUX REGULATORS:

FLUX REGULATORS it assist in regulating the fluid permeability through membrane. add to the wall forming material. Examples:- Poly hydric alcohols (poly alkylene glycols) low molecular weight glycols(poly propylene, poly butylene and poly amylene)

PORE FORMING AGENTS:

PORE FORMING AGENTS Used in the pumps developed for poorly water soluble drug and in the development of controlled porosity or multiparticulate osmotic pumps. Inorganic or organic solid or liquid For example Alkaline metal salts (NaCl, NaBr, Kcl) Alkaline earth metals (Cacl 2 and calcium nitrate) Carbohydrates (glucose, fructose, mannose)

HYDROPHILIC AND HYDROBHOBIC POLYMERS:

HYDROPHILIC AND HYDROBHOBIC POLYMERS Used in the formulation development of osmotic systems containing matrix core. selection of polymer is based on solubility of drug the amount and rate of drug to be released from the pump. Examples of hydrophilic polymers HEC (Hydroxy ethyl cellulose) CMC (carboxy methyl cellulose) HPMC (hydroxyl propyl methyl cellulose) Examples of hydrophobic polymers EC(e thyl cellulose) wax materials, etc .

Osmotic drug delivery devices:

Osmotic drug delivery dev ices There are two categories Implantable The rose and nelson pump Higuchi – leeper pump Higuchi –theeuwas pump Implantable mini osmotic pump

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2. Oral osmotic pump Single chamber osmotic pump Elementary osmotic pump Multichamber osmotic pump Push pull osmotic pump Osmotic pump with nonexpending second chamber

FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON OSMOTIC PUMP):

FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON OSMOTIC PUMP) Drug Chamber Elastic Diaphragm Salt Chamber Rigid Semi permeable membrane Water Chamber Delivery orifice

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Kinetics of pumping from rose nelson pump dMt/dt = (dv\dt).c….. (7) dMt/dt = drug release rate (dv/dt) = volume of water flow in salt chamber C = conc. Of drug in drug chamber Major problem Whenever water came in contact with semipermeable membrane osmotic action began. This needs pump to be store empty and water to loaded prior to use . This drawback overcome by pharmetric devices

PHARMETRIX DEVICE:

PHARMETRIX DEVICE Impermeable membrane placed between the semi permeable membrane and the water chamber. 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

HIGUCHI LEEPER OSMOTIC PUMPS:

HIGUCHI LEEPER OSMOTIC PUMPS No water chamber, and the activation of the device occurs after imbibition of the water from surrounding environment. Has rigid housing. Used for veterinary purpose. 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. Porous Membrane Support MgSO 4 Movable Separator Drug Chamber Rigid Housing Satd. Sol. Of MgSO 4 contg. Solid MgSO 4 Semi-permeable Membrane

HIGUCHI THEEUWES OSMOTIC PUMP:

HIGUCHI THEEUWES OSMOTIC PUMP 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. Wall of flexible collapsible material SPM Coating contg. Solid Osmotic compound Delivery port Osmotic Agent layer Rigid Semi permeable Membrane Fluid to be pumped Delivery port Swollen Osmogen layer Squeezed Drug Core

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Small osmotic pumps of this form are available under the trade name ALZET ® Modification of Higuchi theeuwes pump Uses mixure of citric acid and NaHCo 3 to generate pressure required for delivery of drug When exposed to water ,the mixture produces Co 2 gas which exerts pressure on elastic diaphragm and deliver drug from device .

Alzet osmotic pump:

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 a convenient and reliable method for controlled agent delivery in vivo .

Advantages:

Advantages continuous administration of short half-life proteins and peptides. for chronic dosing of laboratory animals. Minimize unwanted experimental variables and ensure reproduciblility consistent results. Eliminate the need for nighttime or weekend dosing. Reduce handling and stress to laboratory animals. enough for use in mice or very young rats. Allow for targeted delivery of agents to virtually any tissue. Cost-effective research tool. Expose the agent at predictable level.

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ALZET pumps have 3 concentric layers: Rate-controlling, semi-permeable membrane Osmotic layer Impermeable drug reservoir 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.

ELEMENTARY OSMOTIC PUMP:

ELEMENTARY OSMOTIC PUMP Rose Nelson pump was further simplified in the form of elementary osmotic pump(by Theeuwes,1975) .

ELEMENTARY OSMOTIC PUMP (EOP) :

ELEMENTARY OSMOTIC PUMP (EOP ) Core containing agent Delivery Or ifice Semi permeable membrane Fabricated as a tablet coated with semi permeable membrane (cellulose acetate).

RELEASE PROFILES :

RELEASE PROFILES The mass delivery rate from the pump can be written as: S d is concentration in drug compartment π f is osmotic pressure of the drug formulation A is surface area h is thickness k is permeability of membrane π e is osmotic pressure of the environment which is negligible So zero order release rate can be expressed as,

LIMITATION OF EOP:

LIMITATION OF EOP semi permeable membrane should be 200-300 μ m These thick coatings lower the water permeation rate 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 .

MODIFICATIONS IN ELEMENTARY OSMOTIC PUMP:

MODIFICATIONS IN ELEMENTARY OSMOTIC PUMP first layer - made up of thick micro porous film that provides the strength required to withstand the internal pressure 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. Delivery orifice Drug chamber semi permeable membrane Outer microporous membrane COMPOSITE MEMBRANE COATING USED TO DELIVER MODERATELY SOLUBLE DRUGS microporous membrane

DELIVERY OF INSOLUBLE DRUG:

DELIVERY OF INSOLUBLE DRUG 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 x x x x x x x x x x x x x x Elastic SPM Rigid SPM Insoluble Particles

MULTICHAMBER OSMOTIC PUMPS:

MULTICHAMBER OSMOTIC PUMPS 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 the water is simultaneously drawn into both the chambers, causing an increase in volume of the chamber and forcing the drug out from the drug chamber. .

Drug delivery process of two chamber osmotic tablet PUSH PULL OSMOTIC PUMP:

Drug delivery process of two chamber osmotic tablet PUSH PULL OSMOTIC PUMP Osmotic Drug Core SPM Delivery Orifice Delivery Orifice Polymer push compartment Expanded push compartment Before operation During operation

DEVICES WITH A NON-EXPANDING SECOND CHAMBER:

DEVICES WITH A NON-EXPANDING SECOND CHAMBER This group subdivided into two subgroups depending upon the function of the second chamber. In one group the second chamber serves for the dilution of the drug solution leaving the device. This is important in cases where drugs causes irritation of GIT. Before the drug can exit from the device, it must pass through a second chamber.

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second group contains two separate simple OROS tablets formed into a single tablet. Two chambers contain two separate drugs both are delivered simultaneously. This system is also known as sandwiched osmotic tablet system (SOTS). sophisticated version of this device consists of two rigid chambers, one contains biologically inert osmotic agent such as sugar or NaCl, and the second chamber contains the drug. When exposed to aqueous environment, water is drawn into both chambers across the semi permeable membrane. The solution of osmotic agent then passes into the drug chamber through the connecting hole where it mixes with the drug solution. insoluble drugs can be delivered by this device. Osmotic agent containing chamber Semi permeable membrane orifice Drug containing chamber Microporous membrane Microporous membrane

LIQUID OSMOTIC SYSTEM (L-OROS):

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 require 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.

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other type of L-OROS system consists of a hard gelatin capsule containing a liquid drug layer, a barrier layer and a push layer surrounded by a semipermeable membrane. L-OROS hardcap system was designed to accommodate more viscous suspensions with higher drug loading Rate controlling membrane Push layer Inner Capsule Delivery orifice Inner Compartment Barrier layer

DUROS®:

DUROS ® continuous therapy for up to one year. The non-biodegradable intended for small drugs, peptides, proteins, DNA and other bioactive macromolecules for systemic or tissue-specific therapy. Viadur ® (leuprolide acetate implant), the first marketed product to incorporate DUROS ® , is indicated for the treatment of advanced prostate cancer. ADVANTAGES deliver highly concentrated and viscous formulations. Improved patient compliance Titanium protects the drug from enzymatic degradation. deliver a drug at a desired dosing rate with high degree of precision.

DUROS SYSTEM:

DUROS SYSTEM

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Affecting factors Compositions of osmotic agent Thickness of semipermeable membrane Surface area

CONTROLLED PORSITY OSMOTIC PUMPS:

CONTROLLED PORSITY OSMOTIC PUMPS Not having any aperture for release of drugs. The drug release is achieved by the pores, which are formed in the semi permeable wall in situ during the operation. The semi permeable coating membrane contains water-soluble pore forming agents. This membrane after formation of pores becomes permeable for both water and solutes. Coating Containing Pore Forming Agents Pore Formation and Subsequent Drug Release Aqueous Environment

SPECIFICATIONS FOR CONTROLLED POROSITY OSMOTIC PUMPS:

SPECIFICATIONS FOR CONTROLLED POROSITY OSMOTIC PUMPS Materials Specifications Plasticizers and flux regulating agents 0 to 50, preferably 0.001 to 50 parts per 100 parts of wall material Surfactants 0 to 40, preferably 0.001 to 40 parts per 100 parts of wall material Wall Thickness 1 to 1000, preferably 20 to 500μm Micro porous nature 5 to 95% pores between 10Å to 100μm Pore forming additives 0.1 to 60%, preferably 0.1 to 50%, by weight, based on the total weight of pore forming additive

SPECIFICATIONS FOR CORE OF CONTROLLED POROSITY OSMOTIC PUMPS:

SPECIFICATIONS FOR CORE OF CONTROLLED POROSITY OSMOTIC PUMPS Property Specifications Core loading (size) 0.05ng to 5g or more (include dosage forms for humans and animals) Osmotic pressure developed by a solution of core 8 to 500atm typically, with commonly encountered water soluble drugs and excipients Core solubility S/ρ, must be 0.1 or lower. Typically this occurs when 10% of the initially loaded core mass saturates a volume of external fluid equal to the total volume of the initial core mas s

ASYMMETRIC MEMBRANE COATED TABLETS:

ASYMMETRIC MEMBRANE COATED TABLETS Coatings have asymmetric structure for reverse osmosis or ultra filtration coating consists of a porous substrate with a thin outer membrane. Asymmetric tablet coating possesses some unique characteristics High water flux The permeability of the coating to water can be adjusted by controlling the membrane structure. The porosity of the membrane can be controlled to minimize the time lag .

FACTORS AFFECTING THE PERFORMANCE OF OSMOTIC DRUG DELIVERY SYSTEM:

FACTORS AFFECTING THE PERFORMANCE OF OSMOTIC DRUG DELIVERY SYSTEM Physico-chemical properties of the drug Solubility Solid or liquid Viscosity (Liquids) Rheological properties Properties of osmotic agent Osmotic pressure difference generated by the agent which ultimately will decide the water influx and in turn the delivery of active. Membrane type and characteristics Wet strength Water permeability Size of delivery orifice Characteristics of the polymer used (Hydration, Swelling)

IN VITRO EVALUATION:

IN VITRO EVALUATION in vitro release of drugs from oral osmotic systems is by conventional USP paddle basket type apparatus. The dissolution medium is distilled water simulated gastric fluid (for first 2-4 h) intestinal fluids (for subsequent hours) In vivo evaluation of oral osmotic systems in dogs(prefrred) Monkey

MARKET PRODUCTS:

MARKET PRODUCTS Products Incorporating ALZA's OROS® Technology Alpress™ LP (prazosin) once-daily extended-release tablet sold in France for the treatment of hypertension. Cardura ® XL (doxazosin mesylate) sold in Germany for the treatment of hypertension. Concerta ® (methylphenidate HCl) CII once-daily extended-release tablet for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients age six and older. Covera-HS ® (verapamil) a Controlled Onset Extended Release (COER-24™) system for the management of hypertension and angina pectoris. Ditropan XL ® (oxybutynin chloride) extended-release tablet for the once-a-day treatment of overactive bladder characterized by symptoms of urge urinary incontinence, urgency and frequency. DynaCirc CR ® (isradipine) once-daily, extended-release tablet for the treatment of hypertensi on.

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Efidac 24 ® (chlorpheniramine) over-the-counter, extended-release tablet providing 24-hour relief from allergy symptoms and nasal congestion. Glucotrol XL ® (glipizide) extended-release tablet used as an adjunct to diet for the control of hyperglycemia in patients with non-insulin-dependent diabetes. Sudafed ® 24 Hour (pseudoephedrine) over-the-counter nasal decongestant for 24-hour relief of colds, sinusitis, hay fever and other respiratory allergies. Procardia XL ® (nifedipine) extended-release tablet for the treatment of angina and hypertension. Volmax ® (albuterol) extended-release tablet for relief of bronchospasm in patients with reversible obstructive airway disease. Products Incorporating ALZA's DUROS ® Implant Technology Viadur ® (leuprolide acetate implant) delivers leuprolide continuously for 12 months as a palliative treatment for advanced prostate cancer.

Present and future trends:

Present and future trends Types of pump application disease drug refrence Osmotic pump Clinical studies Cancer pain hydromorphone Lesser et al.,1996 GITS Clinical studies Better plasma profile nifedipine Grundy and foster 1996 Osmotic pump Research Clinical neovascularisation VEGF Hopkins et al.,1998 OROS Clinical studies B 2 receptor Metaprolol Sandberg et al.,1993 Osmotic pump Reseach Decrease oedema Dexamethason Ikeda et al.,1993 Miniosmotic pump Research Leukemia Doxorubicin and verapimil Slate et al.,1993

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Types of pump application disease drug refrence osmotic pump Clinical studies Hypertensive,asthma Metaprolol Bauer et al.,1994 MOTS research Fungal infection Nystatin Encarnacion,1994 OROS Veterinary use Parasitic infestation Milbemycin Mckellar,1994 Osmotic pump Research Cv disoders Cv drugs Katz et al.,1995 Osmotic pump Research Depression Fluoxamine Boskar et al.,1995 Osmotic pump Clinical studies Hypertension Verapamil White et al.,1995

Conclusion:

Conclusion Therapeutic value of pharmaceutical product depend on 2 factors drug absorption profile Pharmacodyamics of drug Former depend on both dosage form technology and ability of git to to absorb drug Osmotic system technology has been extended to allow rate controlled drug delivery over wide range of aquous solubility of drug. Formulation of once daily can be achieve by osmotic system for short half life of drug Development of controlled porosity pump and asymmetric tablet coating may reduce the expenses over drilling of system

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