JAIPUR NATIONAL UNIVERSITYSchool of Pharmaceutical science

OSMOTIC DRUG DELIVRY SYSTEM

SUPERVISED BY SUBMITTED BY

Mr.Ajay tiwari Vineet gupta

Professor, M.Pharma, 2nd Sem(P.ceutics)

School of Pharmaceutical Sciences, JNU, Jaipur

Jaipur National University, Jaipur.

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

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

Osmotic pressure

• pressure required to prevent the passage

of water through a selective permeable

membrane and into solution of greater

concentration.

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

• Reduced inter patient variability

• Decreased dosing frequency

• Improove patient compliance

• Reduced side effect

Disadvantages

• Expensive

• Rapid development of tolerance

• Chance of toxicity due to dose dumping

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.

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

Van’t Hoff established the analogy between the

Pfeffer results and the ideal gas laws

π = n2RT…….(2)

n2 =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.

Measurement of osmotic pressure by utilizing vapour pressure measurements

π = RT ln (Po/P)/v…….(3)

Po = 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.

The rate of water flow dV/dt = A θ Δπ/l…….(4)

• dV/dt = the water flow across the membrane area A and thickness l with permeability θ

• Δπ = 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

Vs Vd

PUMP HOUSING

DELIVERY ORIFICEMOVABLE

PARTITION

SEMIPERMEABLE MEMBRANE

Vs is volume of osmotic agent compartment

Vd is volume of drug compartment

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

Drugs• Short biological half life

• Highly potent drug

• Required for prolong treatment

• Eg. Nifedipine , virapamil

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• MgSo4

• NaCl

• KCl

• NaHCo3

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

• 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

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%

Other polymers

• Agar acetate

• Amylose triacetate

• Betaglucan acetate

• Polyacetals

• Polyether coplymer

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 • 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 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)

Combination of complexing agent and anionic surfactant

• PVP with SLS

• Polyethylene glycol with SLS

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 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

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 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 (Cacl2 and calcium nitrate)

Carbohydrates (glucose, fructose, mannose)

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(ethyl cellulose) wax materials, etc.

Osmotic drug delivery devices

• There are two categories

1.Implantable

I. The rose and nelson pump

II.Higuchi – leeper pump

III.Higuchi –theeuwas pump

IV.Implantable mini osmotic pump

2. Oral osmotic pump

i. Single chamber osmotic pump

ii.Elementary osmotic pump

iii.Multichamber osmotic pump

iv.Push pull osmotic pump

v.Osmotic pump with nonexpending second chamber

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

Drug Chamber

Elastic Diaphragm

Salt Chamber

Rigid Semi permeable membrane

Water Chamber

Delivery orifice

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

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 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

MgSO4

Movable Separator

Drug Chamber

Rigid Housing

Satd. Sol. OfMgSO4 contg.Solid MgSO4

Semi-permeable Membrane

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. SolidOsmotic compound

Delivery port

Osmotic Agent layer

Rigid Semi permeableMembrane

Fluid to be pumped

Delivery port

Swollen Osmogen layer

Squeezed Drug Core

• Small osmotic pumps of this form are available under

the trade name ALZETALZET®®

Modification of Higuchi theeuwes pump Modification of Higuchi theeuwes pump

• Uses mixure of citric acid and NaHCoUses mixure of citric acid and NaHCo3 3 to generate to generate

pressure required for delivery of drugpressure required for delivery of drug

• When exposed to water ,the mixture produces CoWhen exposed to water ,the mixture produces Co2 2

gas which exerts pressure on elastic diaphragm and gas which exerts pressure on elastic diaphragm and

deliver drug from device .deliver drug from device .

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 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.

• 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

Rose Nelson pump was further simplified in

the form of elementary osmotic pump(by

Theeuwes,1975) .

ELEMENTARY OSMOTIC PUMP (EOP)

Core containing agent

Delivery Or i f ice

Semi permeable membrane

Fabricated as a tablet coated with semi permeable membrane

(cellulose acetate).

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 ⋅−⋅= ππ

( ) [ ] dfz

SkhA

dtdmZ ⋅⋅⋅== π

LIMITATION OF EOP

semi permeable membrane should be 200-300μm 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

• 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 chambersemi permeable membrane

Outer microporous membrane

COMPOSITE MEMBRANE COATING USED TO DELIVER MODERATELY SOLUBLE DRUGS

microporous membrane

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 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 tabletPUSH 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

• 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.

• 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)

• 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.

• 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®

• 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

• Affecting factors– Compositions of osmotic agent

– Thickness of semipermeable membrane

– Surface area

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

Materials Specif ications

Plasticizers and f lux 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 addit ives 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

Property Specif ications

Core loading (size) 0.05ng to 5g or more (include dosage forms for humans and animals)

Osmotic pressure developed by a solut ion of core

8 to 500atm typically, with commonly encountered water soluble drugs and excipients

Core solubil i ty 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

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

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 permeability

Size of delivery orificeCharacteristics of the polymer used (Hydration, Swelling)

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

• 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.

Present and future trendsTypes 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

B2 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

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

ConclusionTherapeutic 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