crdf-1
DESCRIPTION
controlled release drug delivery systemsTRANSCRIPT
A Seminar on A Seminar on
Control Release Oral Drug Delivery SystemControl Release Oral Drug Delivery System
By: By: Uday Sharma Uday Sharma
Dept. of Pharmaceutics Dept. of Pharmaceutics Al Ameen college of PharmacyAl Ameen college of Pharmacy
ContentsContentsIntroduction Introduction
Advantages & Disadvantages Advantages & Disadvantages
Design and Fabrication of Oral SystemsDesign and Fabrication of Oral Systems Dissolution controlled releaseDissolution controlled release Diffusion control release Diffusion control release Diffusion & Dissolution controlled release Diffusion & Dissolution controlled release Ion exchange ResinsIon exchange Resins pH – independent formulation pH – independent formulation Osmotically controlled releaseOsmotically controlled release Hydrodynamically balanced system Hydrodynamically balanced system
IntroductionIntroduction
Controlled releaseControlled release describes a system in which describes a system in which the rate of drug’s release is more precisely the rate of drug’s release is more precisely controlled compared to sustained release productcontrolled compared to sustained release product
oror Delivery of the drug at predetermined rate or /to a Delivery of the drug at predetermined rate or /to a
location according to the need of the body / disease location according to the need of the body / disease state for a definite time period. state for a definite time period.
Drug delivery systemsDrug delivery systems refer to the technology refer to the technology utilized to present the drug to the desired body site utilized to present the drug to the desired body site for drug release and absorptionfor drug release and absorption
Advantages of oral controlled-releaseAdvantages of oral controlled-release
Decreased fluctuation in circulating drug levels, resulting in Decreased fluctuation in circulating drug levels, resulting in reduced toxicity and sustained efficacyreduced toxicity and sustained efficacy
Decreased frequency of dosing.Decreased frequency of dosing.
Increased patient compliance.Increased patient compliance.
Avoidance of night time dosingAvoidance of night time dosing
Reduced patient care time.Reduced patient care time.
Reduction in GI irritation Reduction in GI irritation
Disadvantages of oral controlled-releaseDisadvantages of oral controlled-release
Longer time to achieve therapeutic blood concentrations.Longer time to achieve therapeutic blood concentrations.
Increased variation in bioavailability.Increased variation in bioavailability.
Enhanced first-pass effect.Enhanced first-pass effect.
Dose-dumping.Dose-dumping.
Sustained concentration in overdose cases.Sustained concentration in overdose cases.
Lack of dosage flexibility.Lack of dosage flexibility.
Greater expense.Greater expense.
Properties of drug not suitable for controlled-release Properties of drug not suitable for controlled-release formulationformulation
Very short or very long half-life.Very short or very long half-life.
Narrow therapeutic window.Narrow therapeutic window.
Poor absorption Poor absorption
Low solubility.Low solubility.
Drug concentration not related to pharmacologic or therapeutic Drug concentration not related to pharmacologic or therapeutic effect.effect.
Extensive first pass clearance.Extensive first pass clearance.
Design and Fabrication of Oral SystemsDesign and Fabrication of Oral Systems
Dissolution controlled releaseDissolution controlled release
Diffusion controlled releaseDiffusion controlled release
Diffusion & Dissolution controlled release Diffusion & Dissolution controlled release
Osmotically controlled releaseOsmotically controlled release
Hydrodynamically balanced system deviceHydrodynamically balanced system device
pH – independent formulationpH – independent formulation
Hydrodynamically balanced system Hydrodynamically balanced system
Ion exchange ResinsIon exchange Resins
Dissolution controlled ReleaseDissolution controlled Release
Simplest to prepare.Simplest to prepare.
Drug with a slow dissolution rate is inherently sustained.Drug with a slow dissolution rate is inherently sustained.
Example: digoxin, griseofulvin, salicylamide.Example: digoxin, griseofulvin, salicylamide.
Drugs which produce slow dissolving form when come in Drugs which produce slow dissolving form when come in contact with G.I fluid or absorption pool. contact with G.I fluid or absorption pool.
Example: aluminum aspirin, ferrous sulfateExample: aluminum aspirin, ferrous sulfate..
PrinciplePrinciple
The rate of diffusion from the solid surface to the bulk solution : The rate of diffusion from the solid surface to the bulk solution : rate limitingrate limiting
Flux= (diffusion coefficient) x (concentration gradient) Flux= (diffusion coefficient) x (concentration gradient) J = - D (dc / dx)J = - D (dc / dx) OR OR Flux = flow rate of material (dm / dt ) through a unit area ( A )Flux = flow rate of material (dm / dt ) through a unit area ( A ) J = ( 1 / A ) dm / dt J = ( 1 / A ) dm / dt
If the concentration gradient is linear and thickness of the If the concentration gradient is linear and thickness of the diffusion layer is hdiffusion layer is h
dc / dx = ( Cdc / dx = ( Cbb – C – Css ) / h ) / h
Where: CWhere: Css – concentration at solid surface. – concentration at solid surface.
C Cbb – concentration in the bulk solution – concentration in the bulk solution..
Combining the above equation Combining the above equation
Flow rate of the material is given by:Flow rate of the material is given by:
dm/dt = - ( D A /h ) ( Cdm/dt = - ( D A /h ) ( Cbb – C – Cs s ) = kA (C) = kA (Css – C – Cbb))
WhereWhere
k – Intrinsic dissolution rate constant.k – Intrinsic dissolution rate constant. This equation predicts constant dissolution rate, if all This equation predicts constant dissolution rate, if all
variables are constant.variables are constant.
Dissolution controlled system is of two typeDissolution controlled system is of two type
En-capsulation dissolution control.En-capsulation dissolution control.
Matrix dissolution control.Matrix dissolution control.
Encapsulation Dissolution controlEncapsulation Dissolution control
Drug coated with slowly dissolving polymeric materialDrug coated with slowly dissolving polymeric material
Drug release control by adjusting the thickness and Drug release control by adjusting the thickness and dissolution rate of membranedissolution rate of membrane
Membrane-coated particles: compressed into tablet or placed Membrane-coated particles: compressed into tablet or placed in capsules.in capsules.
Encapsulation dissolution control is of two types:Encapsulation dissolution control is of two types:
microcapsulation microcapsulation
Seed or granules coated products.Seed or granules coated products.
MICROCAPSULATION MICROCAPSULATION
Defined as a means of applying relatively thin coatings to small Defined as a means of applying relatively thin coatings to small particles of solid or droplets of liquids and dispersionsparticles of solid or droplets of liquids and dispersions
Provides a means of converting liquids to solids, Provides a means of converting liquids to solids,
altering colloidal and surface properties,altering colloidal and surface properties,
providing environmental protection, providing environmental protection,
controlling release characteristics or availability of coated controlling release characteristics or availability of coated material material
example: example:
Aspirin encapsulated forAspirin encapsulated for
Taste-maskingTaste-masking
Sustained releaseSustained release
Reduced gastric irritationReduced gastric irritation
Separation in case of incompatibilities-such as Separation in case of incompatibilities-such as CPMCPM
ApplicationsApplications
Sustained releaseSustained release
Taste masking chewable tabletTaste masking chewable tablet
Powders and suspensionsPowders and suspensions
Single layered tablets containing chemically incompatible Single layered tablets containing chemically incompatible ingredientsingredients
New formulation concepts for creams, ointments, aerosols, New formulation concepts for creams, ointments, aerosols, dressings, plasters, suppositories and injectablesdressings, plasters, suppositories and injectables
Drawbacks Drawbacks
Incomplete or discontinuous coating.Incomplete or discontinuous coating.
Inadequate stability or shelf life of sensitive pharmaceutical Inadequate stability or shelf life of sensitive pharmaceutical products.products.
Non – reproducible and unstable characteristic of coated Non – reproducible and unstable characteristic of coated product.product.
Economic limitation.Economic limitation.
Polymers for micro-encapsulationPolymers for micro-encapsulation
Water-soluble resinsWater-soluble resins
Water-insoluble resinsWater-insoluble resins
Waxes and lipidsWaxes and lipids
Water-soluble resinsWater-soluble resinsGelatinGelatin
Povidone (PVP)Povidone (PVP)
CMCCMC
HECHEC
MCMC
PVAPVA
Water-insoluble resinsWater-insoluble resins
Ethyl celluloseEthyl cellulose
Polyamide (Nylon)Polyamide (Nylon)
PolyethylenePolyethylene
Cellulose nitrateCellulose nitrate
Waxes and lipidsWaxes and lipids
ParaffinParaffin
CarnaubaCarnauba
BeeswaxBeeswax
Stearic acidStearic acid
Stearyl alcoholStearyl alcohol
Methods of micro-encapsulationMethods of micro-encapsulation
Pan coatingPan coating
Air suspension coatingAir suspension coating
Coacervation-phase separationCoacervation-phase separation
Spray drying and congealingSpray drying and congealing
Multi-orifice centrifugalMulti-orifice centrifugal
In-situ-polymerizationIn-situ-polymerization
Pan CoatingPan Coating
Consists of applying coating solution to the Consists of applying coating solution to the solid core material in a coating pansolid core material in a coating pan
Core material can be NPS or granules or Core material can be NPS or granules or particles or particles greater than 600 µ in sizeparticles or particles greater than 600 µ in size
Air SuspensionAir Suspension
Also called Wurster processAlso called Wurster process
Consists of dispersing of solid, particulate core Consists of dispersing of solid, particulate core materials is a supporting air stream and spray-materials is a supporting air stream and spray-coating of air-suspended particlescoating of air-suspended particles
Process variables Process variables
Physical properties of core materialPhysical properties of core material
Concentration of coating materialConcentration of coating material
Application rate of coating materialApplication rate of coating material
Volume of airVolume of air
Amount of coating material requiredAmount of coating material required
Inlet and outlet operating tempInlet and outlet operating temp
ApplicationsApplications
Wide variety of coating materials can be appliedWide variety of coating materials can be applied
Solvent solutionsSolvent solutions
Aqueous solutionsAqueous solutions
EmulsionsEmulsions
Dispersions etc Dispersions etc
Air suspension coating is applicable to both Air suspension coating is applicable to both micro-micro-encapsulationencapsulation and and macro-encapsulationmacro-encapsulation
Coacervation-Phase SeparationCoacervation-Phase Separation
Consists of three steps carried out under constant agitation:Consists of three steps carried out under constant agitation:
Formation of three immiscible chemical phasesFormation of three immiscible chemical phases
Deposition of coating andDeposition of coating and
Rigidization of coatingRigidization of coating
Step 1Step 1
Formation of three immiscible chemical phases:Formation of three immiscible chemical phases:
A liquid manufacturing vehicle phaseA liquid manufacturing vehicle phase
A core material phase A core material phase
A coating material phaseA coating material phase
To form the three phases, To form the three phases,
Core material is dispersed in a solution of Core material is dispersed in a solution of coating polymer. The solvent used is liquid coating polymer. The solvent used is liquid manufacturing vehicle phasemanufacturing vehicle phase
The coating material phase is the immiscible polymer The coating material phase is the immiscible polymer
in liquid state is formed by utilization of one of the in liquid state is formed by utilization of one of the methods of phase separation Coacervation:methods of phase separation Coacervation:
By changing temp of polymer solutionBy changing temp of polymer solution
By adding a saltBy adding a salt
By adding a non solventBy adding a non solvent
By adding incompatible polymer to polymer solutionBy adding incompatible polymer to polymer solution
By inducing a polymer-polymer interactionBy inducing a polymer-polymer interaction
Step 2Step 2
Consists of depositing the liquid polymer Consists of depositing the liquid polymer coating upon core materialcoating upon core material
Accomplished by controlled, physical mixing of Accomplished by controlled, physical mixing of the coating material (while liquid) and core the coating material (while liquid) and core material in the manufacturing vehiclematerial in the manufacturing vehicle
Deposition of liquid polymer coating around the core Deposition of liquid polymer coating around the core material occurs if polymer is adsorbed at the interface material occurs if polymer is adsorbed at the interface formed between the core material and the liquid formed between the core material and the liquid vehicle phasevehicle phase
Continued deposition of coating material is promoted Continued deposition of coating material is promoted by a reduction in the total free interfacial energy of by a reduction in the total free interfacial energy of system brought about by decrease of coating material system brought about by decrease of coating material surface area during coalescence of liquid polymer surface area during coalescence of liquid polymer dropletsdroplets
Step 3Step 3
Involves rigidizing the coating, usually by Involves rigidizing the coating, usually by thermal, cross-linking or desolvation thermal, cross-linking or desolvation technique, to form a self-sustaining technique, to form a self-sustaining microcapsulemicrocapsule
Temperature ChangeTemperature Change
Consists of forming a polymer solution at high temp. into which Consists of forming a polymer solution at high temp. into which insoluble drug core material is suspended. insoluble drug core material is suspended.
As temp. is reduced, under controlled conditions of agitation, As temp. is reduced, under controlled conditions of agitation, phase separation of the dissolved polymer occurs in form of phase separation of the dissolved polymer occurs in form of immiscible liquid droplets which coalesce around the dispersed immiscible liquid droplets which coalesce around the dispersed core material particles, thus forming the embryonic core material particles, thus forming the embryonic microcapsulesmicrocapsules
ExampleExample
Microencapsulation of paracetamol with ethylcellulose(EC)Microencapsulation of paracetamol with ethylcellulose(EC)
ProcessProcess EC is soluble in cyclohexane atEC is soluble in cyclohexane at
6060ººC and insoluble at RTC and insoluble at RT
EC is dissolved in cyclohexane at high temp. EC is dissolved in cyclohexane at high temp.
Fine divided drug added with continuous agitationFine divided drug added with continuous agitation
Allow mixture to cool with continuous stirring. This results in Allow mixture to cool with continuous stirring. This results in phase separation/coacervation of EC and microencapsulation phase separation/coacervation of EC and microencapsulation of paracetamolof paracetamol
Further cooling to RT accomplished gelation and solidification of Further cooling to RT accomplished gelation and solidification of
coatingcoating
Microcapsules collected by filtration, decantation or centrifugationMicrocapsules collected by filtration, decantation or centrifugation
Incompatible Polymer AdditionIncompatible Polymer Addition
PrinciplePrinciple Liquid phase separation of polymeric coating material and Liquid phase separation of polymeric coating material and
microencapsulation can be accomplished by utilizing the microencapsulation can be accomplished by utilizing the incompatibility of dissimilar polymers existing in a common incompatibility of dissimilar polymers existing in a common solventsolvent
Example:Example: The microcapsulation of methylene blue hydrochloride with ethyl The microcapsulation of methylene blue hydrochloride with ethyl
cellulose by this mode of phase separation ( incompatible cellulose by this mode of phase separation ( incompatible polymer addition)polymer addition)
NON – SOLVENT ADDITIONNON – SOLVENT ADDITION
A liquid that is a non – solvent for a given solvent for a A liquid that is a non – solvent for a given solvent for a given polymer can be added to a solution of a polymer given polymer can be added to a solution of a polymer to induce phase separation . The resulting immiscible , to induce phase separation . The resulting immiscible , liquid polymer can be utilized to effect liquid polymer can be utilized to effect microcapsulation of an immiscible core material.microcapsulation of an immiscible core material.
SALT ADDITIONSALT ADDITION Soluble inorganic salt can be added to aqueous Soluble inorganic salt can be added to aqueous
solution of certain water soluble polymer to cause solution of certain water soluble polymer to cause phase separation.phase separation.
Example : oil soluble vitamin microcapsulation induced Example : oil soluble vitamin microcapsulation induced by adding sodium sulphateby adding sodium sulphate..
Polymer – Polymer interactionPolymer – Polymer interaction The interaction of oppositely charged polyelectrolyte The interaction of oppositely charged polyelectrolyte
can result in the formation of complex having low can result in the formation of complex having low solubility which leads to phase separation.solubility which leads to phase separation.
Example:Example:
Gelatin and gum ArabicGelatin and gum Arabic
Spray drying / spray congealingSpray drying / spray congealing
• spray dryers offer particle sizes of dried material from 50-250 spray dryers offer particle sizes of dried material from 50-250 microns.microns.•For producing large particles Fluidized Spray Dryers are For producing large particles Fluidized Spray Dryers are employed. employed. •The atomization of the feed solution is done to produce large The atomization of the feed solution is done to produce large droplets droplets •The moist powder is dried in the integrated fluid bed system at The moist powder is dried in the integrated fluid bed system at the bottom of the drying chamber using hot air.the bottom of the drying chamber using hot air.
Seed or granules coated productsSeed or granules coated products
Wide range of drugs are formulated.Wide range of drugs are formulated.
ProcessProcess
NPS is coated with the drug solution.NPS is coated with the drug solution. ¼ th or ¼ th or 11//33 rd seed are coated with the drug which release rd seed are coated with the drug which release
immediately.immediately. Remaining ¾ th or Remaining ¾ th or 22//3 3 rd seeds are coated , by dividing into the rd seeds are coated , by dividing into the
groups with coats of coating material to various thicknessgroups with coats of coating material to various thickness to to produce the effect for desired period.produce the effect for desired period.
Example :Example : Amobarbital & dextroamphetamine sulphateAmobarbital & dextroamphetamine sulphate
Matrix dissolution controlMatrix dissolution control
Drug is sealedDrug is sealed or embedded in the wax or embedded in the wax material.material.
Method of preparation:Method of preparation:
1. Aqueous dispersion 2. congealing
Aqueous dispersion :Aqueous dispersion :
Spraying or placing the wax drug mixture in water & collecting the resulting particles.
Congealing method
Drug is mixed with the wax material & either spray congealed or just congealed & screened.
PrinciplePrinciple
The rate of drug availability is controlled by the rate The rate of drug availability is controlled by the rate of penetration of dissolution fluid into the matrix.of penetration of dissolution fluid into the matrix.
Thus rate can be controlled porosity of tablet matrix, Thus rate can be controlled porosity of tablet matrix, i.e. presence of hydrophobic additives & particles i.e. presence of hydrophobic additives & particles size.size.