Advanced Drug delivery systems

1. Advanced Drug Delivery
Systems

2. The term “drug delivery systems” refers to the
technology utilized to present the drug to the
desired body site for drug release and absorption.
The first drug delivery system developed was the
syringe, invented in 1855, used to deliver medicine
by injection. The modern transdermal patch is an
example of advanced drug delivery system.
The goal of any drug delivery system is to provide a
therapeutic amount of drug to the proper site in the
body to promptly achieve and then maintain the
desired drug concentration.
This idealized objective points to the two aspects most
important to the drug delivery, namely:
*Spatial placement: relates to targeting of a drug
to a specific organ or tissue.
*Temporal delivery of a drug: refers to controlling
the rate of drug delivery to the target tissue.

3. Dosage Forms
There are numerous dosage form into which a drug substance
can be incorporated for the convenient and efficacious treatment
of a disease. Dosage forms can be designed for administration by
all possible delivery routes to maximize therapeutic response.
Dosage Forms Available For Different Administration Routs:
Oral- Solutions, syrups, elixirs, suspensions, emulsions,
gels, powders, granules, capsules, tablets.
Topical- Ointments, creams, pastes, lotions, gels, solutions,
topical aerosols.
Parenteral- Injections (solutions, suspensions, emulsions forms),
implants, irrigation and dialysis solutions.
Rectal- Suppositories, ointments, creams, solutions, powders.
Lungs- Aerosols (solutions, suspensions, emulsions, powder
forms), inhalation, sprays, gases.
Nasal- Solutions, inhalations.
Eye- Solutions, ointments.
Ear- Solutions, suspensions, ointments.

4. Conventional Dosage Form or Immediate – Release
Dosage Form
Conventional / Immediate – release dosage form is a dosage form
which is formulated / designed to give rapid and complete release
of the drug contained therein immediately after administration.
Kinetic scheme for the extra vascular administration the
conventional dosage form of a drug that follows one –
compartment open model for disposition:
Dosage
Form
Absorption Pool Body Compartment
Urine
Drug
Release
Kr
Absorption
( INPUT )
Elimination
( OUTPUT )
Ka
Ke
Kr, Ka and Ke : first order rate constants for drug release, absorption and overall elimination
respectively.

5. Immediate release from a convenient dosage form implies that
Kr >>> Ka. This means that absorption of a drug across a
biological membrane (e.g. GI epithelium) is the rate–timing
step in delivery of the drug to the body compartment.
For non–immediate–release dosage forms Kr <<< Ka.
i.e. release of drug from the dosage form is the rate limiting
step. Therefore the above scheme reduces to the following:
Dosage
Form
Body
Compartment
Urine
Drug
Release
Kr
Elimination
Ke
Essentially, the absorptive phase of the kinetic scheme
becomes insignificant compared to the drug release. Thus the
effort to develop a non–immediate–release dosage form must
be primarily directed at altering the release rate by affecting the
value of Kr.

6. Typical drug blood level vs. time curve / profile for
extra vascular administration of a single dose of the
conventional dosage form of a drug following one –
compartment open model for disposition:
MTC /
MSC
IV rout
Absorption
phase
Ineffective
range
MEC
Therapeutic
range
Rate of drug input
= Rate of drug output
Toxic range
Time

7. Typical drug blood level – time profile for multiple dosage
(non–immediate–release) regimen (equal doses of the
drug at fixed intervals) of a conventional dosage form:
A) For time intervals allowing complete elimination of the
previous dose: A series of isolated single dose profiles
are obtained
MSC
MEC
Dose
Time
Dose Dose

8. B) For the dosing time intervals shorter than the time required
for complete elimination of the previous dose:
MSC
MEC
Time
D DD D D D D D
At the start of the multiple dosage regimen, the blood levels of drug tends
to increase in successive doses. But the rate of drug elimination will
increase as the average blood level of drug rises (first order kinetics) and a
situation is eventually reached when the overall rate of elimination of drug
becomes equal to the overall rate of supply. This situation is called “Steady
State”.
For a drug administered at equal time intervals, the time required
for the average blood levels to reach the 95% of the steady state value is
4.3 times the biological half–life (t½) of the drug. The corresponding figure
for 99% is 6.6 times.

9. Advantages of Conventional Dosage Form:
1. Per unit cost of conventional dosage form is less
than non-immediate release dosage form.
2. More flexibility for the physician for adjusting
dosage form in conventional dosage form.
3. Conventional dosage form can accommodate the
patient variation.
4. No problems with drug having too small half life.
5. Potent drugs can’t be formulated as sustained
release dosage form.

10. Limitations of Conventional Drug Therapy:
1. Unable to maintain therapeutic blood level for a prolonged
period of time.
2. Fluctuation of blood level over successive dosing intervals
(giving peak and valley pattern).
3. Risk of over medication or under-medication because of
drug blood level fluctuation.
4. Require frequent dosing Patient inconvenience + Poor
patient compliance Therapeutic failure / Inefficiency.
5. No therapeutic action during overnight no dose period
Risk of symptom break through in chronic disease.
6. Total amount of drug required is higher over the entire
course of therapy. (compared to SRDF)
7. Local/systemic side effect + overall health care cost is high.

11. Non-Immediate Release Dosage Form
Non-immediate release dosage form is those which do not
release whole amount of drugs contained, immediately after
administration.
Why Non-Immediate Release Dosage Form?
a) Delayed release of an immediate release unit. Ex: Enteric
coated tablet or capsule.
b) Repetitive intermittent release of two or more immediate
release unit incorporated into a single dosage form. Ex:
Repeat action tablet or capsule.
***Although a repeat action dosage form exhibits the same
“peak and valley” pattern as associated with conventional
dosage forms, but it improves patient compliance by reducing
dosing frequency.

12. Types of Non-Immediate Release
Dosage Form :
1. Delayed release dosage form
2. Sustained release dosage form
a) Control release
b) Prolonged release
3. Site specific release dosage form
4. Receptor release dosage form

13. Site–Specific Release and Receptor–
Release Dosage Forms
Site–specific and receptor release dosage
forms offer targeted delivery of a drug directly
to a certain biological location.
In case of site–specific release dosage
forms, the target is the specific receptor for
the drug within an organ or tissue.

14. Sustained Release
Dosage Forms
Sustained release dosage
forms are those dosage forms
which are designed to release
drug continuously at sufficiently
slow or controlled rate over an
extended period of time to
provide prolonged therapeutic
effect.
In case of oral dosage forms,
this period is usually measured
in hours. But in case of
injectable dosage forms, the
period may range from days to
months or even years.

15. Sustained release dosage forms can further
be categorized as:
a) Controlled release dosage forms: those
sustained–release dosage forms which are
designed to release drug at a sufficiently
controlled rate to maintain a constant blood
level over an extended period of time.
b) Prolonged release dosage forms: which
cannot maintain a constant blood level, but the
blood level declines at such a sufficiently slow
rate that it remains within the therapeutic
range for a satisfactory prolonged period of
time.

16. Time (hrs)
MSC
MEC
A
B
Fig: The blood level–time profile of (A) Controlled–
release (B) Prolonged–release dosage form

17. Criteria of a Drug Required for Designing as
Sustained Released Dosage Form:
• They exhibits neither very slow nor very fast
rates (t½<2hrs) of absorption and excretion.
[Drugs having biological half lives of between 4
& 6 hours make good candidates in sustained –
release formulations.]
• They are uniformly absorbed from the GIT.
• They are administered in relatively low dose.
• They are used in the treatment of chronic rather
than acute conditions.
• They possess a good margin of safety.
[Accidental dose dumping from potent drugs
may be strongly hazardous.]

18. Formulation Methods for Oral Sustained–Release
Dosage Forms
The more common methods used in the design of
orally administered sustained release dosage forms
include:
– Reservoir systems or devices
– Matrix Systems or Devices
– Osmotic Pumps or Systems
– Ion–Exchange Resin Complexes
– Other Drug Complexes
– Drug Adsorbates
– Prodrugs

19. 1. Reservoir Systems or Devices
These systems or devices consists of a core of drug material is surrounded
by a coat of retardant barrier (polymeric membrane). The layer of
retardant material separates the drug and the elution medium.
Mechanism of Drug Release from a Reservoir Device: The release
of drug from a reservoir system can take place by four
mechanisms:
A. Diffusion of drug present in the reservoir through the barrier.
Here the barrier is impermeable to the elution medium.
B. Penetration of elution media through the barrier into the
reservoir, dissolution of the drug followed by diffusion of the
dissolved drug through the barrier.
C. Timed erosion of the barrier.
D. Rupture of the barrier as a result of permeation of elution
medium.
Drug
Reservoir
C
B
D
A

20. Common Methods Employed to Develop Reservoir
Systems/ Devices Include:
A. Coating
B. Microencapsulation
A. Coating: A number of reservoir devices can
be prepared by applying the technology of
coating which includes:
a. Mixed release coated granules/ pellets
b. Uniform release coated granules/ pellets
c. Microdialysis cells
d. Drug coat of retardant material over
placebo pellets

21. a. Mixed Release Coated Granules
Drug pellets/ granules are divided into 3 to 4 groups. One
group is left uncoated to provide the initial loading dose and
the other groups of pellets/ granules are coated to different
thicknesses. The various groups are mixed together and
placed in capsules or compressed into tablets.
Mechanism of drug release: Moisture penetration through the
barrier→ swelling of the core → rupture of the barrier
The retardant materials used for coating includes
Combination of waxes, fatty acids, alcohols and esters,
Enteric materials such as cellulose acetate phthalate and
formalized gelatin, Mixture of solid hydroxylated lipids such as
hydrogenated castor oil or glyceryl trihydroxy-stearate mixed
with modified celluloses.
Examples of drugs designed as SRDF by this method include
Erythromycin, Pancreatin etc.

22. b. Uniform Release Coated Granules / Pellets
In this method, drug granules / pellets are uniformly coated by
a retardant material that slowly release drug over sufficiently
prolonged period of time.
Retardant materials employed for this purpose include
hydrolyzed styrene maleic acid copolymer, partially
hydrogenated cotton seed oil etc.
Examples of drugs designed as SRDF by this technique
include Crystals of ascorbic acid, Methylprednisolone etc.

23. c. Microdialysis Cells
Drug pellets are coated with a mixture of ethyl
cellulose (a water insoluble and pH insensitive
polymer) and sodium chloride particles or some other
water soluble materials (e.g. polyethylene glycol).
Leaching of the sodium chloride molecules from the
film results in dialytic membrane. This allows
permeation of water, dissolution of drug and diffusion
of drug through the essentially intact membrane.
Examples of drugs designed as SRDF by this
technique are Nitroglycerin, Propoxyphene, Aspirin
etc.

24. d. Drug Coat of Retardant Material over Placebo
Pellets
The drug is suspended in the coating of retardant
material applied onto placebo pellets. The prepared
pellets are placed in capsules. The drug is released
by erosion or rupture of the barrier.
Retardant materials employed include polyethylene
glycol, modified ethyl cellulose, shellac or cellulose
acetate phthalate.
Example of drugs designed as SRDF by this
technique is theophylline

25. B. Microencapsulation:
Microencapsulation means encapsulation of drug
material in microscopic size particles of a ‘wall forming’ material.
The most common method of microencapsulation is
coacervation. There are other techniques; like, spray drying.
Drug designed as SRDF by microencapsulation is KCl.
Coacervation: In this technique, the prospective wall–forming
material e.g. gelatin, is dissolved in water. The drug material to
be microencapsulated is added to the solution and the two–
phase mixture is thoroughly stirred until the drug material is
broken up to the desired particle size.
Then a solution of a second material (usually acacia) is
added which concentrates gelatin into tiny liquid droplets called
“coacervates” that encircle drug particles.
The particles are coated to different thicknesses, mixed
together and compressed into tablets or placed in capsules.
The drug is released by dissolution of coating materials.

26. 2. Matrix System or Devices
In these systems or devices, the drug is dispersed
(embedded) in a matrix of retardant material, which may be
encapsulated in particulate form or compressed into tablets.
Fig. Network model (Drug is
insoluble in the retardant
material)
Fig. Dispersion model
(Drug is soluble in the
retardant material)

27. Mechanisms of Drug release from a matrix device takes
place by any one or a combination of the followings:
1. Penetration of water/ eluting media into the matrix, dissolution of
the drug creating channels followed by diffusion of the drug
through the channels (pore diffusion). This occurs when the
matrix is insoluble in water, and the drug is insoluble in the
matrix but soluble in water.
2. Primarily diffusion of drug through the matrix and secondarily
partition between matrix and water. This occurs when the
matrix is insoluble in water, but the drug is soluble in the matrix
and has a high solubility in water / elution media.
3. Primarily partition between matrix and water / elution media and
secondarily diffusion through the matrix. This occurs when the
matrix is water insoluble, but the drug is soluble in the matrix
and has low water solubility.
4. Erosion. This occurs when the matrix is insoluble in water but
potentially erodable.

28. Retardant Materials Used in Matrix Devices
Three classes of retardant materials are used to formulate
matrix devices:
1. Insoluble plastics / plastic materials / “Skeleton” matrix
Examples: polyethylene, polyvinyl chloride, methyl
acrylate – methacrylate copolymer and ethyl cellulose
2. Insoluble but potentially erodable materials
Examples: waxes, lipids and related materials. Specific
examples include carnauba wax, castor wax (hydrogenated
castor oil) and triglycerides.
3. Hydrophilic polymers
Examples: These are insoluble inert polymers.

29. 3. Osmotic Systems / Pumps
These systems employ osmotic pressure as the driving force to
cause the release of drug. A constant release of drug can be
achieved if a constant osmotic pressure is maintained and a
few other features of the system are controlled.
A number of osmotic pumps / systems have been designed by
pharmaceutical manufacturers including:
1. Oral Osmotic Systems
2. Push – Pull Osmotic System
3. Multi Directional Osmotic Drug Absorption
System

30. Mechanism of Drug Release:Mechanism of Drug Release: GI fluid enter theGI fluid enter the
tablet core across the semi-permeable membrane →tablet core across the semi-permeable membrane →
dissolve drug→ creates an osmotic gradient acrossdissolve drug→ creates an osmotic gradient across
the membrane →pumps the drug out through thethe membrane →pumps the drug out through the
delivery orifices.delivery orifices.
The rate of drug solution release is approximatelyThe rate of drug solution release is approximately
one to two drops per hour.one to two drops per hour.

31. 4. Ion – Exchange Resin Complexes
Ion – exchange resins are water insoluble polymers containing
salt forming groups on the polymer chain.
Resins used are special grades of styrene / divinyl benzene
copolymers that contain substituted acidic groups (carboxylic and
sulfonic for cation exchanges) or basic groups (quaternary
ammonium for anion exchanges).
Drug is bound to the resin by repeated exposure of the resin to
the drug in a chromatographic column or by prolonged contact of
the resin with the drug solution.

32. For example, drug-resin salts may be prepared by percolation of
the sodium salt of the resin with a concentrated solution of a drug
hydrochloride salt. The following equation represents the drug
release in-vivo:
Resin – SO3Na + Drug HCl → NaCl + Resin-SO3. Drug H
Similarly drug-resinates are prepared by reaction of sodium salts
of acidic drugs with resin chloride.
Resin – NH4Cl + Drug Na → NaCl + Resin-NH4. Drug
Release in-vivo :
Resin – NH4.Drug + NaCl → Drug Na + Resin-NH4Cl
The resin.drug complex is then washed with ion-free water and
dried. The resulting product can be encapsulated, tabletted or
suspended in ion-free vehicles.

33. 5. Other Drug Complexes
Certain drug substances that are only slowly soluble in the
body fluids are inherently long acting (Griseofulvin).
Thus drugs that are, high water soluble may be bound
to suitable complexing agents to form complexes which are
poorly water soluble and consequently give sustained action.
The steps or mechanism involved in controlling the release of
drug from drug complexes in GI fluid can be illustrated as
follows:
Examples include:
Tannic acid complexes of basic drugs like amphetamine and
antihistamines.
Other complexing agents to prepare complexes of basic drugs
include polygalacturonic acid, algenic acid and arabogalactose
sulfate.
Dissolution Dissociation
DC . solid DC . solution D

34. 6. Drug Adsorbate
Drug adsorbates represent a special case of complex
formation in which the product is essentially insoluble.
Drug availability is determined only by the rate of dissociation
(desorption) and, therefore access of the adsorbent surface to
water as well as the effective surface area of the adsorbate.
The mechanism involved in controlling the release of drug from
adsorbates can be illustrated as follows:
The adsorbate, can be formulated as liquid suspensions,
tablets or capsules.
Desorption
AD. Solid D

35. 7. Prodrugs
Prodrugs are therapeutically inactive drug derivatives
that regenerate the parent drug in-vivo by enzymatic or non-
enzymatic hydrolysis.
The steps or mechanisms involved in controlling release of
drug from a prodrug can be depicted by the following scheme:
Desorption Absorption
PD. Solid PD. Solution PD. Plasma
Metabolism
D
Elimination

36. Parenteral Sustained Release Dosage Forms
The most common types of dosage forms used for
parenteral sustained-release drug therapy are:
1. Intramuscular Injections
2. Implants for subcutaneous tissues and
various body cavities
3. Transdermal systems/devices

37. Intramuscular Injections
The intramuscular injections used for sustained-
release drug therapy may be a number of types
including:
1. Drug complexes
2. Aqueous suspensions
3. Oil solution and oil suspension
4. Emulsions

38. Implants
Implants are drug-bearing polymeric device which are
implanted subcutaneously or in various body cavities. This is
one of the oldest and most highly developed forms of drug
delivery. This method finds particular applicability to cases
where chronic administration of drug over period ranging from
days to years is required.
Examples include: Insulin for diabetes, Pilocarpine for
glaucoma, Immune agents for various diseases and allergies,
Contraceptive steroids, Narcotic antagonists, Antibiotics,
Anticancer drugs, Anti-hypertensive drugs.
The polymer materials must be biocompatible and nontoxic.
They are usually of the following types: Hydrogels, Silicones,
Polyethylene, Ethylene vinyl acetate (EVA) copolymers,
Biodegradable polymers.

39. There are four types of implantable devices
based on the site of implantation. These
include:
1. Subcutaneous devices
2. Intravaginal devices
3. Intrauterine devices
4. Intraocular devices

40. USP Requirements and FDA Guidance for
Sustained-Release Dosage Forms:
The USP contains general chapters and specific tests to
determine the drug release capabilities of sustained release
tablets & capsules.
Release of Drug: The USP test for drug release for sustained
release dosage forms is based on drug dissolution from the
dosage unit against test time. According to USP the individual
monographs contain specific criteria for compliance with the test
and the apparatus and test procedures to be release tablets.
Uniformity of Dosage Units: Modified release tablets &
capsules must meet the USP standard for uniformity for
conventional dosage units. Uniformity of dosage units may be
demonstrated by either of two methods, weight variation or
content uniformity.

41. In vitro-In Vivo Correlations: In vitro-in vivo relationships
(IVIVRs) or in vitro-in vivo correlations (IVIVCs) one critical
to the development of oral sustained release products.
Asserting (IVIVCs) is important through out product
development, clinical evaluation, submission of an
application for FDA approval for marketing and during post
approval for any proposed formulation or manufacturing
changes.
In 1997, The FDA published a guidance document,
sustained release Oral Dosage Forms: Development,
Evaluation and Application of in-Vitro / in-Vivo
Correlations.
It provides guidance to sponsors of new drug applications
(NDAs) for sustained release oral products.

42. Labeling:
The USP indicates labeling requirements for modified-
release dosage form in addition to general labeling
requirements. The requirements are specific to the
monograph article.
For example, the label of Aspirin Delayed
release tablets must state that, the tablets are enteric
coated.
The labeling for Theophylline extended release
capsules must indicate whether the product is
intended for every 12 or 24 hours and state with which
in vitro drug release test are described in the
monograph.

43. Conventional Drug Therapy
1. Rapid and complete release of
drug immediately after
administration.
2. Absorption is the rate-limiting
step (kr >>> ka).
3. Blood level fluctuates (Peak and
Valley).
4. There is risk of overmedication
or under medication at periods
of time.
5. Frequent dosing.
6. Patient non compliance.
Therapeutic inefficiency / failure.
7. Inconvenience of patient.
Sustained-Release Drug Therapy
1. Slow/controlled release of drug over
an extended period of time.
2. Drug release from the dosage form is
the rate-limiting step (ka >>> kr ).
3. Constant blood level is maintained
over a prolonged period (Reduced
fluctuation).
4. Reliable therapy as the risk is
minimized.
5. Reduced frequency of dosing.
6. Improved patient compliance.
7. Enhanced patient convenience with
day-time and night-time medication.
Comparison between conventional and sustained-release drugs

44. 8. No therapeutic action during
overnight no dose period.
9. Risk of symptom breakthrough.
10. Incidence and severity of
untoward effects related to high
-peak plasma concentration ↑.
11. More total dose over the entire
course of therapy.
12. More side effects.
13. Health care cost ↑.
14. Permits prompt testing of
therapy.
15. Incidence of severity of GI side
effects due to dose dumping of
irritant drugs ↑.
16. More flexibility for physician in
adjusting dosage required.
8. Maintains therapeutic action during
overnight no dose period.
9. Improved treatment of many chronic
diseases (minimizing symptom
breakthrough).
10. Incidence and severity of untoward
effects related to high – peak plasma
concentration ↓.
11. Less total dose over the entire
course of therapy.
12. Minimize/eliminate incidence of
local/systemic side effects.
13. Health care cost ↓.
14. Does not prompt.
15. Incidence of severity of GI side
effects due to dose dumping of irritant
drugs ↓.
16. Less flexibility.

45. 17. Can accommodate abnormal
cases of disease safety offering
drug disposition etc.
18. ↓ Chance of at any site of GIT
(local irritation ).
19. No problems for drugs with too
short half lives.
20. Per unit cost is less. ↓
21.
17. Can not accommodate.
18. ↑ Chance of at any site of GIT (local
irritation).
19. Not suitable for drugs with too short
half lives, drugs needing specific
requirements for absorption from GIT.
20. Per unit cost is more. ↑
21.
Time Time