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02/10/16 RAGHAVENDRA KUMAR GUNDA
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GUIDED BY:
MR.A.KISHORE BABU SIR M.PHARM
ASSISTANT PROFESSER
DEPT.OF PhARmAcEuTIcS
A.m.REDDY mEmORIAL cOLEGE OF PhARmAcY
PRESNTED BY :
RAGHAVENDRA KUMAR GUNDA
(Y 10MPH0621)
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DRUG:It is a chemical agent intended for cure, prevention, mitigation, treatment or therapy for a disorder/disease in human being and animal
DOSAGE FORM:It is defined as the combination of active drug component along with non drug moieties
CONTROLLED RELEASE:One which delivers the drug at a pre-determined rate locally or systemicallyFor specified long period of time
SUSTAINED RELEASE:The system of prolonged release either Systemically or locally.
CONVENTIONAL RELEASE:Immediate/Prompt release dosage forms
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The frequency of administration /dosing interval of any drug depends upon
HALF LIFE, MEAN RESIDENCE TIME(MRT), THERAPEUTIC INDEX
For conventional release the dosing interval much shorter than it’s halflife so following limitations were observed
POOR PATIENT COMPLIANCEPEAKVALLEY PDC VS TIMEFLUCTUATIONS IN DRUG LEVELSOVER MEDICATION
MISSING OF DOSE
CSS IS DIFFICULT
FOR NARROW TI DRUGSUNDER MEDICATION
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• Reduced potencies because of partial degradation
• Toxic levels of administration• Increase costs associated with
excess dosing• Compliance issue due to
administration pain
Challenges in Oral Drug Delivery
Development of drug delivery system Delivering a drug at therapeutically effective rate to desirable site.
Modulation of GI transit time Transportation of drug to target site.
Minimization of first pass elimination
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Why control drug delivery?
Goal of more sophisticated drug delivery techniques
1.Deploy to a target site to limit side effects
2.Shepard drugs through specific areas of the body without degradation
3.Maintain a therapeutic drug level for prolonged periods of time
4.Predictable controllable release rates
5.Reduce dosing frequent and increase patient compliance
Toxicity level
Injection
Controlled release
Therapeutic Level
Time
As the cost and complexity of individual drug molecules has risen the problems with the classical delivery strategies over
took their benefits.
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Hence there is a need to Develop a better, safer drugs with long half-life with larger Therapeutic Index
Effective, safer use of existing drugs through Concepts& Techniques of Controlled Release Drug Delivery System
To minimize the fluctuation in PDC
To attain feasibility for CR of drugs
Correlation in In-vivo In-vitro aspects& Models
To optimize the delivery of medication to achieve good therapeutic response
The total amount of drug administered is sed
Some times Drug Interactions also prolongs the release
Ex:probencid the excretion of PENICILLIN
-
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REDUCTION IN DOSING FREQUNCY
SE FLUCTUATION IN CIRCULATING DRUG LEVEL
PATIENT COMPLIANCE
AVOIDANCE OF NIGH TIME DOSING
MORE UNIFORM EFFECT(PHARMACOLOGICAL)
REDUCTION IN GI IRRITATION AND OTHER RELATED SIDE EFECTS
IMPROVED EFFICACY/SAFETY RATIO
Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of GIT.
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Dose dumping. Reduced potential for accurate dose adjustment.Need of additional patient education.Stability problem.Poor Invivo-Invitro correlationPoor systemic availability(depends upon GI residing time)Increased potential for first pass clearanceHigh cost as compared individual
Drug reaches to liver via portal vein, higher the oral dose, greater possibility of saturating hepatic metabolism. Smaller dose/ slow release from formulation less chance to saturate
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RATE CONTROLLED DRUG DELIVERY SYSTEM
RATE PRE PROGRAMMED
POLYMER MEMBRANE PERMEATION CONTROL
MATRIX DIFFUSION
MICRO RESERVOIR PARTITIONED
ACTIVATION MODULATED
PHYSICALHYDRATION, IONTOPHORESIS, SONOPHORESIS
HYDRODYNAMIC,VAPOUR,OSMATIC PRESSURES
MAGNETIC
CHEMICAL
PH ACTIVATED
HYDROLYSIS
IONIZATION
BIOCHEMICALENZYME ACTIVATED
BIOCHEMICAL ACTIVATED
FEED BACK REGULATED
SITE TARGETTED
BIO EROSION BIO RESPONSIVE
EX: INSULIN
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History of Controlled Drug Delivery
Wurster technique 1949
Coacervation (liquid encapsulation) 1953 Mircroencapsulation 1960’s
• 65% of all current drugs use some form of micro-encapsulation
Implants 1970’s Transdermal 1980’s Site directed systems 1990’s
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SOME SUBSTANCES AVAILABLE FOR CONTROLLED RELEASE ARE AS FOLLOWSVITAMINSMINERALSHORMONESDRUGS DRUGS
DIURETICS & CVS DRUGS
ACETAZOLAMIDE, ISOSORBIDE, PAPVERINE
ANTIMICROBIALTETRACYCLIN
CNSAMPHETAMINE,
CAFFEINE, PHENOBARBITAL,
PROCHLORPERAZINE
GI BELLADONNA ALKALOIDS,
HYOSCINE, TRI DIHEXETHYL
CHLORIDEPYRIDO STIGMINE
RESPIRATORYAMINOPHYLLINE
CPM, BPM
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COMPOUNDS THAT ARE UNSUITABLE FOR CONTROLLED RELEASE
DEPEND UPON ELEMINATION HALFLIFE AND DOSE i.e t1/2 < 2.0 hours, larger doses of api.
CHARACTERISTIC DRUGS
Not effectively absorbed in Lower Intestine
IBUPROFEN, FERROUS SALTS
Adsorbed, excreted rapidly biological t ½< 1 hr
PENICILLIN-G, FUROSEMIDE
Long biological t ½ > 12 hr DIAZEPAM, PHENYTOIN
Larger doses (> 1 gm) SULPHONAMIDES
Cumulative action& un desirable side effects, drugs with low Therapeutic Index
PHENOBARBITAL,DIGOXIN
Precise dosage titrated to individuals ANTI-COAGULANTS, CARDIAC GLYCOSIDES
No clear advantages for CONTROLLED RELEASE
GRISEOFULVIN
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Dissolution controlled release Diffusion controlled release Diffusion and dissolution controlled release Ion exchange resins pH independent formulations Osmotically controlled release Altered density formulations.
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Dissolution Definition:
Solid substances solubilizes in a given solvent.
Mass transfer from solid to liquid.
Rate determining step: Diffusion from solid to liquid.
Several theories to explain dissolution – Diffusion layer theory (imp) Surface renewal theory Limited solvation theory.
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Dissolution-Controlled Systems
Alternating layers of rate-controlling coats
Group of beads with different coatings
• (Spansule, SmithKline Beecham)
• dC/dt = kd*A(Cs-C) = D/h*A(Cs-C)
• dC/dt=dissolution rate, kd=dissolution rate const
• D=diffusion coefficient, Cs=saturation solubility
• C=concentration of solute in bulk solution
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Types of Dissolution Controlled Systems
Two types of dissolution- controlled, pulsed delivery systems
A: Single bead-type device with alternating drug and rate controlling layer
B: Beads containing drug with differing thickness of dissolving coats
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Bioerodible and Combination Diffusion and Dissolution System
Strictly speaking, therapeutic systems will never be dependent on dissolution only or diffusion only.
Bioerodibile devices, however, constitute a group of systems for which mathematical descriptions of release is complex.
The complexity of the system arises from the fact that, as the polymer dissolves, the diffusion path length for the drug may change. this usually results in a moving-boundary diffusion system.
Zero-order release can occur only if surface erosion occurs and surface area does not change with time.
The inherent advantage of such a system is that the bioerodible property of the matrix does not result in a ghost matrix.
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Representation of a Bioerodible Matrix System
Drug is dispersed in the matrix before release at time = 0. At time = t, partial release by drug diffusion or matrix erosion has occurred
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Characteristics of Bioerodible Matrix Systems
Advantages
• all the advantages of matrix dissolution system
• removal from implant sites is not necessary
Disadvantages
• difficult to control kinetics owing to multiple processes of release
• potential toxicity of degraded polymer
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Bioerodible and Biodegradable Controlled Release Polymers
These polymers are designed to degrade within the body
• Polylactides (PLA)
• Polyglycolides (PGA)
• Polylactide-co-glycolides (PLGA)
• Polyanhydrides
• Polyorthoesters
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Degradation of Biodegradable Polymers
These materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed
Bulk hydrolysis - the polymer degrades in a fairly uniform manner throughout the matrix
Surface Eroding - degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system
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Biodegradable Polymers
Drug delivery from
(a) bulk-eroding and (b) surface-eroding biodegradable systems.
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Noyes Whitney Equation
dc/dt = kD.A (Cs – C )dc/dt = D/h A. (Cs – C)
dc/dt = Dissolution rate. k= Dissolution rate constant (1st order). D = Diffusion coefficient/diffusivity Cs = Saturation/ maximum drug solubility. C =Con. Of drug in bulk solution. Cs-C=concentration gradient. h =Thickness of diffusion layer.
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Matrix Type
Also called as Monolith dissolution controlled system.
Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility. 3.Dissolving at slower rate.
First order drug release.
Drug release determined by dissolution rate of polymer.
Examples: Dimetane extencaps, Dimetapp extentabs.
Soluble drug
Slowly dissolving matrix
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Matrix Dissolution Products
Product Active Ingred. Manufacturer
DimetappExtentabs
Bromphen. Robins
DonnantalExtentabs
..... Robins
QuinidexExtentabs
Quinidine Robins
Tenuate Dospan Diethylprop. Merrel
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Encapsulation
Called as Coating dissolution controlled system.
Dissolution rate of coat depends upon stability & thickness of coating.
Masks colour,odour,taste,minimising GI irritation.
One of the microencapsulation method is used.
Examples: Ornade spansules,
Chlortrimeton Repetabs
Soluble drug
Slowly dissolving or erodible coat
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Encapsulated Dissolution Products
Product Active Ingred Manufacturer
Ornade Spansules PPA, chlorphen. SKB
Contact PPA, others SKB
Diamox Sequels Acetazolamide Lederle(WA)
Chlor-TrimetonRepetabs
Chlorphen. Schering
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Diffusion
Major process for absorption.
No energy required.
Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attainded.
Directly proportional to the concentration gradient across the membrane.
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Matrix Diffusion Types
Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for sustaining the release of highly water soluble drugs. 2. Materials used are hydrophilic gums. Examples : Natural- Guar gum,Tragacanth. Semisynthetic -HPMC,CMC,Xanthum
gum. Synthetic -Polyacrilamides. Examples: Glucotrol XL, Procardia XL
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Matrix system
Rate controlling step:
Diffusion of dissolved drug in matrix.
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Matrix Diffusional Products
Product Manufacturer
Procan SR Parke Davis
Desoxyn Abbot
Choledyl SA Parke Davis
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Higuchi Equation
Q = DE/T (2A.E Cs)Cs.t)1/2
Where , Q=amt of drug release per unit surface area at time t. D=diffusion coefficient of drug in the release medium. E=porosity of matrix. Cs=solubility of drug in release medium. T=tortuosity of matrix. A=concentration of drug present in matrix per unit volume.
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Reservoir System
Also called as Laminated matrix device. Hollow system containing an inner core surrounded
in water insoluble membrane. Polymer can be applied by coating or micro
encapsulation. Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding fluid by diffusion.
Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate.
Examples: Nico-400, Nitro-Bid
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Reservoir diffusion System
Rate controlling steps :
Polymeric content in coating, thickness of coating, hardness of microcapsule.
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Reservoir Diffusional Products
Product Manufacturer
Nico-400 Jones
Nitro- Bid Marion
Nitrospan Rorer
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Dissolution & Diffusion Controlled Release system
Drug encased in a partially soluble membrane.
Pores are created due to dissolution of parts of membrane.
It permits entry of aqueous medium into core & drug dissolution.
Diffusion of dissolved drug out of system.
Ex- Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane.
Insoluble membrane
Pore created by dissolution of soluble fraction of membrane
Entry of dissolution fluid
Drug diffusion
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Osmosis - Movement of solvent from lower to higher concentration.
- The passage of solvent into a solution through semipermeable membrane.
Semipermeable Membrane Molecules are permitted only to one component (Water).
Osmotic pressureIt is the hydrostatic pressure produced by a solution in a space divided by a semipermeable membrane due to difference in concentration of solutes.
Osmotic pressure controlled DDS
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Osmotic Pressure Controlled System
Provides zero order release
Drug may be osmotically active, or combined with an osmotically active salt (e.g., NaCl).
Semipermeable membrane usually made from cellulose acetate.
More suitable for hydrophilic drug.
Examples: Glucotrol XL, Procardia XL,
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Equation
(Q/t) z = Pw Am/ hm (πs-πe )
(Q/t)= Rate of zero order drug release. Pw, Am & hm= water permeability, effective surface area & thickness of semipermeable membrane.
πs= osmotic pressure of saturated solution of osmotically active drug or salt in system.
πe = osmotic pressure of GI fluid.
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Osmotic Pressure Controlled System
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Osmotic Pressure Controlled System
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Modifications
- Immediate release system.- Osmotically active compartment system
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Immediate Release System
Activation of system is done. Dividing a dose into two parts. One third immediate release. Two third controlled release. Encapsulated into semipermeable
membrane. e.g. : Phenyl propanolamine.
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Osmotically active system
Two compartments separated by movable partition.
Osmotically active compartment absorbs water from GIT.
Creates osmotic pressure.
Partition moves upward & then drug releases.
Ex: Nifedipine.
Movable partition
Delivery orifice
Osmotically active compartment
Drug compartment
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Some Popular Brand names used for OCDDS
Spansule capsule ( SK & F ) Sequal capsule (Lederle ) Extentab tablets ( Robins ) Timespan tablet ( Roche ) Dospan tablet ( Merrell Dow ) Chronotab tablet ( Schering ) Plateau capsule ( Marion ) Tempule capsule ( Armour )
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Ion exchange resins It is based on the formation of drug resin complex formed when a ionic
solution is kept in contact with ionic resins. The drug from these complex gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract.
Resin + - Drug - + Cl- goes to resin + Cl- + Drug-
Where x- is cl- conversely Resin - - drug+ + Na +goes resin – Na+ + Drug These systems generally utilize resin compounds of water insoluble cross –
linked polymer. They contain salt – forming functional group in repeating positions on the polymer chain. The rate of drug diffusion out of the resin is sustained by the area of diffusion, diffusional path length and rigidity of the resin which is function of the amount of cross linking agent used to prepare resins
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PH -independent formulations
Drugs administered oraly encountered pH ranging from 7 in mouth,1 to 4 in stomach, and 5 to 7 in small intestine.since most of the drugs are eighter weak acids or weak bases,their release from sustained formulations is PH dependent.
However buffer can be added to the formulation to help maintain a constant PH there by rendering pH-independent release.
To this end,salts of amino acids,citric acid,phthalic acid,phosphoric acid or tartrate acid are commonly used because of their physiological acceptibility.
e.g. propoxyphene in a buffered sustained release formulation, which significantly increase reproducibility
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Altered density formulations
1.High desity approch: the density of the pellets must exceed that of normal stomach content(1.04g/cm3) and should be atleast 1.4
In preparing such formulations,drug can be coated on a heavy core or mixed with heavy inert materials such as barium sulfate,titanium dioxide ,iron oxide.
2.low density approch : Globular shells which have an apparen density lower than that of gastric fluid can be used as a carrier of drug for sustained release purpose.polysterol,poprice,and even popcorn are all good condidates as carriers.
The surface of these empty shells is undercoated with sugar or with a polymeric material such as methacrylic polymer and cellulose acetate pthalate.the undercoated shell is then coated by a mixture of drug with polymers such as ethylcellulose and hydroxypropylcellulose.Final product floats on GIT fluid.
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Conclusion
By and large, these are based on the principles diffusion, dissolution, or ion exchange and, only recently, on the principle of osmosis. Regardless of the mechanism of sustained release, however, more and more of these systems are becoming polymer based.
There are also those which are based on the bioadhesion principle whose goal is to promote the retention of a delivery system, hence drug release, at a specific region in the GI tract
Though CDDS appears appear to be feasible, The Timing for practical development is difficult to predict; safety, cost, efficacy are those factors need to be evaluated.
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BIBLIOGRAPHY
Novel drug delivery system , volume 50, Y.W.Chien, pg nos 1-55
Novel drug delivery system by N.K.jain 4th edition, pg no1-4,54-61
The theory & practice of industrial pharmacy, Leon Lachman , Herbert A.Lieberman, Joseph L.Kanig,3 rd edition. Pg no 430-445
The Eastern pharmacist, november 1993. Sustained release drugs, V R.Gudsoorkar & D.Rambhau ,page 27-32 Biopharmaceuitics & pharmacokinetics, D M.Brahmankar & Sunil B. Jaiswal, 1st edition 1995, pg nos 220-235, 3335-371
Li. V.H., "Influence of drug properties and routes of drug administration on the design of sustained and controlled release systems" Chapter 1 in "Controlled drug delivery : fundamentals and applications" edited by Robinson J.R., VincentLee,2ndedition,Marcel Dekker Inc., Volume 29, 1978: 5-36pp
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Continue……………
Hui ho-wah, "Design and fabrication of oral controlled release drug delivery systems“ chapter 9 in "Controlled drug delivery; fundamentals and applications", edited by Robinson J.R., Vincent Lee, 2nd edition, Marcel Dekker Inc., Volume 29, 1978: 391-420pp.
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Joseph.R.Robinson pointed out the importance of drug delivery system “Unless a drug can be delivered to it’s target area at a rate and concentration that minimize the side effects and maximize the therapeutic effect of drug will not be maximally beneficial to patient and in the extreme an otherwise useful drug may be discarded ”
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