OSMOTIC DRUG DELIVERY SYSTEM

LIST OF CONTENTS

INTRODUCTION ADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM REPORTED CASES REGARDING LIMITATIONS AND

ADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM PRINCIPLE OF OSMOSIS BASIC COMPONENTS OF OSMOTIC PUMPOSMOTIC PUMPS FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON

OSMOTIC PUMP) PHARMETRIX DEVICE HIGUCHI LEEPER OSMOTIC PUMPS HIGUCHI THEEUWES OSMOTIC PUMP ELEMENTARY OSMOTIC PUMP MULTICHAMBER OSMOTIC PUMPS CONTROLLED PORSITY OSMOTIC PUMPS

ASYMMETRIC MEMBRANE COATED TABLETS PULSATILE DRUG DELIVERY OSMOTIC PUMPS DELAYED-DELIVERY OSMOTIC DEVICES VOLUME AMPLIFIER DELIVERY DEVICE OSMOTIC DEVICES THAT USE SOLUBILITY MODIFIERS OSMOTIC DEVICES FOR USE IN ORAL CAVITY OSMOTIC DEVICE THAT DELIVER DRUG BELOW

SATURATION MISCELLANEOUS DEVICES SPECIALIZED COATINGSPROCESSING AND PERFORMANCE IMPROVEMENTIN VITRO EVALUATIONMARKET PRODUCTSREFERENCES

INTRODUCTION

Osmotic drug delivery uses the osmotic pressure of drug or other solutes (osmogens or osmagents) for controlled delivery of drugs. Osmotic drug delivery has come a long way since Australian physiologists Rose and Nelson developed an implantable pump in 1955.

ADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM

The delivery rate of zero-order (which is most desirable) is achievable with osmotic systems. Delivery may be delayed or pulsed, if desired.For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic conditions which is mainly attributed to the unique properties of semipermeable membrane (SPM) employed in coating of osmotic formulations.

Graph shows nifedipine release from push pull osmotic pump in artificial gastric and intestinal fluid. The release profile for both media are similar and not affected by pH.

ADVANTAGES

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

Figure shows the cummulative amount of nifidipine released from push pull osmotic pump (POPP) in vitro and in the GIT tract of dogs as a function of time.

ADVANTAGES

The release from osmotic systems is minimally affected by the presence of food in the gastrointestinal tract (GIT). This advantage is attributed to design of osmotic systems. Environmental contents do not gain access to the drug until the drug has been delivered out of the device.Production scale up is easy.

DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM

Toxicity due to dose dumping. Rapid development of tolerance. Additional patient education and counseling is

required. Hypersensitvity reaction may occur after

implantation.

REPORTED CASES REGARDING LIMITATIONS AND ADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM

During quality control of nifedipine GITS (Gastrointestinal therapeutic System) tablets, it was observed that several batches show different release patterns of the drug. It was found that non uniform coating around the tablet produced different membrane thicknesses, which was responsible for differences in release pattern among different patches.

Another case was reported for Osmosin (Indomethacin OROS), which was first introduced in UK in 1983. A few months after its introduction frequent incidences of gastointestinal reactions (hemorrhage and perforation)was observed by the Committee on the Safety of Medicines, and Osmosin was withdrawn from market.

PRINCIPLE OF OSMOSIS

Osmosis refers to the process of movement of solvent from lower concentration of solute towards higher concentration of solute across a semi permeable membrane.

Abbe Nollet first reported osmotic effect in 1748, but Pfeffer in 1877 had been the pioneer of quantitative measurement of osmotic effect.

Pfeffer measured the effect by utilizing a membrane which is selectively permeable to water but impermeable to sugar. The membrane separated sugar solution from pure water. Pfeffer observed a flow of water into the sugar solution that was halted when a pressure p was applied to the sugar solution. Pfeffer postulated that this pressure, the osmotic pressure π of the sugar solution is proportinal to the solution concentration and absolute temperature.

Van’t Hoff established the analogy between the Pfeffer results and the ideal gas laws by the expression

π = n2RT----------------------(1) Where n2 represents the molar concentration of sugar (or other

solute) in the solution, R depicts the gas constant, and T the absolute temperatue.

This equation holds true for perfect semipermeable membranes and low solute concentrations.

Another method of obtaining a good approximation of osmotic pressure is by utilizing vapour pressure measurements and by using expression:

π = RT ln (Po/P)/v -------- (2) Where Po represents the vapour pressure of the

pure solvent, P is the vapour pressure of the solution and v is the molar volume of the solvent. As vapour pressure can be measured with less effort than osmotic pressure this expression is frequently used.

Osmotic pressure for soluble solutes is extremely high. This high osmotic pressure is responsible for high water flow across semipermeable membrane.

The rate of water flow dictated by osmotic pressure can be given by following equation,

dV/dt = A θ Δπ/l ----------------------- (3) Where dV/dt represents the water flow across the

membrane area A and thickness l with permeability θ.

Δπ depicts the difference in osmotic pressure between the two solutions on either side of the membrane.

NOTE- This equation is strictly applicable for perfect semipermeable membrane, which is completely impermeable to solutes.

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

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

systems

Vs Vd

PUMP HOUSING

DELIVERY ORIFICEMOVABLE

PARTITION

SEMIPERMEABLE MEMBRANE

Vs is volume of osmotic agent compartment

Vd is volume of drug compartment

When a single osmotic driving agent is used, the pumping rate of the osmotic device of (volume per unit time) is defined by

Q/t = Pw Sm [γm (πs- πe)-(ΔPd+ΔPc)] ------------ (4) Pw is permeability of semi permeable membrane to water; Sm is effective surface area of the membrane; γm is osmotic reflection coefficient of the membrane; πs and πe are the osmotic pressure of saturated solution of

osmotic driving agent and of the environment where device is located, respectively;

ΔPd is elevation of internal pressure generated in the drug formulation compartment as the result of water influx into osmotic agent compartment;

ΔPc is pressure required to deform drug formulation compartment inward.

If the net osmotic pressure gradient [γm (πs- πe)] is constant and the hydrostatic pressure (ΔPd+ΔPc) is negligibly small, equation (4) can be simplified to:

Q/t = Pw Sm (πs- πe) -------------- (5)

And a zero order rate of drug release from osmotic device can be achieved if following conditions are met:

The amount of osmotic driving agent used is sufficient to maintain a saturated solution in the osmotic agent compartment i.e. πs is constant.

The environmental osmotic activity is either constant or negligibly small i.e. (πs- πe) ≈ constant.

The osmotic reflection coefficient is constant and very close to unity i.e. γm≈1. That means ideal semi permeable membrane, selectively permeable to water but not to osmotic drug agent, should be used.

A sufficiently large delivery orifice and a highly deformable partition should be used. So, ΔPd =ΔPc≈0.

BASIC COMPONENTS OF OSMOTIC PUMP

DRUGDrug itself may act as an osmogen

and shows good aqueous solubility (e.g., potassium chloride pumps).

But if the drug does not possess an osmogenic property, osmogenic salt and other sugars can be incorporated in the formulation.

OSMOGEN / OSMAGENT / OSMOTIC DRIVING AGENT

For the selection of osmogen, the two most critical properties to be considered are osmotic activity and aqueous solubility.

Osmotic agents are classified as,Inorganic water soluble osmogens:Magnesium

sulphate, Sodium chloride, Sodium sulpahte, Potassium chloride, Sodium bicarbonate,etc.

Organic polymeric osmogens:Na CMC, HPMC, HEMC, etc.

Organic water soluble osmogens:Sorbitol, Mannitol,etc.

SEMIPERMEABLE MEMBRANE

Semipermeable membrane must possess certain performance criteia:

It must have sufficient wet strength and water permeability. It should be selectively permeable to water and biocompatible. Cellulose acetate is a commonly employed semipermeable

membrane for the preparation of osmotic pumps. Some other polymers such as agar acetate, amylose

triacetate, betaglucan acetate, poly (vinylmethyl) ether copolymers, poly (orthoesters), poly acetals, poly (glycolic acid) and poly (lactic acid) derivatives.

The unique feature of semipermeable membrane utilized for an osmotic pump is that it permits only the passage of water into the unit, thereby effectively isolating the dissolution process from the gut environment.

HYDROPHILIC AND HYDROBHOBIC POLYMERS

These polymers are used in the formulation development of osmotic systems containing matrix core.

The selection of polymer is based on the solubility of drug as well as the amount and rate of drug to be released from the pump.

The highly water soluble compounds can be co-entrapped in hydrophobic matrices and moderately water soluble compounds can be co-entrapped in hydrophilic matrices to obtain more controlled release.

Examples of hydrophilic polymers are Hydroxy ethyl cellulose, carboxy methyl cellulose, hydroxyl propyl methyl cellulose, etc.

Examples of hydrophobic polymers are ethyl cellulose, wax materials, etc.

WICKING AGENTS

It is defined as a material with the ability to draw water into the porous network of a delivery device.

The function of the wicking agent is to draw water to surfaces inside the core of the tablet, thereby creating channels or a network of increased surface area.

Examples: colloidon silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide,sodium lauryl sulphate (SLS), low molecular weight polyvinyl pyrrolidone (PVP), bentonite, magnesium aluminium silicate, polyester and polyethylene,etc.

SOLUBILIZING AGENTS

Non swellable solubilizing agents are classified into three groups:Agents that inhibits crystal formation of the

drugs or otherwise act by complexation of drug (e.g., PVP, PEG, and cyclodextrins)

A high HLB micelle forming surfactant, particularly anionic surfactants (e.g., Tween 20, 60, 80, poly oxy ethylene or polyethylene containing surfactants and other long chain anionic surfactants such as SLS).

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

SURFACTANTS

They are added to wall forming agents. The surfactants act by regulating the surface

energy of materials to improve their blending in to the composite and maintain their integrity in the environment of use during the drug release period.

Examples: polyoxyethylenated glyceryl recinoleate, polyoxyethylenated castor oil having ethylene oxide, glyceryl laurates, etc.

COATING SOLVENTS

Solvents suitable for making polymeric solution that is used for manufacturing the wall of the osmotic device include inert inorganic and organic solvents.

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

PLASTICIZERS

Permeability of membranes can be increased by adding plasticizer, which increases the water diffusion coefficient.

Examples: dialkyl pthalates, trioctyl phosphates, alkyl adipates, triethyl citrate and other citrates, propionates, glycolates, glycerolates, myristates, benzoates, sulphonamides and halogenated phenyls.

FLUX REGULATORS

Flux regulating agents or flux enhancing agent or flux decreasing agent are added to the wall forming material; it assist in regulating the fluid permeability through membrane.

Poly hydric alcohols such as poly alkylene glycols and low molecular weight glycols such as poly propylene, poly butylene and poly amylene,etc. can be added as flux regulators.

PORE FORMING AGENTS

These agents are particularly used in the pumps developed for poorly water soluble drug and in the development of controlled porosity or multiparticulate osmotic pumps.

The pore formers can be inorganic or organic and solid or liquid in nature.

For example Alkaline metal salts such as sodium chloride,

sodium bromide, potassium chloride, etc. Alkaline earth metals such as calcium chloride and

calcium nitrate Carbohydrates such as glucose, fructose,

mannose,etc.

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

Drug Chamber

Elastic Diaphragm

Salt Chamber

Rigid Semi permeable membrane

Water Chamber

Delivery orifice

PHARMETRIX DEVICE

This device is composed of impermeable membrane placed between the semi permeable membrane and the water chamber.

These allows the storage of the pump in fully water loaded condition. The pump is activated when seal is broken. Water is then drawn by a wick to the membrane surface and pumping action begins.

This modification allows improved storage of the device, which on demand can be easily activated.

HIGUCHI LEEPER OSMOTIC PUMPS It has no water chamber, and the activation of the device occurs after

imbibition of the water from surrounding environment. It has a rigid housing. Widely employed for veterinary use. It is either swallowed or implanted

in body of an animal for delivery of antibiotics or growth hormones to animal.

Modification: A layer of low melting waxy solid, is used in place of movable separator to separate drug and osmotic chamber.

Porous Membrane Support

MgSO4

Movable Separator

Drug Chamber

Rigid Housing

Satd. Sol. OfMgSO4 contg.Solid MgSO4

Semi-permeable Membrane

HIGUCHI THEEUWES OSMOTIC PUMP

In this device, the rigid housing is consisted of a semi permeable membrane. The drug is loaded in the device only prior to its application, which extends advantage for storage of the device for longer duration.

The release of the drug from the device is governed by the salt used in the salt chamber and the permeability characteristics of outer membrane.

Diffusional loss of the drug from the device is minimized by making the delivery port in shape of a long thin tube.

Small osmotic pumps of this form are available under the trade name Alzet®.

Wall of flexible collapsible material

SPM

Coating contg. SolidOsmotic compound

Delivery port

Osmotic Agent layer

Rigid Semi permeableMembrane

Fluid to be pumped

Delivery port

Swollen Osmogen layer

Squeezed Drug Core

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

ALZET OSMOTIC PUMP ALZET OSMOTIC PUMP

ALZET OSMOTIC PUMP ALZET OSMOTIC PUMP ADVANTAGESADVANTAGES

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.

Principle of OperationPrinciple of Operation

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

ALZET pumps work by osmotic displacement. Water enters the pump across the outer, semi-permeable membrane due to the presence of a high concentration of sodium chloride in the osmotic chamber. The entry of water causes the osmotic chamber to expand, thereby compressing the flexible reservoir and delivering the drug solution through the delivery portal.

ALZETALZET®® Osmotic Pumps are available in three sizes Osmotic Pumps are available in three sizes

ALZET BRAIN INFUSION KITSALZET BRAIN INFUSION KITS

ELEMENTARY OSMOTIC PUMP

Rose Nelson pump was further simplified in the form of elementary osmotic pump(by Theeuwes,1975) which made osmotic delivery as a major method of achieving controlled drug release.

ELEMENTARY OSMOTIC PUMP (EOP)

Core containing agent

Delivery Orifice

Semi permeable membrane

It essentially contains an active agent having a suitable osmotic pressure.It is fabricated as a tablet coated with semi permeable membrane, usually cellulose acetate.A small orifice is drilled through the membrane coating. This pump eliminates the separate salt chamber unlike others. When this coated tablet is exposed to an aqueous environment, the osmotic pressure of the soluble drug inside the tablet draws water through the semi permeable coating and a saturated aqueous solution of drug is formed inside the device. The membrane is non-extensible and the increase in volume due to imbibition of water raises the hydrostatic pressure inside the tablet, eventually leading to flow of saturated solution of active agent out of the device through the small orifice. The process continues at a constant rate till the entire solid drug inside the tablet is eliminated leaving only solution filled shell. This residual dissolved drug is delivered at a slower rate to attain equilibrium between external and internal drug solution.

RELEASE PROFILES

• The mass delivery rate from the pump can be written as:

• Sd is concentration in drug compartment• πf is osmotic pressure of the drug formulation• A is surface area• h is thickness • k is permeability of membrane• πe is osmotic pressure of the environment which is negligible• So zero order release rate can be expressed as,

defz

SkhA

dtdm

dfz

SkhA

dtdmZ

PROBLEM

• Area of semi permeable membrane of an elementary osmotic pump is 2.7 cm2, thickness is 0.031 cm, permeability coefficient is 2.1*10-6 cm2/atm*h and the osmotic pressure is 225 atm, calculate the rate of delivery of the solute under zero-order conditions if the concentration of saturated solution at 37°C is 290 mg/ cm3?

dm/dt = (A/h)k(π) Cs = 2.7 cm2 / 0.031 cm × 2.1*10-6 cm2/atm*h × 225 atm × 290 mg/ cm3

= 11.93 mg/h

LIMITATION OF EOP

Generally in osmotic pumps the semi permeable membrane should be 200-300μm thick to withstand pressure with in the device.

These thick coatings lower the water permeation rate, particularly for moderate and poorly soluble drugs.

In general we can predict that these thick coating devices are suitable for highly water soluble drugs.

This problem can be overcome by using coating materials with high water permeabilities. For example, addition of plasticizers and water soluble additive to the cellulose acetate membranes, which increased the permeability of membrane up to ten fold.

MODIFICATIONS IN ELEMENTARY OSMOTIC PUMP• The first layer is made up of thick micro porous film that provides

the strength required to withstand the internal pressure, while second layer is composed of thin semi permeable membrane that produces the osmotic flux.

• The support layer is formed by:• Cellulose acetate coating containing 40 to 60% of pore

forming agent such as sorbitol.

Delivery orifice

Drug chamberInner microporous membrane

Outer semi permeable membrane

COMPOSITE MEMBRANE COATING USED TO DELIVER MODERATELY SOLUBLE DRUGS

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

xx

x

x

x

x

x

x

x

x

x

x

xx

Elastic SPM

Rigid SPM

Insoluble Particles

MULTICHAMBER OSMOTIC PUMPS

• Multiple chamber osmotic pumps can be divided into two major classes

a) Tablets with a second expandable osmotic chamber

b) Tablets with a non-expanding second chamber

a) Tablets with a second expandable osmotic chamber

• In the tablets with a second expandable osmotic chamber, the water is simultaneously drawn into both the chambers in proportion to their respective osmotic gradients, eventually causing an increase in volume of the chamber and subsequently forcing the drug out from the drug chamber.

• The matrix should have sufficient osmotic pressure to draw water through the membrane into the drug chamber. Under hydrated conditions matrices should have to be fluid enough to be pushed easily through a small hole by the little pressure generated by the elastic diaphragm.

• OROS® technology employs osmosis to provide precise, controlled drug delivery for up to 24 hours and can be used with a range of compounds, including poorly soluble or highly soluble drugs.

OROS ORAL DRUG DELIVERY TECHNOLOGY

Drug delivery process of two chamber osmotic tablet

Osmotic Drug Core

SPM

Delivery Orifice Delivery Orifice

Polymer push compartment Expanded push compartment

Before operation During operation

LIQUID OSMOTIC SYSTEM (L-OROS)

• A liquid formulation is particularly well suited for delivering insoluble drugs and macromolecules such as polysaccharide and polypeptides.

• Such molecules requie external liquid components to assist in solubilization, dispersion, protection from enzymatic degradation and promotion of gastrointestinal absorption.

• Thus the L-OROS system was designed to provide continuous delivery of liquid drug formulation and improve bioavailability of drugs.

• Another 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. The L-OROS hardcap system was designed to accommodate more viscous suspensions with higher drug loading than would be possible using softcap design.

Rate controlling membrane

Push layer

Inner Capsule

Delivery orifice

Inner Compartment

Barrier layer

LIQUID DRUG DELIVERY OTHER THAN L-OROS

USE OF POROUS PARTICLES• The controlled release of liquid

active agent formulations is provided by dispersing porous particles that contain the liquid active agent formulation in osmotic push-layer dosage forms.

• The liquid active agent formulations may be absorbed into the interior pores of the material in significant amounts and delivered to the site of administration in the liquid state.

• Microcrystalline cellulose, porous sodium carboxymethyl cellulose, porous soya bean fiber and silicon dioxide—all of which have high surface area and good absorption properties— and can be used indosage form described here in.

OROS TRI-LAYER

DUROS®

• DUROS® implants are designed to bring the benefit of continuous therapy for up to one year. The non-biodegradable, osmotically driven system is intended to enable delivery of 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 palliative treatment of advanced prostate cancer.

ADVANTAGES• Can deliver highly concentrated and viscous formulations.• Improved patient compliance• Titanium protects the drug from enzymatic degradation.• The system can be engineered to deliver a drug at a

desired dosing rate with high degree of precision.

DUROS SYSTEM

• Affecting factors– Compositions of osmotic agent

– Thickness of semipermeable membrane

– Surface area

b) DEVICES WITH A NON-EXPANDING SECOND CHAMBER:

• This group can be 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. Water is also drawn osmotically into this chamber either due to osmotic pressure of the drug solution or because the second chamber that bears water-soluble diluents such as sodium chloride.

Drug

Interior Orifice

Drug in diluted soln.

Wall

Second Compartment

Interiorwall

First Compartment

Exit Orifice

• The second group of non-expanding multichamber devices essentially 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).

• A more 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 before escaping through the micro porous membrane that forms part of the wall around the drug chamber. Relatively insoluble drugs can be delivered using this device.

Osmotic agent containing chamber

Semi permeable membrane

orifice

Drug containing chamber

Microporous membrane

CONTROLLED PORSITY OSMOTIC PUMPS

They are 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

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 and polymerpH insensitive pore forming additive (solid or liquid) preferably 0.1 to 40% by weight

SPECIFICATIONS FOR CORE OF CONTROLLED POROSITY OSMOTIC

PUMPSProperty 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 To get continuous, uniform release of 90% or greater of the initially loaded core mass solubility, S, to the core mass density, ρ, that is 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 mass

ASYMMETRIC MEMBRANE COATED TABLETS

Here, the coatings have an asymmetric structure, similar to asymmetric membranes made for reverse osmosis or ultra filtration, in that the coating consists of a porous substrate with a thin outer membrane.

Asymmetric tablet coating possesses some unique characteristics, which are more useful in development of osmotic devices they are as follows:

High water fluxes can be achieved. 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 before drug delivery begins and allowing the drug to be released from large number of delivery ports.

PULSATILE DRUG DELIVERY

• Delivering a drug in one or more pulses is sometimes beneficial, from the required pharmacological action point of view.

• Mechanical and drug solubility–modifying techniques have been implemented to achieve the pulsed delivery of drugs with an osmotic system.

SOLUBILITY MODULATION FOR PULSED RELEASE

The composition described in the patents comprised the drug salbutamol sulfate and modulating agent sodium chloride.

Pulsed delivery is based on drug solubility. Salbutamol’s solubility is 275 mg/mL in water and 16 mg/mL in a saturated solution of sodium chloride. Sodium chloride’s solubility is 321 mg/mL in water and 320 mg/mL in a saturated solution. These values show that the solubility of the drug is a function of the modulator concentration, whereas the modulator’s solubility is largely independent of the drug concentration.

The tablet is similar to elementary osmotic pump, with a mixture of salbutamol and sodium chloride in the tablet core.

The release profile of the device is constant for salbutamol until the sodium chloride becomes exhausted, afterwards the remaining drug is delivered as a large pulse.

This rlease pattern is exploited for nocturnal asthma in which pulsatile delivery of salbutamol is desirable.

PULSATILE DELIVERY BASED ON AN EXPANDABLE ORIFICE.

• The system is in the form of a capsule from which the drug is delivered by the capsule’s osmotic infusion of moisture from the body.

• The delivery orifice opens intermittently to achieve a pulsatile delivery effect. The orifice forms in the capsule wall, which is constructed of an elastic material.

• As the osmotic infusion progresses, pressure rises within the capsule, causing the wall to stretch.

• Elastomers such as styrene-butadiene copolymer can be used.

Osmogen Semi permeable Membrane

Separating Barrier

Elastic Cap

Movable piston

Drug Solution

Tiny orifice opened upon stretches under theOsmotic pressure

PORT SYSTEM•The Port® System (Port Systems, LLC) consists of a gelatin capsule coated with a semipermeable membrane (eg, cellulose acetate) housing an insoluble plug (eg, lipidic) and an osmotically active agent along with the drug formulation.

•When in contact with the aqueous medium, water diffuses across the semipermeable membrane, resulting in increased inner pressure that ejects the plug after a lag time. The lag time is controlled by coating thickness. The system showed good correlation in lag times of in-vitro and in-vivo experiments in humans.

DELAYED-DELIVERY OSMOTIC DEVICES

Because of their semipermeable walls, osmotic devices inherently show a lag time before drug delivery begins. Although this characteristic is usually cited as a disadvantage, it can be used advantageously.

The delayed release of certain drugs (e.g., drugs for early morning asthma or arthritis) may be beneficial. The following slides describes other means to further delay drug release.

TELESCOPIC CAPSULES FOR DELAYED RELEASE

The dispenser comprises a housing that has first- and second-wall sections in a slideable telescoping arrangement.

The housing maintains integrity in its environment of use. The device consists of two chambers; the first contains the drug

and an exit port, and the second contains an osmotic engine. A layer of wax-like material separates the two sections.

To assemble the delivery device, the desired active agent is placed into one of the sections by manual- or automated-fill mechanisms.

The bilayer tablet with the osmotic engine is placed into a completed cap part of the capsule with the convex osmotic layer pointed into the closed end of the cap and the barrier layer exposed toward the cap opening. The open end of the filled vessel is fitted inside the open end of the cap, and the two pieces are compressed together until the cap, osmotic bilayer tablet, and vessel fit together tightly.

As fluid is imbibed through the housing of the dispensing device, the osmotic engine expands and exerts pressure on the slideable connected first and second wall sections.

During the delay period, the volume of the reservoir containing the active agent is kept constant; therefore, a negligible pressure gradient exists between the environment of use and the interior of the reservoir. As a result, the net flow of environmental fluid driven by the pressure to enter the reservoir is minimal, and consequently no agent is delivered for the period.

A delayed release telescopic capsule release contents after expansion.

Second Wallsection

Drug

Internal Compartment

First wallsection

Push plates

Push means

DELAYED-RELEASE DELIVERY BASED ON MULTIPLE COATINGS

The osmotically driven pump can be miniaturized to a size suited for swallowing or implanting. The pump may be used to administer a drug in a fluid form after an initial activation period during which essentially no drug is administered.

The basic components of the pump are semi permeable membrane (SPM) that encapsulates an osmotically effective solute and drug and a discharge port through which the drug is dispensed. A micro porous outer cover surrounds the SPM and protects it from an external aqueous environment.

A water-swellable composition is positioned between the end of the SPM and the outer cover.

As the pump is placed in an aqueous environment, water from the environment passes through the micro porous portion of the outer cover into the water swellable composition. The water swellable composition absorbs water, expands, and in piston-like fashion displaces the outer cover, thereby exposing the SPM to the aqueous environment and activating the osmotic pump.

The time required for the water-swellable composition to absorb water, expand, and displace the outer cover provides an initial activation period during which essentially no drug is delivered by the pump.

By suitably adjusting the membrane composition and structure, a predetermined activation period in the range of 3–18 h is achieved.

ENTERIC AND COLON TARGETED OSMOTIC DOSAGE FORMS

Use of osmotic systems for the pH triggered burst of the active agent is disclosed.

The devices are designed for oral administration, either in the form of tablets or capsules.

If used in tablets, the core consists of the drug, osmagent, diluents, and superdisintegrants. The tablets are coated first by SPM walls of insufficient thickness and then overcoated with the pH-triggered coating solution.

The pH-triggered solution contains polymers such as cellulose acetate phthalate, pH-sensitive Eudragit grades, and insoluble polymers. The patent claims that using only pH-sensitive materials to achieve site-specific delivery is difficult because the drug often leaks out of the dosage form before it reaches the release site or desired delivery time.

VOLUME AMPLIFIER DELIVERY DEVICE

One of the limitations with osmotic devices, is the incomplete release of the drug.

Here we will see the use of volume amplifiers to deliver the entire drug contained in the system.

The device consists of a core, an SPM, and a delivery orifice. In addition to the drug and the osmagent, the compartment contains a volume amplifier to increase the amount of agent delivered from the system.

The amplifier consists of a membrane surrounding a gas-generating couple with the membrane formed of an expandable material that is permeable to fluid and impermeable to the couple.

Gas generating couple

Volume Amplifier

Gas

EFFERVESCENT ACTIVITY-BASED SYSTEMS

• The osmotic device comprises a semi permeable wall that surrounds a compartment housing a drug that exhibits limited solubility under neutral and acid conditions and a compound capable of releasing carbon dioxide in the presence of an acid.

• As fluid is imbibed through the wall into the compartment at a rate determined by the wall’s permeability and the osmotic pressure gradient across the wall, a basic solution containing drug and compound is formed, which is delivered from the compartment through the passageway.

• The released compound reacts with the acid in the environment at the device–environment interface and evolves carbon dioxide, thereby providing an effervescent suspension that delivers the drug to the environment in a finely dispersed form over time. Thus the agent is delivered in a form that is rapidly absorbed and does not block the orifice of the delivery device.

• Drugs that can be delivered by such a system are those that exhibit a propensity for rapid precipitation in an environment that has a pH less than 7 (e.g., the stomach). A few examples are the anti-inflammatory arylcarboxylicacids such as indomethacin, aspirin, diclofenac, fenoprofen, flufenamic acid and prioxicam.

• The osmotic device without the compound releases the drug in the presence of an artificial gastric fluid containing hydrochloric acid; however, the drug precipitates onto the wall of the device and the exit port of the passageway and is therefore not observed in the fluid of the environment. This problem is rectified with the use of an effervescent system.

OSMOTIC DEVICES THAT USE SOLUBILITY MODIFIERS

For slightly soluble drug carbamazepine System consists of a core, crystal habit modifier

and osmotic driving agent. Crystal habit modifying agent is useful only when

drug exists in more than one crystalline form and when desired form of the drug is not the most stable form.

Crystal modifying agent modifies the solubility of the drug.

The change in solubility should be significant.

For slightly soluble drugThe core consists of a drug with limited

solubility in water or physiological environments, a nonswelling solubilizing agent to enhance the solubility of the drug, and an osmagent.

In addition, a nonswelling wicking agent is dispersed throughout the composition. A delivery system for nifedipine used colloidal silicon dioxide, polyvinylpyrrolidone, and sodium lauryl sulfate as nonswelling wicking agents.

For sparingly soluble drug The core consists of an active ingredient that is

sparingly soluble in water, a hydrophilic polymeric swelling agent composed of a mixture of a vinylpyrrolidone–vinyl acetate copolymer with an ethylene oxide homopolymer, and a water-soluble substance for inducing osmosis.

This mixture has the surprising advantage that pressure produced during swelling does not cause the system to rupture and that the swelling speed is uniform, which allows almost constant amounts of active ingredient to be released from the system. Theophylline, aspirin, carbamazepine and nifedipine have been delivered by this system.

Use of Vitamin E tocopheryl polyethylene glycol succinate (TPGS)

Vitamin E tocopheryl polyethylene glycol succinate (TPGS)–drug compositions to obviate the need for surfactants or nonevaporated cosolvents. The advantage of using a TPGS–drug solid solution is that insoluble drugs can be considered soluble for the purpose of getting the drug out of the osmotic device.

Cyclosporine has been cited as an example in patent.

OSMOTIC DEVICES FOR USE IN ORAL CAVITY

Unique advantage of nicotine delivery by an oral osmotic device.

• The system consists of a nicotine salt and an optional alkaline salt, which is capable of reacting with the nicotine salt in the presence of water to form a nicotine base. The conversion of nicotine salt to a nicotine base may take place within or outside the device and in the patient’s mouth. The nicotine base or salt is delivered from the compartment through a passageway in the wall.

• The advantage is that nicotine salt exhibits good stability and a long shelf life, and the nicotine base exhibits excellent absorption through oral mucosal membranes.

OSMOTIC DEVICE THAT DELIVER DRUG BELOW SATURATION

• These types of delivery devices are useful for dispensing drugs that are irritants to mucosal and GIT tissue such as potassium chloride, aspirin, and indomethacin.

• The system comprises a first wall of a semi permeable material that surrounds a compartment containing a drug formulation and has a passageway through the wall for releasing agent from the compartment. A second wall is positioned away from the first wall and is constructed of a micro porous or hydrogel material. Because of the distance between the two walls, a distribution zone interposed between the first and second walls exists

MISCELLANEOUS DEVICES• The device has a centrally located expandable core that is completely

surrounded by an active substance-containing layer, which is completely surrounded by a membrane.

• The core consists of an expandable hydrophilic polymer and an optional osmagent. The composition immediately surrounding the core comprises an active substance, an osmagent, and an osmopolymer. The membrane is micro porous in nature and may have a delivery orifice.

• The device is capable of delivering insoluble, slightly soluble, sparingly soluble, and very soluble active substances to the environment.

Exit Orifice

Microporous membrane

CoreActive Agentlayer

SPECIALIZED COATINGS

• The wall in this case is formed of a semipermeable hydrophobic membrane that has pores in the wall. The pores are substantially filled with a gas phase. The hydrophobic membrane is permeable to water in the vapor phase and is impermeable to an aqueous medium at pressures less than 100 Pa. The drug is released by osmotic pumping or osmotic bursting upon the imbibition of sufficient water vapor into the device core.

• These devices minimize incompatibilities between the drug and the ions (such as hydrogen or hydroxyl) or other dissolved or suspended materials in the aqueous medium because contact between the drug and the aqueous medium does not occur until after the drug is released, which results from the SPM’s selective permeability for water vapor.

FACTORS AFFECTING THE PERFORMANCE OF OSMOTIC DRUG

DELIVERY SYSTEM

Physico-chemical properties of the drug• Solubility• Solid or liquid• Viscosity (Liquids)• Rheological propertiesProperties 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 permeabilitySize of delivery orificeCharacteristics of the polymer used (e.g. Hydration,

Swelling etc.)

PROCESSING AND PERFORMANCE IMPROVEMENT

Improvement of adhesion between core and semipermeable membrane.

• The tablet core containing the drug and other required components is evenly coated with a discrete layer of a water-soluble (or water-dispersible) and water-permeable non osmotically active solid polymeric binder to a level of less than10%.

• The SPM is then coated on the tablet. Enhancing the startup and performance of osmotic drug

delivery systems.• The osmotic delivery system should include a liquid or gel

additive that surrounds the osmotic agent to enhance startup and lubricate the osmotic agent.

• The liquid or gel additive is an incompressible lubricating fluid that fills any air gaps between the osmotic agent and the walls of a chamber and substantially reduces startup delays.

IN VITRO EVALUATION

• The in vitro release of drugs from oral osmotic systems has been evaluated by the conventional USP paddle and basket type apparatus.

• The dissolution medium is generally distilled water as well as simulated gastric fluid (for first 2-4 h) and intestinal fluids (for subsequent hours) have been used.

• The standard specifications, which are followed for the oral controlled drug delivery systems are equivalently applicable for oral osmotic pumps.

• In vivo evaluation of oral osmotic systems has been carried out mostly in dogs. Monkeys can also be used but in most of the studies the dogs are preferred.

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 hypertension.

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.

Advantages and disadvantages of osmotic drug delivery system. (2 marks)

Basic components of osmotic pump (2 marks)

Modification of elementary osmotic pump (2 marks)

Oros technology in detail (5 marks)Factors affecting performance

characteristics of osmotic pump (2 marks)

Note on controlled porosity pumps (2 marks) Note on pulsatile and delayed release osmotic

pumps (10 marks) In vitro evaluation of osmotic pumps (2 marks) Note on processing and performance

improvement. (5 marks)

Verma R., Mishra B. and Garg S., Osmotically controlled oral drug delivery; Drug Development and Industrial Pharmacy, 26(7), 695-708 (2000)

Kaushal M.and Garg S., “ An Update on Osmotic Drug Delivery Patents”; Pharmaceutical Technology, August 2003 38-45.

Theeuwes F.,”Elementary Osmotic Pump”, Journal of Pharmaceutical Science;64(12):1987-1991(1975).

Theeuwes F., Journal of Pharmaceutical Science;72:253(1983).

Chein Y., Novel Drug Delivery Systems:398-407

Wong P.,Gupta S. and Stewart B. Modified Release Drug Delivery Technology: Osmotically controlled tablets:101-114

Fara J. and and Ray N.; Drug Delivery Devices, Fundamentals and Applications, :137-175

Santus G., and Baker R., “Osmotic Drug Delivery: A Review of the Patent Literature,” J. Controlled Release 35, 1–21 (1995).

Swarbrick J. and Boylan J, “Encyclopedia of Pharmaceutical Technology”, Vol. 3: 297-300

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