85 3.Theoretical Analysis 3.1.Oral Controlled Release Drug Delivery System Definition: It provides the continuous oral delivery of drugs at predictable and reproducible kinetics for predetermined period throughout the course of GIT. 140 Advantages: 1.) Reduction in plasma drug level fluctuations. 2.) Reduction in adverse effects and health care cost. 138 Polymers used: These are broken down into biologically acceptable molecules that are metabolized and removed from the body. Poly (2-hydroxy ethyl methacrylate) PolyN vinyl pyrrolidine Polyvinyl alcohol Polyacrylic acid Polyacrylamide Polyethylene glycol Additional Polymers 3 Polylactides Polyglycolides Polyanhydrides
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3.Theoretical Analysis
3.1.Oral Controlled Release Drug Delivery System
Definition:
It provides the continuous oral delivery of drugs at predictable and
reproducible kinetics for predetermined period throughout the course of
GIT.140
Advantages:
1.) Reduction in plasma drug level fluctuations.
2.) Reduction in adverse effects and health care cost.138
Polymers used:
These are broken down into biologically acceptable molecules that are
metabolized and removed from the body.
Poly (2-hydroxy ethyl methacrylate)
PolyN vinyl pyrrolidine
Polyvinyl alcohol
Polyacrylic acid
Polyacrylamide
Polyethylene glycol
Additional Polymers3
Polylactides
Polyglycolides
Polyanhydrides
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Natural Polymers
Albumin
Gelatin
Chitosan
Cellulose
Collagen
Continuous Release Systems
These release the drug for prolonged time with normal transit of dosage
form. Various systems are –
1) Dissolution Controlled Release Systems :
In this drug, particle is coated with polymer layer which controls the rate
of release of drug.
(i) Encapsulated Dissolution Control: The individual particles or
granules are coated with slowly dissolving material, compressed
directly into tablets as in spansules.141
(ii) Matrix Dissolution Control: Drug is homogenously dispersed
throughout a rate controlling medium which controls the drug
dissolution by controlling rate of dissolution fluid penetration into
matrix.
2) Diffusion Controlled Release Systems :
In this, diffusion of dissolved drug through a polymeric barrier occurs.
The two types are –
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Reservoir Devices (Laminated Matrix Devices) :
In this, water insoluble polymeric material encloses a core of drug,
partitions into membrane and exchange with fluid surrounding
tablet and additional drug will enter the membrane diffuse to
periphery and exchange with surrounding media.141
Matrix Devices :
In this, solid drug is dispersed in a insoluble matrix and the drug
release is dependent on rate of drug diffusion and not on solid
dissolution rate.
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3) Diffusion and Dissolution Controlled Release Systems:
Drug core is with partially soluble membrane where dissolution part of
membrane allows for diffusion of contained drug through pores in
polymer coat.
4) Ion Exchange Resins:
Resins are special granules passes ion active site for acidic/cationic
drugs.
5) pH Independent Formulation :
By mixing basic/acidic drug with buffering agents and finally coating
with GI fluid permeable film forming polymer.141
6) Osmotic Pressure Controlled Systems:
A drug fabricated by semi-permeable membrane is delivered by osmosis
through delivery orifice.140
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The hydrodynamic pressure created squeezes the collapsible drug
reservoir to release medicament through delivery orifice.141
Delayed Transit and Continuous Release Systems:
These detain residence time in stomach by prolonging residence time in
GIT.
Altered Density Systems:
By altering density, the residence time of drug is prolonged.
Mucoadhesive Systems:
The bioadhesive polymer continuously releases a fraction of drug into
intestine over prolonged periods of time.
Size Based System:
Based on size, the gastric emptying is delayed allowing once daily dosing
Intestinal Release Systems:
Drugs designed to prevent destabilization in gastric pH.
Colonic Release Systems:
These are used in ulcerative colitis to deliver drug in colon.140
Currently Marketed Oral Controlled Release Systems:
1.) Coating tablets, granules and non pereil sugar beads.
2.) Matrix systems made of swellable or non-swellable polymers.
3.) Slowly eroding devices.
4.) Osmotically controlled devices.
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3.2. Methods of Preparation of Nanoparticles
Definition of Nanoparticles:
Nanoparticles are defined as particulate dispersions or solid
particles with a size range of 10-1000 nm.
These are more reactive because of their greater surface area per
unit weight than larger particles.
Methods of Preparation:
1.) Preparation from natural macromolecules
2.) Emulsion Based method
3.) Coacervation method
4.) Salting-out methods
5.) Controlled Gelatin process
6.) Direct Precipitation method
Preparation of Nanoparticles from Natural Macromolecules:
By using proteins such as albumin, gelatin, leguminor vicillin and
polysaccharides such as alginates and agarose, a water in oil emulsion is
prepared and is subjected to subsequent heat denaturation or chemical
cross linkng of macromolecules. These proteins and polysaccharides
have a wide interest because of their properties of biodegradability and
biocompatibility.
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Emulsion based Method:
In this process, emulsification of an aqueous solution of albumin
in vegetable oil142 (cottonseed oil) is carried at room temperature and is
homogenized. This highly dispersed emulsion is added to a large volume
of preheated oil at about 7120C under constant stirring.144 This leads to
coagulation of solid nanospheres of albumin by denaturation due to
immediate vaporization of water. Then, the suspension is allowed to cool
down at room temperature in an ice bath.
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Coacervation Method :
This is a controlled desolvation method in which, nanoparticles are
produced by phase separation process in an aqueous medium and is
subsequently stabilized by crosslinking with Glutaraldehyde. This
method is mainly to overcome the utilization of large amount of organic
solvent to obtain nanoparticles.144
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Salting-out Methods :
An aqueous phase of saturated electrolytes like Magnesium acetate
and Magnesium chloride with PVA as stabilizing and viscosity increasing
agent is added to acetone solution of polymer under vigorous stirring.
Electrolytes in aqueous phase prevent the miscibility of aqueous and oil
phases. The addition of aqueous phase is carried until a phase inversion
occurs to form o/w emulsion. Then, the equilibrium between the two
phases is disrupted by adding pure water sufficiently to allow complete
diffusion of acetone into water thereby, spherical nanospheres are
formed by polymer precipitation.145 This techniques permits the usage of
water miscible solvents like acetone and tetrahdyrofuran instead of
traditional chlorinated solvents and also avoids the usage of surfactants
to produce nanospheres. A broad spectrum of polymers including PLA,
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methacrylic acid and co-polymers such as cellulose derivatives can be
employed in this technique.
Controlled Gelation Process :
By changing the pH, temperature or by addition of appropriate
counteriors in the protein or polysaccharides, phase separation is
induced in aqueous solution. In this, nanospheres are produced by
induction of divalent cation, calcium chloride and are stabilized by
polyelectrolytic complexation with a polyamine, poly (L-lysine).
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Direct Precipitation Method :
In this, direct polymer precipitation is induced in an aqueous
medium with or without surfactant by progressive addition of polymer
solution under stirring without emulsification. The solvent is vaporized
under reduced pressure after nanoparticle formation. But completely
miscible solvents with aqueous phase, mainly acetone and also ethanol
and methanol should be only used for precipitation.
3.3. Standardization of Nanoparticles
Particle Size:
Particle size determines the in-Vivo distribution, biological fate,
tonicity and the targeting ability of nanoparticle system and also
influences drug loading, drug release and stability of nanoparticles. Due
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to their smaller size and relative mobility, nanoparticles have relatively
higher intracellular uptake compared to the microparticles.
Desai et al. 146 found that 100 nm particles had a 2.5 fold greater
uptake that 1µm particles and 6 fold greater uptake than 10µm
microparticles in a caco 2 cell line.
Smaller particles have larger surface area where drug associated
would be at or near the particle surface leading to fast drug release.
Hence, the challenge is always to formulate the nanoparticles with
smallest size possible with maximum stability.
Currently, the fastest and most routine method of determination of
particle size is by Photon Correlation Spectroscopy or Dynamic Light
Scattering which requires the viscosity of medium to be known and is the
diameter of the particle determined by Brownian motion147 and Light
Scattering properties.
The results are usually verified by Scanning or Transmission Electron
Microscopy(SEM/TEM)
Scanning Electron Microscopy:
SEM is an instrument that produces largely magnified image by
using electrons instead of light to form an image. Electron gun produces
a beam of electrons which follows the vertical path through the
microscope between electromagnetic fields and lenses towards the
sample due to which electrons and X-rays are ejected from sample.
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Detectors collect the X-rays, backscatter electrons and secondary
electrons and convert them to signal and produce a final image on
screen.
The water must be removed from sample before the water would
vaporize in the vaccum.
Surface properties of Nanoparticles:
Zeta potential of a nanoparticle reflects the electric potential of particles
and is used to characterize the surface charge properties and to
determine whether the charged particle is encapsulated within the centre
or adsorbed on to the surface of nanocapsule.
Drug loading:
2 methods – 1) Incorporation method
2) Adsorption/Absorption method
It depends on solid state drug solubility in matrix material or polymer.
Macromolecules of protein show greatest loading efficiency when loaded
at a point nearer to its isoelectric point.12 when it has minimum
solubility and maximum absorption.
Drug Release:
The drug release rate depends on:
1) Solubility of drug
2) Desorption of surface bound/adsorbed drug
3) Drug diffusion through matrix
4) Matrix erosion/degradation149
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5) Combination erosion and diffusion process
Methods to study the in-Vitro release of drug are:
a. Side by side diffusion cells
b. Dialysis bag diffusion
c. Reverse dialysis bag technique150
d. Agitation followed by centrifugation
e. Ultrafiltration or centrifugal ultrafiltration technique
3.4. Evaluation of Bio-pharmaceutical Parameters
Pharmacokinetics is defined as kinetics of drug adsorption,
distribution, metabolism and excretion and their relationship with the
pharmacologic, therapeutic or toxicologic response in man and animals.
Pharmacokinetic Parameters:
1) Peak Plasma Concentration Cmax140: Expressed in mcg/ml
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It is also known as Maximum drug concentration or peak height
concentration.
When Cmax is attained by a drug in the plasma, the absorption rate is
equal to the elimination rate of the drug.
We can calculate plasma concentration by using equation,
2) Time of Peak Concentration (Tmax)151: Expressed in hrs. It is
defined as the time taken for a drug to reach the peak concentration in
plasma.
Useful in estimating the rate of absorption.
tpeak = Ιn (Ka/Ke) / (Ka-Ke)
Cp = [ F*Dose*Ka (e-Ket – e-Kat) ] / V* (Ka – Ke)
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3) Area Under the Curve (AUC): Expressed in mg/ml hr. It represents
the total integrated area under the plasma level-time profile and
expresses the total amount of drug that comes into the systemic
circulation after its administration.
Estimation of AUC : 1) By using trapezoidal rule
2) By integration method
4.) Half-Life (140,152): Defined as the time period required for the
concentration of drug to decrease by one half.
Ct = Coe-Kt
Co/2 = Coe-K/2 log Co/2 = log Co – Kt1/2/2.303
For Zero order : t1/2 = Co/2Ko
For First order: t1/2 = 0.693/K
Relationship between the elimination rate constant and t1/2 given by,
K=0.693/t1/2
Other equations used for calculating are, t1/2 = 0.693/K,
T1/2 = 0.693Vd/cl
5.) Absorption Rate Constant: Differential Equations, Drug amount to
be absorbed Xg
Drug in GIT → Drug in patient → Drug eliminated
Xg = F.Dose.e-Kat
Ka is calculated by using,
i) Method of residuals and
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ii) Wagner Nelson Method
6.) Bioavailability16 : It is Defined as the extent or rate at which active
moiety enters systemic circulation thereby, accessing the site of action.
The most reliable measure of a drug‟s bioavailability is by measuring
AUC.
AUC α the total amount of unchanged drug that reaches systemic