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ASSIGNMENT ON SUSTAINED
RELEASE ORAL DOSAGE FORMS
(2018-2019)
PRESENTED BY: KAJAL A. PRADHAN
M.PHARM. SEM-1
PHARMACEUTICS
#Introduction
>>The oral route of drug delivery is typically considered the preferred and most patient-
convenient means of drug administration .With many drugs the basic Goal of therapy is to
achieve a steady-state blood or tissue level that is therapeutically effective and nontoxic for an
extended period of time.
>>Sustain release system are considered a wiser approach for the drugs with short half-lives and
which require repeated dosing, they are easy to formulate and are irrespective of absorption
process from gastrointestinal tract after oral administration.
#Concept of sustained release dosage form:-
>>Sustained release dosage form is the term used to identify a drug delivery system that are
designed to achieve a prolonged therapeutic effect by continuously releasing medication over an
extended period of time after administration of single dose form.
>>This dosage design embodies a process of either drug modification or dosage form
modification, the absorption process & subsequently drug action can be controlled. In the case of
orally administer this period is measured in hours while in the case of injectable this period
varies from days to months.
>>Sustained release dosage form is defined as well characterized and reproducible dosage form,
which is designed to control drug release profile at a specified rate to achieve desired drug
concentration either in blood plasma or at targeted site.
#Criteria of drug to formulate as sustained release dosage forms:-
a) Desirable half life
b) High therapeutic index.
c) Small dose.
d) Desirable absorption & solubility characteristic
e) Desirable absorption window.
f) First pass clearance.
#Advantage
1.Improved patient compliance
>Less frequent dosing.
>Reduced night time dosing.
2. Better drug utilization
>reduction in total amount of drug used
3. Decreased local &systemic effects
>Due to dose reduction.
4. Increased bioavailability.
5. Increased reliability of therapy.
6. Extend duration of action.
#Disadvantage
>Termination of therapy can be done i.e. immediate change in therapy cannot be done if any
adverse effects seen.
>No dose adjustment can be done.
>Costly process &equipment are involved in manufacturing of sustained drug release.
>Drug with narrow absorption are poor candidate for sustained release.
#Theory
Mechanism:-
>>Most of sustained release dosage form follows the mechanism of diffusion, dissolution or
combination of both ,to produce slow release of drug at predetermined rate.
Design and fabrication:-
>>Drug kinetics are assumed to be adequately approximated by a one-body compartment model
i.e. drug distribution is sufficiently rapid so that a steady state is immediately attained between
the central &peripheral compartments i.e. the blood-tissue transfer rate constants, k12&k21,are
large.
>>Under the foregoing circumstances, the drug kinetics can be characterized by three
parameters: the elimination rate constant (ke) or biological half-life {t1/2=0.693/ke}, the
absorption rate constant {ka}, and the apparent volume of distribution {Vd}, which defines the
apparent body space in which drug is distributed. A large Vd value {e.g.100 L} means that drug
is extensively distributed into extra-vascular space: a small Vd value {e.g.10 L} means that drug
is largely confined to the plasma.
>>For the two-body-compartment representation of drug kinetics, Vc is the volume of the central
compartment, including both blood and any body water in which drug is rapidly perfused .
>>The loading or immediately available portion of the dose {Di}, the maintenance or slowly
available portion of the dose {Dm}, the time{Tm} at which release of maintenance dose begins
{i.e..the delay time between release of Di and Dm}, and
the specific rate of release {kr} of the maintenance dose.
>>The body drug- level time profile that characterizes an ideal peroral sustained release dosage
form after a single administration. Tp is the peak time, & h is the total time after administration in
which drug is effectively absorbed. Cp is the average drug level to be maintained constantly for a
period of time is equal to {h-Tp} hours; it is also the peak blood level observed after
administration of a loading dose.
>>to obtain a constant drug level, the rate of drug absorption must be made equal to the rate of
elimination.
Zero-order release approximation
>>A design consisting of a loading dose & a zero-order release maintenance dose, as described
by Robinson and Eriksen . If a zero-order release characteristic can be implemented in a practical
formulation, the release process becomes independent of the magnitude of maintenance dose &
does not change during the effective maintenance period.
1 .Estimation of kro:- eq.{2} is derived by considering that at the steady state the Rate of
absorption is constant and equal to the Rate of elimination, i.e. Rate of absorption=ka. Xa=Rate
elimination = ke. Xb where Xa is amount of drug at the absorption site, Xb is the body drug
content , which is set equal to Vd. Cp, or Am in eq. {1}, the body drug content to be maintained
constant. If absorption of the loading dose is effectively complete, kaXa=kro
2 .Estimation of Tm:- Release of maintenance dose is set at the peak time for the loading dose
eq.{3} is used to calculate the peak time from known value absorption {2 hr-1} and elimination
{0.21 hr} rate constants. Since eq.{3} applies only to one-compartment model Tm ,which is
actually 0.5 hrs, is significantly overestimated.
3 .Estimation of dm: The maintenance dose is estimated as the product of release rate and
maintanence time {eq.6}, corrected for the bioavilabilty factor, F {eq. 4}, which is the fraction of
the administered dose absorbed from a reference non-sustained release dosage form. The F-value
as estimated the as the ratio of the area under plasma curve{AUC-value} measured after oral
administration to the AUC-value observed after intravenous administration of the same dose of
the drug.
4 .Estimation of Di: The loading dose is that portion of the total dose that is initially released as a
bolus and is therefore immediately available for absorption. It results in a peak blood level equal
to the desired level to be maintained. eq.{7}
allows estimation of Di if dm is delayed. If release of dm is not delayed, the loading dose
calculated using eq. {7} is adjusted for the quantity of drug provided by the zero-order release
process in time tm as shown by eq.{8}.
First-order release approximation
>>The rate of release of drug from the maintenance portion of the dosage form should be zero-
order if the amount of drug at the absorption site is to be remain constant. Most currently
marketed sustained release formulations, however, do not release a constant rate.
>>The rate of appearance of drug at the absorption site can be approximated by an exponential
or first –order process in which the Rate of drug release is function only of the amount of drug
remaining in dosage form. Expression that can be used to estimate the design parameter for
optimised first order release models.
Three different design are considered:- Simultaneous release of Dm and Di, Delayed release of
Dm where Tm = TP , Delayed release of Dm where Tm > TP
Method-1. Simultaneous release of Dm and Di :- The crossing time, Ti, is the time at
which blood level profiles produced by administration of separate loading and maintenance
doses intersect. The closest approximation to the ideal profile is obtained if the crossing point is
made at least equal to the desired maintenance period (h – Tp). Eq. (9), is an approximation of
Eq. (11) where , ke > kr1. The maintenance dose is estimated from the the initial release rate, i.e.
kr1Dm = KeAm = kr0. The loading dose is estimated by correcting the immediate release dose
required to achieve the maintenance level for the quantity of drug delivered by the maintenance
dose in the time Tp.
Method-2. Delayed release of Dm:- Tm = Tp. If Dm is larger and kr, is made small,
maintenance dose is released as a pseudo-zero-order process. As a first approximation, kr1 may
be estimated as the reciprocal of the maintenance time. Dm is then calculated as in method 1.
Better approximation of a zero-order response can be obtained if Dm is increased and kr1 is
reduced to maintain the product kr1Dm constant.
Method 3. Delayed release of Dm :-Tm > TP, Increasing the delay time, Tm , allows the use
of faster release rates. A period equal to the time at 99 % of the loading dose has been absorbed
is selected using eq. (10). The release rate constant is iteratively calculated from Eq. (11) such
that a peak is obtained from the maintenance dose at the midpoint of the maintenance time. The
amount of drug required to produce a second peak at this time is the maintenance dose,
calculated from Eqs (12, 13).
>>Method 1&2 have disadvantages that large maintenance doses are required, resulting in a
significant loss of drug available for absorption .Method 1 represent a design that is least
efficient in term of the dose required to achieve the design objective. Drugs characterized by
large loading doses and small biologic half-lives could not be practically formulated in these
designs.
>>Optimization of sustained release dosage form design requires minimization of the total dose
delivered and maximization of the duration of drug release .In case of the zero-order model,
adjustment of the maintenance dose is a function only of the duration of time. Design based on
simultaneous release of Dm and Di requires the minimum total dose. Optimum first-order designs
are those in which Dm is delayed beyond the peak obtained from the loading dose.
#Implementation of design
1. Approaches based on drug modification:-
a.Complex formation:- In the case of drug complexes, the effective release rate is a function of
two processes: the rate of dissolution of the solid complex into the biological fluids and the rate
of dissociation of the solid complex in solution.
>If the rate of dissolution is grater then the rate of dissociation, a zero release pattern might
be realized because the concentration of complex is maintained at its saturation point if the
solubility of the complex is sufficiently low so that excess solid complex is present during most
of the effective maintenance time
b. Drug adsorbate preparation:- It represent a special case of complex formation in which the
product is essentially insoluble drug availability is determined only by the rate of dissociation
and therefore, access of the adsorbents surface to water as well as the effective surface area of
the adsorbate
c. Prodrug synthesis:- They are therapeutically inactive drug derivative that regenerate the parent
drug by enzymatic or non enzymatic hydrolysis. Example of drugs from which prodrugs
designed for prolonged action have been synthesized include isoproterenol , isoniazid and
penicillin
2. Approaches based on dosage form modification:-
a. Embedded matrix:-
>In this drug is embedded in a matrix of a retardant material and compressed into tablets .The
retardant materials may be:-
1. Skeleton matrix forming e.g. PVC
2. Water insoluble but potentially erodible e.g. stearyl alcohol, carnuba wax
3. Polymer forming hydrophilic matrices e.g. methyl cellulose, sodium carboxy methyl cellulose
b. Barrier principle:-
>A layer of retardant material is imposed between the drug and elution medium (the formulation
may be in the form of granules or tablets)
>Coating used are
1. Solid hydroxylated lipid
2. Formalized gelatin
# Sustained release formulation:-
1. Encapsulated slow release granules
2. Tabletted slow release granulations
3. Matrix tablet
4. Drug complexes
5. Ion activated systems
6. pH based system:-
a. pH dependent system
b. pH independent system
7. Altered density system:-
a. Low density micro-pellets
b. High density micro-pellets
8. Colonic release system
#MATRIX TABLET
>> Matrix tablet is defined as “Oral solid dosage form in which active pharmaceutical ingredient
is uniformly dispersed throughout polymeric matrices (hydrophilic or hydrophobic) which
retards the drug release rate.
>>Matrix tablets can be formulated by either direct compression or wet granulation method by
using a variety of hydrophilic or hydrophobic polymers.
>>The rate of drug release from the matrix is primarily governed by rate and extent of water
penetration, swelling of polymer, dissolution and diffusion of drug. Thus, sustained release
matrix tablet can offer better patient compliance and could be quite helpful in treatment of
chronic diseases.
>>In a matrix system, the drug substance is homogenously mixed into the rate controlling
material as crystalline, amorphous or in rare cases molecular dispersion
>>Drug bioavailability which is critically dependent on the drug polymer ratio may be modified
by inclusion of diluents such as lactose in place of polymer in low-milligram-potency
formulations
>> 3 methods may be used to disperse drug & additive in the retardant base:-
>>Drug with high drug:polymer ratio,a wet granulation process is required. Low-milligram-
potency formulations may be directly compressed or granulated using alcohol if the polymer is
not in a form amendable to direct compression
1. Solvent evaporation technique can be used, in which a solution or dispersion of drug &
additive is incorporated into the molten wax phase, the solvent is removed by evaporation.
2. Dry blends of ingredients may be slugged & granulated.
3. Fusion technique, in which drug and additive are blended into the molten wax matrix at
temperatures slightly above the melting point
#Advantage
• Easy to manufacture.
• Cost effective.
• Improved patient compliance.
• Sustained release formulations avoid the high blood concentration.
• Reduce drug toxicity by slowing down drug absorption.
• Enhanced drug stability in GI milieu.
• Minimize the local and systemic side effects.
• No see-saw fluctuations in plasma drug concentration profile.
• Less amount of drug is required
#Disadvantage
• Matrix needs to be removed after drug release.
• Costly in comparison to conventional dosage form.
• Presence of food and gut transition time can affect the release rate.
#Mechanism of drug release:
>>The mechanism involved in drug release includes either diffusion
or dissolution .On exposure with aqueous solution hydration of matrix takes place as a result it
swells to block up existing pores, dissolution of the contents takes place. Due to gel formation a
viscous solution is formed which give rise to a positive pressure which opposes the liquid entry
& causes the disintegration of matrix.
#Retardants used in matrix tablet formulation are:-
#Various matrix systems are:-
1.Lipid matrix system
Principle:-Wax matrices are a simple concept. They are easy to manufacture using standard
direct compression, roller compaction or hot melt granulation.
>>Release depend on an aqueous medium dissolving the channelling agent, which leaches out of
the compact, so forming a porous matrix of tortuous capillaries. The active agent diffuses out of
the matrix through water filled capillaries &dissolves in aqueous medium. These matrices are not
now in common usage.
>> A typical formulation consists of:-
•active drug
•wax matrix former
•channelling agent
•solubilizer& pH modifier
•antiadherent/glidant
•lubricant
2 .Insoluble polymer matrix systems:-
>>Drug release from inert matrices has been compared to the leaching from a sponge. The
release rate depends on drug molecules in aqueous solution diffusing through a network of
capillaries formed between compacted polymer particles.
>>The release rate of a drug from an inert matrix can be modified by changes in the porosity and
tortuosity of the matrix i.e. its pore structure.
>>Compression force controls the porosity of the matrix, which in turn controls drug release
4 types of drug release from insoluble matrix can be considered:-
•drug molecularly dissolved in the matrix and drug diffusion occurs by a solution-diffusion
mechanism
•drug dispersed in the matrix and then after dissolution of the drug,diffusion occurs via a
solution-diffusion mechanism
•drug dissolved in the matrix and diffusion occurs through water-filled pores in the matrix
•drug dispersed in the matrix and then, after dissolution,diffusion occurs through water-filled
pores
3 .Hydrophilic colloid matrix systems:-
>>Hydrophilic polymer matrix systems are widely used for designing oral controlled drug
delivery dosage forms because of their flexibility to provide a desirable drug release profile, cost
effectiveness, and broad regulatory acceptance. However, the use of hydrophilic matrix alone for
extending drug release for highly water soluble drugs is restricted due to rapid diffusion of the
dissolved drug through the hydrophilic gel network.
>>For such drugs it becomes essential to include hydrophobic polymers in the matrix system.
This leads to the conclusion that matrix tablets seem to be most promising when developing an
oral controlled release formulation.
>>These delivery system are also called a swellable-soluble matrices
#Principle:- The system comprises a mixture and lubricant/glidant.On contact with water ,the
hydrophilic colloid components swell to form a hydrated matrix layer. This then controls the
further diffusion of water into the matrix.Diffusion of the drug through the hydrated matrix layer
controls its rate of release. The outer hydrated matrix layer will erode as it becomes more dilute.
The rate of erosion depends on the nature of the colloid.
Types of hydrophilic matrix
1.True gels:-
>The diffusion pathway is via the continuous phase in the interstices of the gel.
>The crosslink are more or less fixed after the gel has formed.
>Bulk viscosity generally does not correlate well with diffusion.
>The bulk viscosity of the gel is derived from the structure of the crosslinked polymeric chains
with a contribution from
the continuous phase.
2.Viscous matrices:-
>The diffusion pathways is via the continuous phase trapped between the adjacent polymeric
chains.
>There are no fixed crosslinks.
>The bulk viscosity is related to the entanglement of adjacent polymer chains which are free to
move within the
continuous phase
>Bulk viscosity may correlate with diffusion
#Components of hydrophilic matrix delivery system:-
•Active drug
•Hydrophilic colloids
•Matrix modifier
•Solubilizer
•Compression
•Lubricant
•Glidant
#Drug release from hydrophilic colloid matrices:-
>Surface drug dissolves and gives a 'brust effect'
>The hydrophilic polymer hydrates and an outer gel layer forms
>The gel layer becomes a barrier to uptake of further water and to the transfer of drug
>Drug release occurs by diffusion through the gel layer;insoluble drug is released by erosion
followed by dissolution.
>Following erosion, the new surface becomes hydrated and forms a new gel layer
References:-
>Lachman/Lieberman’s-The Theory and Practice of Industrial Pharmacy, Fourth Edition, page
no.597-616
>Aulton’s Pharmaceutics-The Design and Manufacture of Medicines, Third edition, page
no.490-495
Questions
1. Comment: Sustained release formulation gives a constant release.
2. What are the approach based on drug modification in sustained release dosage form?
3. Draw general pharmacokinetic model of an ideal peroral sustained release dosage form?
4. Enlist sustained release formulation?
5. What are the criteria to formulate sustained release dosage form?
6. Design of zero order release was given by whom?
7. What is the release pattern of sustained dosage form if zero-order release design is
implemented?
8. What are the approach based on dosage form modification in sustained release dosage
form?
9. Enumerate and explain design for first order release in sustained release dosage form?
10. Which materials are used as retardants in matrix tablet?
11. What are the component of hydrophilic matrix drug delivery system?
12. Explain mechanism of drug release from hydrophilic colloid matrixes?
13. What are the types of drug release from insoluble matrix?
14. What a typical formulation of lipid matrix system consists of?
15. Explain in short mechanism of drug release from matrix system?
16. Give advantage and disadvantage of matrix tablet?
17. Methods of preparation of matrix system?
18. Comment: Sustained release can be established through matrix system.
19. Give advantage and disadvantage of sustained release dosage form?
20. Explain types of hydrophilic matrix?
sustained release oral dosage forms
sustained release oral dosage forms
sustained release oral dosage forms
sustained release oral dosage forms
sustained release oral dosage forms

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sustained release oral dosage forms

  • 1. ASSIGNMENT ON SUSTAINED RELEASE ORAL DOSAGE FORMS (2018-2019) PRESENTED BY: KAJAL A. PRADHAN M.PHARM. SEM-1 PHARMACEUTICS
  • 2. #Introduction >>The oral route of drug delivery is typically considered the preferred and most patient- convenient means of drug administration .With many drugs the basic Goal of therapy is to achieve a steady-state blood or tissue level that is therapeutically effective and nontoxic for an extended period of time. >>Sustain release system are considered a wiser approach for the drugs with short half-lives and which require repeated dosing, they are easy to formulate and are irrespective of absorption process from gastrointestinal tract after oral administration. #Concept of sustained release dosage form:- >>Sustained release dosage form is the term used to identify a drug delivery system that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose form. >>This dosage design embodies a process of either drug modification or dosage form modification, the absorption process & subsequently drug action can be controlled. In the case of orally administer this period is measured in hours while in the case of injectable this period varies from days to months. >>Sustained release dosage form is defined as well characterized and reproducible dosage form, which is designed to control drug release profile at a specified rate to achieve desired drug concentration either in blood plasma or at targeted site. #Criteria of drug to formulate as sustained release dosage forms:- a) Desirable half life b) High therapeutic index. c) Small dose. d) Desirable absorption & solubility characteristic e) Desirable absorption window. f) First pass clearance. #Advantage 1.Improved patient compliance
  • 3. >Less frequent dosing. >Reduced night time dosing. 2. Better drug utilization >reduction in total amount of drug used 3. Decreased local &systemic effects >Due to dose reduction. 4. Increased bioavailability. 5. Increased reliability of therapy. 6. Extend duration of action. #Disadvantage >Termination of therapy can be done i.e. immediate change in therapy cannot be done if any adverse effects seen. >No dose adjustment can be done. >Costly process &equipment are involved in manufacturing of sustained drug release. >Drug with narrow absorption are poor candidate for sustained release. #Theory Mechanism:- >>Most of sustained release dosage form follows the mechanism of diffusion, dissolution or combination of both ,to produce slow release of drug at predetermined rate. Design and fabrication:- >>Drug kinetics are assumed to be adequately approximated by a one-body compartment model i.e. drug distribution is sufficiently rapid so that a steady state is immediately attained between the central &peripheral compartments i.e. the blood-tissue transfer rate constants, k12&k21,are large. >>Under the foregoing circumstances, the drug kinetics can be characterized by three parameters: the elimination rate constant (ke) or biological half-life {t1/2=0.693/ke}, the absorption rate constant {ka}, and the apparent volume of distribution {Vd}, which defines the
  • 4. apparent body space in which drug is distributed. A large Vd value {e.g.100 L} means that drug is extensively distributed into extra-vascular space: a small Vd value {e.g.10 L} means that drug is largely confined to the plasma. >>For the two-body-compartment representation of drug kinetics, Vc is the volume of the central compartment, including both blood and any body water in which drug is rapidly perfused . >>The loading or immediately available portion of the dose {Di}, the maintenance or slowly available portion of the dose {Dm}, the time{Tm} at which release of maintenance dose begins {i.e..the delay time between release of Di and Dm}, and the specific rate of release {kr} of the maintenance dose. >>The body drug- level time profile that characterizes an ideal peroral sustained release dosage form after a single administration. Tp is the peak time, & h is the total time after administration in which drug is effectively absorbed. Cp is the average drug level to be maintained constantly for a period of time is equal to {h-Tp} hours; it is also the peak blood level observed after administration of a loading dose. >>to obtain a constant drug level, the rate of drug absorption must be made equal to the rate of elimination. Zero-order release approximation >>A design consisting of a loading dose & a zero-order release maintenance dose, as described by Robinson and Eriksen . If a zero-order release characteristic can be implemented in a practical formulation, the release process becomes independent of the magnitude of maintenance dose & does not change during the effective maintenance period.
  • 5. 1 .Estimation of kro:- eq.{2} is derived by considering that at the steady state the Rate of absorption is constant and equal to the Rate of elimination, i.e. Rate of absorption=ka. Xa=Rate elimination = ke. Xb where Xa is amount of drug at the absorption site, Xb is the body drug content , which is set equal to Vd. Cp, or Am in eq. {1}, the body drug content to be maintained constant. If absorption of the loading dose is effectively complete, kaXa=kro 2 .Estimation of Tm:- Release of maintenance dose is set at the peak time for the loading dose eq.{3} is used to calculate the peak time from known value absorption {2 hr-1} and elimination {0.21 hr} rate constants. Since eq.{3} applies only to one-compartment model Tm ,which is actually 0.5 hrs, is significantly overestimated. 3 .Estimation of dm: The maintenance dose is estimated as the product of release rate and maintanence time {eq.6}, corrected for the bioavilabilty factor, F {eq. 4}, which is the fraction of the administered dose absorbed from a reference non-sustained release dosage form. The F-value as estimated the as the ratio of the area under plasma curve{AUC-value} measured after oral administration to the AUC-value observed after intravenous administration of the same dose of the drug. 4 .Estimation of Di: The loading dose is that portion of the total dose that is initially released as a bolus and is therefore immediately available for absorption. It results in a peak blood level equal to the desired level to be maintained. eq.{7} allows estimation of Di if dm is delayed. If release of dm is not delayed, the loading dose calculated using eq. {7} is adjusted for the quantity of drug provided by the zero-order release process in time tm as shown by eq.{8}. First-order release approximation >>The rate of release of drug from the maintenance portion of the dosage form should be zero- order if the amount of drug at the absorption site is to be remain constant. Most currently marketed sustained release formulations, however, do not release a constant rate.
  • 6. >>The rate of appearance of drug at the absorption site can be approximated by an exponential or first –order process in which the Rate of drug release is function only of the amount of drug remaining in dosage form. Expression that can be used to estimate the design parameter for optimised first order release models. Three different design are considered:- Simultaneous release of Dm and Di, Delayed release of Dm where Tm = TP , Delayed release of Dm where Tm > TP Method-1. Simultaneous release of Dm and Di :- The crossing time, Ti, is the time at which blood level profiles produced by administration of separate loading and maintenance doses intersect. The closest approximation to the ideal profile is obtained if the crossing point is made at least equal to the desired maintenance period (h – Tp). Eq. (9), is an approximation of Eq. (11) where , ke > kr1. The maintenance dose is estimated from the the initial release rate, i.e. kr1Dm = KeAm = kr0. The loading dose is estimated by correcting the immediate release dose required to achieve the maintenance level for the quantity of drug delivered by the maintenance dose in the time Tp. Method-2. Delayed release of Dm:- Tm = Tp. If Dm is larger and kr, is made small, maintenance dose is released as a pseudo-zero-order process. As a first approximation, kr1 may be estimated as the reciprocal of the maintenance time. Dm is then calculated as in method 1. Better approximation of a zero-order response can be obtained if Dm is increased and kr1 is reduced to maintain the product kr1Dm constant. Method 3. Delayed release of Dm :-Tm > TP, Increasing the delay time, Tm , allows the use of faster release rates. A period equal to the time at 99 % of the loading dose has been absorbed is selected using eq. (10). The release rate constant is iteratively calculated from Eq. (11) such that a peak is obtained from the maintenance dose at the midpoint of the maintenance time. The amount of drug required to produce a second peak at this time is the maintenance dose, calculated from Eqs (12, 13).
  • 7. >>Method 1&2 have disadvantages that large maintenance doses are required, resulting in a significant loss of drug available for absorption .Method 1 represent a design that is least efficient in term of the dose required to achieve the design objective. Drugs characterized by large loading doses and small biologic half-lives could not be practically formulated in these designs. >>Optimization of sustained release dosage form design requires minimization of the total dose delivered and maximization of the duration of drug release .In case of the zero-order model, adjustment of the maintenance dose is a function only of the duration of time. Design based on simultaneous release of Dm and Di requires the minimum total dose. Optimum first-order designs are those in which Dm is delayed beyond the peak obtained from the loading dose. #Implementation of design 1. Approaches based on drug modification:- a.Complex formation:- In the case of drug complexes, the effective release rate is a function of two processes: the rate of dissolution of the solid complex into the biological fluids and the rate of dissociation of the solid complex in solution. >If the rate of dissolution is grater then the rate of dissociation, a zero release pattern might be realized because the concentration of complex is maintained at its saturation point if the solubility of the complex is sufficiently low so that excess solid complex is present during most of the effective maintenance time b. Drug adsorbate preparation:- It represent a special case of complex formation in which the product is essentially insoluble drug availability is determined only by the rate of dissociation and therefore, access of the adsorbents surface to water as well as the effective surface area of the adsorbate c. Prodrug synthesis:- They are therapeutically inactive drug derivative that regenerate the parent drug by enzymatic or non enzymatic hydrolysis. Example of drugs from which prodrugs designed for prolonged action have been synthesized include isoproterenol , isoniazid and penicillin
  • 8. 2. Approaches based on dosage form modification:- a. Embedded matrix:- >In this drug is embedded in a matrix of a retardant material and compressed into tablets .The retardant materials may be:- 1. Skeleton matrix forming e.g. PVC 2. Water insoluble but potentially erodible e.g. stearyl alcohol, carnuba wax 3. Polymer forming hydrophilic matrices e.g. methyl cellulose, sodium carboxy methyl cellulose
  • 9. b. Barrier principle:- >A layer of retardant material is imposed between the drug and elution medium (the formulation may be in the form of granules or tablets) >Coating used are 1. Solid hydroxylated lipid 2. Formalized gelatin # Sustained release formulation:- 1. Encapsulated slow release granules 2. Tabletted slow release granulations 3. Matrix tablet 4. Drug complexes 5. Ion activated systems 6. pH based system:- a. pH dependent system b. pH independent system 7. Altered density system:- a. Low density micro-pellets b. High density micro-pellets 8. Colonic release system #MATRIX TABLET
  • 10. >> Matrix tablet is defined as “Oral solid dosage form in which active pharmaceutical ingredient is uniformly dispersed throughout polymeric matrices (hydrophilic or hydrophobic) which retards the drug release rate. >>Matrix tablets can be formulated by either direct compression or wet granulation method by using a variety of hydrophilic or hydrophobic polymers. >>The rate of drug release from the matrix is primarily governed by rate and extent of water penetration, swelling of polymer, dissolution and diffusion of drug. Thus, sustained release matrix tablet can offer better patient compliance and could be quite helpful in treatment of chronic diseases. >>In a matrix system, the drug substance is homogenously mixed into the rate controlling material as crystalline, amorphous or in rare cases molecular dispersion >>Drug bioavailability which is critically dependent on the drug polymer ratio may be modified by inclusion of diluents such as lactose in place of polymer in low-milligram-potency formulations >> 3 methods may be used to disperse drug & additive in the retardant base:- >>Drug with high drug:polymer ratio,a wet granulation process is required. Low-milligram- potency formulations may be directly compressed or granulated using alcohol if the polymer is not in a form amendable to direct compression 1. Solvent evaporation technique can be used, in which a solution or dispersion of drug & additive is incorporated into the molten wax phase, the solvent is removed by evaporation. 2. Dry blends of ingredients may be slugged & granulated. 3. Fusion technique, in which drug and additive are blended into the molten wax matrix at temperatures slightly above the melting point #Advantage • Easy to manufacture. • Cost effective.
  • 11. • Improved patient compliance. • Sustained release formulations avoid the high blood concentration. • Reduce drug toxicity by slowing down drug absorption. • Enhanced drug stability in GI milieu. • Minimize the local and systemic side effects. • No see-saw fluctuations in plasma drug concentration profile. • Less amount of drug is required #Disadvantage • Matrix needs to be removed after drug release. • Costly in comparison to conventional dosage form. • Presence of food and gut transition time can affect the release rate. #Mechanism of drug release: >>The mechanism involved in drug release includes either diffusion or dissolution .On exposure with aqueous solution hydration of matrix takes place as a result it swells to block up existing pores, dissolution of the contents takes place. Due to gel formation a viscous solution is formed which give rise to a positive pressure which opposes the liquid entry & causes the disintegration of matrix. #Retardants used in matrix tablet formulation are:-
  • 12. #Various matrix systems are:- 1.Lipid matrix system Principle:-Wax matrices are a simple concept. They are easy to manufacture using standard direct compression, roller compaction or hot melt granulation. >>Release depend on an aqueous medium dissolving the channelling agent, which leaches out of the compact, so forming a porous matrix of tortuous capillaries. The active agent diffuses out of the matrix through water filled capillaries &dissolves in aqueous medium. These matrices are not now in common usage. >> A typical formulation consists of:- •active drug •wax matrix former •channelling agent •solubilizer& pH modifier •antiadherent/glidant •lubricant 2 .Insoluble polymer matrix systems:- >>Drug release from inert matrices has been compared to the leaching from a sponge. The release rate depends on drug molecules in aqueous solution diffusing through a network of capillaries formed between compacted polymer particles. >>The release rate of a drug from an inert matrix can be modified by changes in the porosity and tortuosity of the matrix i.e. its pore structure. >>Compression force controls the porosity of the matrix, which in turn controls drug release 4 types of drug release from insoluble matrix can be considered:- •drug molecularly dissolved in the matrix and drug diffusion occurs by a solution-diffusion mechanism •drug dispersed in the matrix and then after dissolution of the drug,diffusion occurs via a solution-diffusion mechanism •drug dissolved in the matrix and diffusion occurs through water-filled pores in the matrix •drug dispersed in the matrix and then, after dissolution,diffusion occurs through water-filled pores 3 .Hydrophilic colloid matrix systems:- >>Hydrophilic polymer matrix systems are widely used for designing oral controlled drug delivery dosage forms because of their flexibility to provide a desirable drug release profile, cost effectiveness, and broad regulatory acceptance. However, the use of hydrophilic matrix alone for extending drug release for highly water soluble drugs is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. >>For such drugs it becomes essential to include hydrophobic polymers in the matrix system. This leads to the conclusion that matrix tablets seem to be most promising when developing an oral controlled release formulation. >>These delivery system are also called a swellable-soluble matrices #Principle:- The system comprises a mixture and lubricant/glidant.On contact with water ,the hydrophilic colloid components swell to form a hydrated matrix layer. This then controls the
  • 13. further diffusion of water into the matrix.Diffusion of the drug through the hydrated matrix layer controls its rate of release. The outer hydrated matrix layer will erode as it becomes more dilute. The rate of erosion depends on the nature of the colloid. Types of hydrophilic matrix 1.True gels:- >The diffusion pathway is via the continuous phase in the interstices of the gel. >The crosslink are more or less fixed after the gel has formed. >Bulk viscosity generally does not correlate well with diffusion. >The bulk viscosity of the gel is derived from the structure of the crosslinked polymeric chains with a contribution from the continuous phase. 2.Viscous matrices:- >The diffusion pathways is via the continuous phase trapped between the adjacent polymeric chains. >There are no fixed crosslinks. >The bulk viscosity is related to the entanglement of adjacent polymer chains which are free to move within the continuous phase >Bulk viscosity may correlate with diffusion #Components of hydrophilic matrix delivery system:- •Active drug •Hydrophilic colloids •Matrix modifier •Solubilizer •Compression •Lubricant •Glidant #Drug release from hydrophilic colloid matrices:- >Surface drug dissolves and gives a 'brust effect' >The hydrophilic polymer hydrates and an outer gel layer forms >The gel layer becomes a barrier to uptake of further water and to the transfer of drug >Drug release occurs by diffusion through the gel layer;insoluble drug is released by erosion followed by dissolution. >Following erosion, the new surface becomes hydrated and forms a new gel layer
  • 14. References:- >Lachman/Lieberman’s-The Theory and Practice of Industrial Pharmacy, Fourth Edition, page no.597-616 >Aulton’s Pharmaceutics-The Design and Manufacture of Medicines, Third edition, page no.490-495
  • 15. Questions 1. Comment: Sustained release formulation gives a constant release. 2. What are the approach based on drug modification in sustained release dosage form? 3. Draw general pharmacokinetic model of an ideal peroral sustained release dosage form? 4. Enlist sustained release formulation? 5. What are the criteria to formulate sustained release dosage form? 6. Design of zero order release was given by whom? 7. What is the release pattern of sustained dosage form if zero-order release design is implemented? 8. What are the approach based on dosage form modification in sustained release dosage form? 9. Enumerate and explain design for first order release in sustained release dosage form? 10. Which materials are used as retardants in matrix tablet? 11. What are the component of hydrophilic matrix drug delivery system? 12. Explain mechanism of drug release from hydrophilic colloid matrixes? 13. What are the types of drug release from insoluble matrix? 14. What a typical formulation of lipid matrix system consists of? 15. Explain in short mechanism of drug release from matrix system? 16. Give advantage and disadvantage of matrix tablet? 17. Methods of preparation of matrix system? 18. Comment: Sustained release can be established through matrix system. 19. Give advantage and disadvantage of sustained release dosage form? 20. Explain types of hydrophilic matrix?