osmotic drug delivery system
TRANSCRIPT
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
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
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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.
• 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