CONCEPT AND SYSTEM DESIGN FOR RATE-CONTROLLED DDS PRESENTED BY : GANDHI SONAM MUKESHCHANDRA Dept. of Industrial Pharmacy
CONTENTS Introduction. Defination. Advantages. Disadvantages. Delivery rates. Pharmacokinetic consideration. Modes of drug release. Controlled release therapeutic system. Mechanism of control release.
INTRODUCTION CONTROLLED RELEASE DRUG DELIVERY SYSTEM: Controlled drug delivery system has been introduced to overcome the drawback of fluctuating drugs levels associated with conventional dosage forms. Introduced to be an ideal drug delivery system. Development of novel & potent drug delivering system. Development of new, better & safe drug with larger therapeutic index. Effective & safer use of existing drugs through concept & techniques of controlled delivery system.
DEFINATION Controlled drug delivery system is theone which delivers the drug at a predeterminedrate, locally or systematically for a specifiedperiod of time.
ADVANTAGES» Reduction in dosing frequency.» Reduced fluctuations in circulatory drug levels.» Avoidance of night time dosing.» Increase the patient compliance.» More uniform effect.» Decrease side effect like reduced GI irritation.
DISADVANTAGES» High cost .» Poor in-vitro & in-vivo correlation.» Dose dumping.» Reduced potential for dose adjustment.» Increases the first pass effect.
CONTROLLED DRUG DELIVERY SYSTEM: Controlled drug delivery systems is the onewhich delivers the drug at a predetermined rate , locally orsystematically for a specified period of time. SUSTAINED DELIVERY SYSTEM: Sustained delivery systems means the release of active agent is slower thanconventional formulation, but is significantly effected by an external environment.Ex: enteric coated tablets. IMMEDIATE RELEASE DDS : Release drug immediately in blood to achieve therapeutic effective level.
» HOW TO ACHIVE CONTOLLED- RELEASE DRUG ADMINISTRATION:- The therapeutic efficacy of a drug, under clinical conditions is not simply function of it’s intrinsic pharmacological activity of equal importance in the path of drug molecule must taken from the site of administration to sites of action.» Various conditions the drug molecules encounter along the path of distribution may alter either the effectiveness of the drug or affect the amount of the drug reaching the site of pharmacologic action.
» As illustrated in the flow diagram all of these intermediate steps can be grouped & Classified in to three main branches.1. Pharmaceutics2. Biopharmaceutics /Pharmacokinetics3. Pharmacodynamic/Clinical Pharmacology
DELIVERY RATES» Most of the release profiles from delivery systems are categorized in to three main types.1. zero order release» In the simplest release pattern called zero order release.» In zero order release, the delivery rate remains constant.» The release rate from these devices is given as, dMt/dt = kWhere, k is constant, t is time & Mt representing the mass of active agent released.
2. First order release:» The release rate is directly proportional to the amount of active ingredient loaded in device. Mathematically, this may be represented as:- dMt/dt=k (Mo-Mt)Where, Mo=mass of active moiety in the device.» This indicated that the release rates declines exponentially with time & with depletion of active ingredient the release rate approaches zero.
3. Square-root of time or t-1/2 release:» Release of drug is linear with the reciprocal of the square root of times.» Following equation represents such release profile, dMt /dt=k/t1/2» In classes of control release device ,one of these pattern are used.
absorptio actio n nConventional dosage actionControl release dosage
Modes of Drug ReleaseBasically there are three basic modes of drug delivery:- 1) Targeted delivery. 2) Controlled release. 3) Modulated release.1. Targeted delivery: It refers to the systemic administration of a drug carrier with the goal of delivering the drug to specific cell , tissue or organs .
2. Controlled release:- It refers to the use of a delivery device withobjective of the releasing the drug in patient body atpredetermined rate .3. Modulated release:- It implies use of a drug delivery device thatrelease the drug at a variable rate, controlled byenvironmental condition , biofeedback , sensor input or anexternal control device.
Controlled release therapeutic systemIt may be passive preprogrammed or active preprogrammed or active self programmed. Passive preprogrammed: - Category in which the release rate is predetermined & is no influenced or altered by the external biological environment. Active preprogrammed system:- It include most metered insulin pumps whose release rate can be regulated by source external to the body. Active self-programmed therapeutic system:- Modulated release rate according to information gathered by the sensor with changing biological environment like change in blood sugar level in diabetes.
Controlled release polymeric system can be classified acc. to the mechanism Primary control release is achieved by diffusion, degradation and swelling followed by diffusion.» Diffusion.» Swelling.» Degradation (biodegradation/ bioerodable) system.
CLASIFICATION OF CONTROLLED RELEASE SYSTEM I. Rate programmed DDS II. Activation modulated DDS III. Feedback regulated DDS IV. Site-targating DDS
I. Rate preprogrammed DDS:A) Diffusion controlled or polymer matrix diffusion controlled DDS Reservoir system. Monolithic matrix delivery system.B) Polymer membrane permeation controlled drug delivery system Encapsulation dissolution control . Matrix dissolution control.C) Micro reservoir partition controlled drug delivery
I) RATE PROGRAMMED DDS:» The release of drug molecules from the delivery system has been preprogrammed at specific rate profiles.» This was accomplished by system design, which controls the molecular diffusion of drug molecules in and across the barrier medium within or surrounding the delivery system.
A) Diffusion controlled or polymer-matrix diffusion controlled DDS:» These systems are broadly divided into two categories. 1. Reservoir systems. 2. Monolithic systems
1. Reservoir system:» In membrane controlled reservoir system the therapeutic agent is contained in a core surrounded by a thin polymer membrane and the active agent is released to the surrounding environment by diffusion process through the rate limiting membrane for the reservoir type of system.» These systems consist of a reservoir either solid drug ,dilute solution or highly concentrated drug solution within a polymer matrix.
Eg:- Implantable dosage/oral system Transdermal system
2) Monolithic- matrix delivery system: In monolithic matrix delivery system the therapeuticagent is dispersed in polymer matrix and drug release iscontrolled by its diffusion from the matrix into thesurrounding environment.
» To formulate such system polymer and active agent are mixed to form a homogenous system.» With the passage of time and continuous drug release, the delivery rate normally decreases in these type of systems.
The basic mechanism of drug release from these two systems are fundamentally different Matrix system Reservoir system• Suitable for both non degradable and • Degradable reservoir system may be difficult design. degradable system.• Achievement of ‘zero order’ release is • Achievement of zero order release is difficult. easy.• No danger of dose dumping in case of • Danger of dose dumping . rapture. • Very easy to fabricate in wide range of• very easy to fabricate in a wide range size and shape. of size and shape .• Water soluble drugs have a tendency to burst from the system.
B) Polymer membrane permeation CDDS 1. Encapsulation dissolution control. 2. Matrix dissolution control.» In this type of system, drug formulation is partially or totally encapsulated within a drug reservoir compartment. it is drug release surface is covered by a rate controlling polymer member having a specific permeability.» The drug reservoir may exist in solid, suspension or solution form.
1. Encapsulation dissolution control» These systems involve coating of individual particle of drug with a slow dissolution material.» The coated particles can be compressed directly into tablets or placed in capsules.
2. Matrix dissolution control:» In this approach drug is dispersed in a slow dissolving matrix consist of polymers.» The rate of penetration of dissolution fluid into the matrix determines the drug dissolution and subsequent release.
C) Micro Reservoir Partition Controlled DDS:(dissolution and diffusion controlled release system) In such systems, the drug core is enclosed in a partially soluble membrane. pores are thus created due to dissolution of parts of the membrane whichpermit entry of aqueous medium into the core and hencedrug dissolution. Allow diffusion of dissolved drug out of the system.
» The rate of drug release dq/ dt from this DDS is defined by,
II) Activation modulated CDDS:» In this group of CRDDS, the release of drug molecules from the delivery system is activated by some physical, chemical method.» Biochemical process facilitated by the energy supplied externally.
1) OSMOTIC PRESSURE ACTIVATED DDS:» Depends upon osmotic pressure to activate release.» Rate of release controlled by osmotic gradient.» Can also be controlled by water permeability, effective surface area of semi permeable housing.» E.g. Alzet osmotic pump.
2) HYDRODYNAMIC PRESSURE ACTIVATED DDS:» It can be fabricated by enclosing a collapsible, impermeable container which contains a liquid drug formulation to form drug reservoir compartment.» A composite laminate of an absorbent layer and a swellable, hydrophilic polymer layer is sandwiched between the drug reservoir compartment and housing.» In the GIT laminate absorbs the GI fluid through the annular opening at the lower end of housing and becomes increasingly swollen , which generate hydrodynamic pressure in the system.
» The hydrodynamic pressure thus created forces the drugs reservoir component to reduce in volume and causes the liquid drug formulation to release through the delivery orifice.
3) VAPOUR PRESSUR ACTIVATED DDS:» Depends upon vapour pressure.» Pumping compartment contain fluorocarbon fluid which vaporized at body temp at implantation site and create vapour pressure.» Pressure moves partition upwards and this force causes the delivery of drug solution.
4) MECHANICALLY ACTIVATED DDS: In this system, the drug reservoir solution formulation retained in a container equipped with a mechanically activated pumping system. A typical example of this type of system is development of a metered dose nebulizer for intranasal administration. The drug reservoir is contained in a container equipped with a mechanically activated pumping system. The volume of delivered solution is controllable as small as 10-100 l.
5) MAGNETICLLY ACTIVATED DDS: In this type of DDS the drug reservoir isdispersion of peptide or polymer matrix from whichmacromolecular drug can delivered only at a relatively slowrate . This low rate of delivery can be improved byincorporation of electromagnetically triggered vibrationmechanism into the polymer delivery device.
6) SONOPHORESIS ADDS: In that ultrasonic energy used to activate the delivery of drug from a polymeric drug delivery device. This system is fabricated from either a non-degradable or bio-degradable polymer. The enhanced release was also observed in non erodible system exposed to ultrasound where the release rate is diffusion controlled.
7) IONTOPHORESIS ACTIVATED DDS:» It is defined as the permeation of ionized drug molecule across biological membrane under the influence of electric current.» This type of DDS uses electric current to activate and to modulate the diffusion of the charged drug molecule across a biological membrane.» The iontophoresis facilitate skin permeation rate of a charged molecule it consist of three components and is expressed by, Jiisp= Jp +Je +Jc
8) HYDRATION ACTIVATED DDS (Swellingcontrolled system)» This type of ACDDS depends on the hydration induced swelling process to activate the drug.» In this system the drug reservoir is homogeneously dispersed in a swellable polymer matrix fabricated from a hydrophilic polymers.» The release of drug is controlled by the rate of swelling of polymer.
9) pH ACTIVATED DDS:• Delivery of drug only in region of specific PH ranges.• Drug containing core fabricated with PH sensitive polymer combination.• E.g. in GIT coating membrane resist action of gastric fluid & protect gastric degradation.
10. ION ACTIVATED DDS:» Ionic or charged drug can only be delivered by this system.» System preparation: complexing ionic drugs.» ( complex of cationic or anionic + resin having N(CH3)3 groups= system)» ( Granules of system impregnate the agent (e.g. polyethylene glycol 4000) that reduce rate of swelling and then coated by water insoluble membrane. (ethylene cellulose).» Membrane works as rate controlling barrier to modulate influx of ions as well as release of drug from system.
11) HYDROLYSIS ACTIVATED DDS:» Depends on hydrolysis to activate the release.» Can be fabricated as implantable device.» System prepared from bio-degradable polymers only. e.g poly (lactic-glycolic), poly (anhydride)» Release of drug achieved by hydrolysis induced degradation of polymer chain.» Rate of release controlled by rate of polymer degradation.
12) ENZYME ACTIVATED DDS:» Need enzymatic processes to activate release of drug.» System activates by the enzymatic hydrolysis of bio polymers by specific enzyme in tissue.» E.g development of albumin micro sphere that release 5- flurouracil in controlled manner by protease activated biodegradation.
III. Feedback regulated DDS:» Release of drug activates by triggering agent in the body and also regulated by its concentration via some feedback mechanism.» Some feedback regulated systems: 1. Bio-erosion - regulated DDS 2. Bio-responsive - regulated DDS 3. Self regulating DDS
1. Bioerosion regulated DDS:» Feedback regulated DDS concept applied.» Consist of drug dispersed bio- erodible polymer ( poly- vinyl methyl ether)» Coated with immobilized urease.» In neutral PH polymer erodes very slowly.» In presence of urease, urea is converted into ammonia ; present at surface of system
• Causes increase in PH and rapid degradation of polymer matrix and also release of drug molecules.
2. Bio responsive DDS:» Feedback regulated concept.» Device having drug reservoir enclosed by bio-responsive polymeric membrane.» The drug permeability controlled by biochemical agent in tissue where system is located.» E.g. glucose-triggered insulin delivery system.
In this system theamount of drug deliveredis bioresponsive to theconcentration of thebiochemical agent. The drug reservoiris enclosed in a polmericmatrix.
3. Self regulating DDS:» Depends on reversible and competitive mechanism to activate and to regulate the release of drug.» Drug reservoir is drug complex , encapsulated within semi permeable polymeric membrane.» Release of drug from delivery system activated by membrane permeation of biochemical agent from the tissue in which the system is located.
» This system depends on reversible and competitive binding mechanism to activate and regulate the release of drug» The release of drug depends on the concentratin of the biochemical agent in the tissue,» Eg: insulin-sugar-lectin complex.
Effect of System Parameters on CDDS:» Various parameters which affect the overall controlled drug release profile are:1. Polymer solubility.2. Solution solubility.3. Partition coefficient.4. Polymer diffusivity.5. Solution diffusivity.6. Drug loading dose7. Surface area.