Powerpoint presentation on controlled drug delivery system. Its introduction, terminologies, rationale, advantages, disadvantages, selection of drug, approaches for designing controlled release formulations and physicochemical and biological properties of drug

1. CONTROLLED DRUG DELIVERY SYSTEM
Presented By:
Ms. Srushti P Chahande
Mpharm-II (Pharmaceutics)
Department of Pharmaceutical Sciences,
Rashtrasant Tukdoji Maharaj Nagpur University,
Nagpur- 440033
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2. CONTENTS:
1. Introduction
2. Definitions
3. Rationale of Controlled DDS
4. Advantages of Controlled DDS
5. Disadvantages of Controlled DDS
6. Selection of drug candidate for Controlled DDS
7. Approaches for designing controlled release formulations
8. Physicochemical and Biological properties of drug relevant to control release
formulation.
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3.  INTRODUCTION:
1. To achieve as well as to maintain the drug concentration within the therapeutically effective range
needed for treatment, it is often necessary to take conventional drug delivery system several times a
day. This results in a significant fluctuation in drug levels.
2. Recently, several technical advancements have been made. They have resulted in the development of
new techniques for drug delivery. These techniques are capable of controlling the rate of drug
delivery, sustaining the duration of therapeutic activity, and/or targeting the delivery of drug to a
tissue
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4.  DEFINITIONS:
1. Sustained-release:
• These are dosage forms designed to release (liberate) a drug at a predetermined rate in order
to maintain a constant drug concentration for a specific period of time with minimum side
effects
• Any of the dosage form that maintains therapeutic blood or tissue levels of drug by continuous
release of medication for a prolonged period of time, after administration of a single dose.
• The onset of its pharmacologic action is often delayed, and the duration of its therapeutic
effect is sustained
2. Controlled-release:
• Controlled release dosage form is a dosage form that release one or more drugs continuously
in predetermined pattern for a fixed period of time, either systemically or locally to specified
target organ.
• Designed to slowly release a drug in the body in a prolonged controlled fashion.
• The release of drug ingredients from a controlled-release drug delivery system proceeds at a
rate profile that is not only predictable kinetically, but also reproducible from one unit to
another.
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5. Figure 1: A hypothetical plasma concentration-time profile from conventional
multiple dosing and single doses of sustained and controlled DDS.
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6.  RATIONALE OF CONTROLLED DRUG DELIVERY SYSTEM:
1. The basic rationale of a controlled release drug delivery system is to optimize the
biopharmaceutics, pharmacokinetics, and pharmacodynamics properties of a drug
in such a way that its utility is maximized
through reduction in side effects and cure or control of disease condition in the shortest
possible time by using smallest quantity of drug, administered by most suitable route.
2. To provide a location specific action within the GIT.
3. To avoid an undesirable local action within the GIT.
4. To provide programmed delivery pattern.
5. To increase the extend of absorption/bioavailability.
6. To extend the time of action of drug after administration.
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7.  ADVANTAGES:
1. Total dose is low.
2. Reduced GI side effects and other toxic effects.
3. Reduced dosing frequency
4. Better patient acceptance and compliance.
5. Less fluctuation in plasma drug levels.
6. More uniform drug effect.
7. Better stability of drug.
8. Reduction in total health care cost.
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8.  DISADVANTAGES:
1. Decreased system availability
2. Poor invitro-invivo relation
3. Retrieval of drug is difficult in case of toxicity, poison or hyper-sensitivity
reaction.
4. The physician has less flexibility in adjusting the dosage regimen.
5. This is fixed by dosage form design.
6. All drugs are not suitable candidates for controlled release medication.
7. Drugs with long biological half life (e.g. Digoxin-34 hours) are inherently long
acting and thus are viewed as questionable candidates for sustained release
formulations.
8. Drugs with narrow requirements for absorption (e.g. drugs which depend on
position of G1T for optimum absorption are also poor candidates).
9. Drugs like Riboflavin and ferrous salt, which are not effectively absorbed in
lower intestine are poor candidates.
10. Drugs which are having very short half life (Furosemide) are not suitable
candidates.
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9.  SELECTION OF DRUG CANDIDATE FOR CONTROLLED DRUG
DELIVERY SYSTEM:
i] Oral Route:
The drug should have following properties to be a succesful candidate
• It must get absorbed through the entire length of GIT.
• Main limitation is transit time (mean of 14 hours), which can be extended for 12-24 hours.
• Dose as high as 1000mg can be given through this route.
ii] Intramuscular/subcutaneous route:
This route is preferred because-
• The action is to be prolonged for 24 hours to 12 months.
• Small amount of drug is administered (2ml/2gm).
• Factors important are solubility of drug in surrounding tissue, molecular weight, partition
coefficient and pKa of drug.
iii] Transdermal route:
This route is selected for drugs which-
• Show extensive first pass metabolism upon oral administration or drugs with low dose.
• Important factors to be considered are partition coefficient of drugs, contact area, skin
condition, skin permeability of drug, skin perfusion rate, etc.
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10.  CONTROL RELEASE DOSAGE FORM RELEASE FORMULATION DESIGNS
1. Dissolution controlled release
• Encapsulation Dissolution control
• Seed or granule coated
• Micro encapsulation
• Matrix Dissolution control
2. Diffusion controlled release
• Reservoir type devices
• Matrix type devices
3. Diffusion and Dissolution controlled systems
4. Ion exchange resins
5. pH-Independent controlled release systems
6. Osmotically controlled release
7. Hydrodynamically balance system
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11. [I] DISSOLUTION CONTROLLED RELEASE SYSTEM
• Sustain release oral products employing dissolution as the rate limiting
step are the principle involves in this system
• To achieve this type of approach, the drug particles can be coated with
material of varying thickness or by dispersing them in a polymeric
matrix.
Figure 2: Schematic of Dissolution controlled release systems
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12. Figure 3: The common forms of dissolution controls formulation
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13. Dissolution controlled drug release system can be divided in to following categories:
(1) Encapsulation Dissolution control (2) Seed or Granule coated
(3) Microencapsulation (4) Matrix Dissolution control
(1) Encapsulation Dissolution control:
This method involves the coating of particles or granules of drug with slow dissolving materials
(2) Seed or Granule coated:
There are several ways to prepare a drug coated product
• A common method is to coat the seeds with the drug followed by a coat of slow dissolving
materials such as carbohydrate sugar and cellulose, polyethylene glycol, polymeric material,
and wax.
(3) Microencapsulation
• Coacervation / phase separation techniques
• Interfacial polymerization
• Precipitation
• Hot melt
• Salting out
• solvent evaporation
• Electrostatic method.
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14. (4) Matrix dissolution control:
• It is also called as monoliths.
• The drug is dispersed in media such as bees wax, carnauba wax, caster oil etc which control
drug dissolution by controlling the penetration of dissolution fluid in to matrix.
• This can be controlled by altering the porosity of the tablet matrix, the presence of
hydrophobic additives, and the wettability of the tablet and particle surface.
Figure 4: Dissolution Controlled Release Systems
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15. [II] DIFFUSION CONTROLLED RELEASE SYSTEM
There are two type of the diffusion controlled release system :
(1) Reservoir type devices
(2) Matrix type devices
(1) Reservoir type devices:
The drug release mechanism across the membrane involves its partitioning into the
membrane and release into the surrounding fluid by diffusion.
Figure 5: Reservoir type devices
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16. • The flux of drug, J, across a membrane in the direction of decreasing concentration is given by
Fick’s first law:
J= -D dc/dx
Where, D= Diffusion coefficient in area/time
dc/dx= Change of concentration with distance
• In term of the amount of drug release, the release rate is given by:
dM/dt = ADK ΔC / l
Where, A = Area
D = Diffusion coefficient
K = The partition coefficient of the drug between the membrane and drug core
l = Diffusion path length
ΔC = Concentration difference across the membrane
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17. (2) Matrix type devices:
• In this system, a solid drug is dispersed in an insoluble matrix.
• The rate of drug release is dependent on “the rate of drug diffusion” but not “the rate of solid
dissolution”.
The drug release from this system is given by following equation:
Q = [ Dε / T ( 2A - εCs ) Cs t ]1/2
Where, Q = weight in grams of drug released per unit surface area
D = diffusion coefficient of drug in the release medium
ε = porosity of matrix
T = tortuosity of the matrix
Cs = solubility of drug in the release medium
A = concentration of drug in the tablet
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18. [III] DIFFUSION AND DISSOLUTION CONTROLLED SYSTEM:
The main feature of this system is that the drug core is enclosed with a
partially soluble membrane.
Figure 6: Diffusion and Dissolution Controlled System
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19. The release profile of the drug from this type of the product can be described by following
equation :
Release rate = AD ( C1 – C2 ) / l
Where,
A = Surface area
D = Diffusion coefficient of the drug through pores
l = Diffusion pathways
C1 = Concentration of drug in cores
C2 = Concentration of drug in dissolution medium
• The fraction of soluble polymer in the coat will be the dominant factor controlling drug
release.
• Such a system has been demonstrated to provide a zero order release of KCl from a tablet
and doing the minimize gastrointestinal irritation effect of this compound.
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20. [IV] ION EXCHANGE RESIN:
• This method involves the drug release characteristics depends on the ionic environment of
the resin containing drug and should be less effective to the environmental condition such
as enzyme content end pH.
Resin[N(CH3)]+X¯ + Z – Resin [N(CH3)]+Z + X -
(Drug-charged resin)
• The release rate can be controlled by coating the drug resin complex using the one of the
microencapsulating process.
Figure 7: Ion exchange resin
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21. • Improvement of this ion exchange type drug delivery system is occurs by the
development of the pennkinetic system.
• In these system, the drug containing resin granules treated with the polymer such as
PEG- 400 and further coated with the water soluble polymer such as ethyl cellulose act
as a rate limiting barrier to control the drug release.
Figure 8: Drug containing resin granules
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22. [V] pH – INDEPENDENT CONTROLLED RELEASE SYSTEM:
• This system involves the granules are designed for the oral controlled release of
acidic and basic drugs at the rate that is independent of the ph in the GI tract.
• They are prepared by mixing a basic or acidic drugs with one or more buffering
agents, granulating with excipients and finally coating with a GI fluid permeable
film forming polymer.
• When the GI fluid permeates through the membrane , the buffering agents adjust
the suitable constant ph, there by constant rate of the drugs release occurs.
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23. [VI] OSMOTICALLY CONTROLLED RELEASE SYSTEM
• In this type of drug delivery system, the osmotic pressure is the driving force that
generates constant drug release.
Figure 9: Osmotically controlled release system
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24. • To regulate the flow of GI fluid for penetration through the semi permeable membrane, a
layer of bioerodible polymer can be applied to the external surface of the semi permeable
membrane.
• Several other modification of osmotic pressure controlled drug delivery have been
develop.
• One system consists of two compartments separated by the movable partition
• Another modified system is one in which delivery orifice is absents.
• In these system, the GI fluid is penetrate, hydraulic pressure is built up inside until the
wall ruptures and the contents are release to the environments.
• Osmotic controlled release system requires osmotic pressure to be effective and is
independent of its environments.
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25. [VII] HYDRODYNAMICALLY BALANCE SYSTEM
• This system is design to prolong GI residence time of drug in area of the GIT to
minimized drug reaching its absorption site in the solution state.
• This type of the tablet or capsules having the less density compared to the GI fluid
density.
• This type of tablet is prepared by granulating a mixture of drug, excipients, and
hydrocolloids such as hydroxyethylcellulose, hydroxypropyle cellulose, and
hydroxypropylmethylcellulose.
 Classification of Hydrodynamically Balance System:
(a) Effervescent Floating Dosage Form
(b) Non effervescent Floating dosage Form
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26. (a) Effervescent Floating Dosage Form:
• These are matrix type of system prepared with swellable polymer such as
methylcellulose, chitosan, and various effervescent compounds like sodium
bicarbonate, tartaric acid, and citric acid.
• These type of tablet comes in contact with the acidic gastric contents, Co2 is
liberated and gets entrapped in swollen hydrocolloids, providing buoyancy to the
dosage form.
Figure 10: Mechanism of action in effervescent floating dosage form
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27. (b) Non effervescent Floating dosage Form:
• This system is prepared from gel forming or swellable cellulose type of hydrocolloids,
polysaccharides, and matrix forming polymer like acrylates.
• After the oral administration, this dosage forms sweiis in contact with gastric fluid and
attain a bulk density of G.I.
• The air entrapped within the swollen matrix imparts buoyancy to dosage form.
• The formed swollen gel – like structure acts as a reservoir and allows sustained release of
drug through the gelatinous mass.
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28.  PHYSICOCHEMICAL AND BIOLOGICAL PROPERTIES OF DRUG:
[I] PHYSICOCHEMICAL PROPERTIES:
a) Aqueous solubility.
b) Partition coefficient
c) Drug stability
d) Protein binding
e) Molecular size and diffusivity.
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29. 1. AQUEOUS SOLUBILITY
 It is an important consideration in its biological performance as a SDRF.
 Aqueous solubility of a drug exerts its control on the absorption process in two ways:
(i) By influence on the dissolution rate of a compound which establish the drug
concentration in solution and the driving force for tissue permeation.
(ii) By its effect on the ability of the drug to penetrate tissues which is determined in part
by its solubility in the tissue.
 Dissolution rate is related to aqueous solubility which is given by NOYES-WHITNEY’S
EQUATION
dc/dt=KDA.Cs
Where, dc/dt=dissolution rate
KD=dissolution rate constant
A= total surface area of drug particle
Cs=aqueous saturation solubility of drug
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30. 2. PARTITION COEFFICIENT
 Between the time that a drug is administered and the time it is eliminated from the
body.
 It diffuse through a variety of biological membranes that act primarily as lipid like
barriers.
 The major criteria in evolution of the ability of a drug to penetrate these lipid
membranes is it apparent oil-water partition co-efficient, defined as:
K=Co/Cw
 Where,
Co=equilibrium concentration of all forms of the drug.
Cw=equilibrium concentration of all forms of in an aqueous phase.
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31. 3. DRUG STABILITY
 In oral dosage forms, loss of drug through acid hydrolysis or metabolism in GIT.
 A drug in solid state undergoes degradation at much slower rate than drug in
suspension/solution.
 Drugs with low aqueous solubility have low dissolution rate and usually suffer oral
bioavailability problems.
 Aqueous solubility of weak acids and base is governed by pka value and pH of the medium
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32. 4. PROTEIN BINDING
 Distribution of drug in to extra space is governed by dissociation of drug from protein.
 Drug-protein complex acts as reservoir in the vascular space for sustained drug release to extra
vascular tissue for drug exhibiting high degree protein binding.
 Some drugs shows higher degree protein binding
Ex- Diazepam shows greater than 95% protein binding
Figure 11: Protein binding and kinetics of protein binding
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33. 5. MOLECULAR SIZE AND DIFFUSIVITY
 Ability of drug to diffuse through membrane is called as diffusivity, is a function of
molecular size.
 In most of polymers, its possible to logD empirically to some function of molecular size
as
LogD=-Sv log V+Kv=-Sm log M+Km
Where,
V=molecular volume
M=molecular weight
Sv,Sm,Kv,Km are constants value of D is related to size and shapes of drugs
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34. [II] BIOLOGICAL PROPERTIES:
1. Absorption
2. Distribution
3. Metabolism
4. Elimination and Biological half-life
5. Side Effects and Safety Considerations
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35. (1) ABSORPTION
 Rate, extent, and uniformity of absorption are the important factors when considering
sustained release.
 Since the rate limiting step in drug delivery from a sustained release is its release from
dosage form , rather than absorption, a rapid release is essential if the system is
successful
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36. (2) DISTRIBUTION
 The distribution of drug in to vascular and extravascular spaces in the body is an important factor in
its overall elimination kinetics.
 This influences the formulations of that drug in to a sustain release, primarily by restricting the
magnitude of release rate and dose size.
 Volume of distribution obeys only one compartment model
V = dose/Co
Where, Co –plasma drug concentration
 Apparent volume of distribution is merely a propotionately constant that relates the drug
concentration in blood or plasma to the total amount of drug in the body.
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37.  For two compartment models
Vss= (1+ k12/k21)V1
Where,
k12-rate constant for distribution of drug from central to peripheral compartment
k21-peripheral to central
Vss-drug concentration in blood or plasma at steady state to the total amount of
drug
 If the amount of drug in central compartment p, is the known amount of drug in peripheral
compartment T.
 Hence total amount of drug in body can be calculated by;
T/p= k12 (k21-β)
Where,
β=slow disposition rate constant
T/p=estimates the relative distribution of drug B/w compartments
Vss=estimate extent of distribution in body
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38. 3) METABOLISM
 Metabolism is the conversion of a drug to another chemical form and this is considered
in the design of sustained release system for the drugs.
 Factors associated with metabolism
1. Ability of the drug to induce or inhibit enzyme synthesis.
2. Fluctuating drug blood level and first pass metabolism Ex- nitroglycerine
Figure 12: General pathway of Drug Metabolism
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39. 4) ELIMINATION AND BIOLOGICAL HALF-LIFE
The rate of elimination of drug is described quantitatively by its biological half life
t1/2= 0.693 v/cls
Where, V=volume of distribution
cls=systemic clearence
cls = I.V administered dose
AUC
where, AUC=area under curve, sq.cm
Significance of Half life
 Drug having shorter half life requires frequent dosing, making it desirable to develop
SDRS.
 This will be opposite for drugs with higher half lives.
 Drug with half life less than 2 hrs and those with more than 8hrs should not be used.
Ex of drugs with half life less than 2hrs: Ampicillin, furosemide, penicillin
Ex of drugs with half life more than 8hrs: Diazepam, digitoxin, digoxin
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40. 5) SIDE EFFECTS AND SAFETY CONSIDERATIONS
 Minimizing side effect for a particular drug done by controlling its plasma
concentration and using less total drug over time course of therapy.
 To measure margin of safety of drug its therapeutic index is considered.
TI= TD50/ED50
Where,
TD50-Median toxic dose
ED50-Median effective dose
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41. THANK-YOU
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