I am a pharmacist. These slides describe biotechnology topic. I hope students get good benefits about it.

1. NOVEL DRUG DELIVERY
SYSTEMS
Dr.Talib Hussain,
Lecturer, IPS, UVAS, Lahore.

2. INTRODUCTION
• The drug delivery systems are classified in five generations
• Conventional drug delivery systems are those which offer better
drug administration and achieve therapeutic response
immediately, i.e. Tablets, Capsules, Syrups, Parenteral, creams
and gels.
• Major problems of conventional systems are lack of control on
drug release and failure to deliver drug at therapeutic site.
• The release rate of the drug was controlled effectively in
modified release systems classified under third generation DDS.

3. INTRODUCTION CONT.…
• The delivery of drug at the therapeutic site at a controlled rate is
a major problem of modified release systems
• Targeted drug delivery systems are classified in forth generation
DDS are termed as Novel Drug Delivery Systems (NDDS).
• NDDS are systems that deliver the drug to the targeted site at a
release rate according to the need of body/organ/tissue.
• These systems are either active targeted or passive targeted
systems
• These are classified as Novel GIT DDS and Novel Parenteral
(Vesicular) DDS

4. NOVEL GIT DRUG DELIVERY SYSTEMS
• These are systems that deliver drug at a controlled rate to
targeted therapeutic or targeted absorption site by oral
administration of system.
• Oral route is most suitable administration route and if it can target
disease site at therapeutic concentration for desired therapy
duration then it will be most superior system than parenteral.
• These systems are classified in four classes
a. Gastro-retentive drug delivery systems (GRDDS)
b.pH-Controlled DDS (Colon targeted DDS)
c. Oral Osmotic Pumps
d.Ion-Exchange Controlled DDS

5. GASTRO-RETENTIVE DRUG DELIVERY
SYSTEM (GRDDS)
• Gastro-retentive drug delivery is
an approach to prolong gastric
residence time, thereby
targeting site-specific drug
release in the upper
gastrointestinal tract (GIT) for
local or systemic effects.

6. GASTRO-RETENTIVE DDS (GRDDS)
• Gastro-retentive drug delivery systems can remain in the gastric
region for longer period of time and hence significantly prolong
the gastric residence time of drugs.
• Prolonged gastric retention improves bioavailability, reduces
drug waste, and improves solubility for drugs that are less
soluble in a high pH environment.
• It has applications also for local drug delivery to the stomach and
proximal small intestines.
• Controlled gastric retention may be achieved by the mechanisms
of mucoadhesion, flotation, sedimentation, expansion, modified
shape systems, or by the simultaneous administration of
pharmacological agents that delay gastric emptying.

7. FACTORS EFFECTING ORAL DRUG
DELIVERY
• There are several factors that effect oral drug administration
1) GIT transit time
2) Physicochemical properties (interactions of drug with GIT)
3) Pharmacokinetics of drug
• GIT transit time
• It is time of retention of food contents and drugs in GIT.
• Stomach 30 minutes (pH 1-3, fasting) to 1 hour (pH 4.3-5.4, feed)
• Duodenum <0.5 h (pH 6, fasting) to <0.5 h (pH 5.4, feed)
• Jejunum and ilium 1.7 h (pH 6-7, fasting pH, 5.4-5.6, feed)
• Ilium 1.3 h (pH 6.6-7.4, fasting and feed)
• Colon 13.5 h (pH 6.8-7, fasting and feed)

8. ABSORPTION WINDOW
• There is a variable absorption of drugs in various parts of GIT
• There are certain portion of GIT from where drug is maximally absorbed and
are various portions where it is not well absorbed.
• An acidic drug has maximum absorption in stomach and duodenum but least
in intestine, this generate the concept of absorption window
• Absorption window refers to specific portion / area of GIT where major
portion of drug is absorbed is called absorption window of drug.
• To formulate a site-specific orally administered controlled release dosage
form, it is desirable to achieve a prolong gastric residence time by the drug
delivery.
• Prolonged gastric retention time (GRT) in the stomach could be
advantageous for local action e.g. treatment of peptic ulcer, etc.

9. FACTORS DEVELOPING ABSORPTION WINDOW
A. Physicochemical factors
❖There are three physicochemical factors leading to absorption window
1. pH dependent solubility
❖If drug solubility is dependent on pH of GIT then acidic drug will get
soluble in stomach only
2. pH dependent stability
❖If the drug is degraded in different pH of GIT then it should be
absorbed before reaching the specific pH
3. Enzymatic degradation of drugs
❖Many drugs are degraded by gut enzymes mainly present in
small/large intestine so it can only remain active in stomach

10. PHYSIOLOGICAL FACTORS
• There are two physiological factors that leads to A.W. concept
1. Mechanism of drug absorption
• The drug is absorbed by either Active transport, Facilitated transport,
or Passive transport. Active and facilitated diffusion occur in only
certain parts of GIT. If a drug is only absorbed by these mechanisms
then it is absorption window of drug.
2. Degradation by microorganisms
• GIT is full of millions of different microbes i.e. More than 1000 species
of microbes in colon of GIT
• 1010 to 1 million bacteria in one gram of feces
• 10 million viruses in one gram of feces
• 1000 parasite cysts in one gram of feces

11. BIOCHEMICAL FACTORS
• There are two biochemical factors that leads to A.W. concept
1. Metabolic enzymes
• Various metabolic enzymes are present in GIT which have protective
action on ingestion of toxins, drugs, bacteria etc. that degrade them
2. Multidrug Efflux Pump
• When drugs/toxins are absorbed from GIT then these pumps push the
drug back into lumen of GIT. These pumps are made of P-Glycoprotein
and have natural diffusion mechanism

12. CLASSIFICATION OF GRDDS
• It is classified into following categories

13. POTENTIAL DRUG CANDIDATES FOR GRDDS
• 1. Drugs acting locally in the stomach (active in stomach), e.g. Antacids and
drugs for H. Pylori viz., Misoprostol
• 2. Drugs that are primarily absorbed in the stomach, e.g. Amoxicillin
• 3. Drugs that are poorly soluble at alkaline pH, e.g. Furosemide, Diazepam,
Verapamil, etc.
• 4. Drugs with a narrow window of absorption, e.g. Cyclosporine,
Methotrexate, Levodopa, etc.
• 5. Drugs which are absorbed rapidly from the GI tract, e.g. Metronidazole,
tetracycline.
• 6. Drugs that degrade in the colon, e.g. Ranitidine, Metformin HCl.
• 7. Drugs that disturb normal colonic microbes, e.g. antibiotics against
Helicobacter pylori.

14. DESIGN CONSIDERATION OF GRDDS
GIT motility
• Smooth muscle subunits linked by gap junctions generates motility in GIT.
• Muscle subunits work in a tonic or a phasic fashion.
• Tonic contractions are maintained for several minutes up to hours in the
sphincters of the tract and anterior stomach.
• Phasic contractions consist of brief periods of both relaxation and contraction,
occurring in the posterior stomach and the small intestine.
• Motility may be overactive (hypermotility), leading to diarrhea or vomiting, or
underactive (hypomotility), leading to constipation or vomiting; either may
cause abdominal pain.
• In fasting state, there are definite muscle patterns (waves of electrical activity)
constituting motility of GIT called as Migrating Motor Complex (MMC).

15. MIGRATING MOTOR COMPLEX
• These motor complexes trigger peristaltic waves, which facilitate
transportation of indigestible substances from the stomach,
through the small intestine, past the ileocecal sphincter, and into
the colon.
• The MMC occurs every 90–230 minutes during the interdigestive
phase (i.e., between meals) and is responsible for the rumbling
experienced when hungry.
• It also serves to transport bacteria from the small intestine to the
large intestine and to inhibit the migration of colonic bacteria into
the terminal ileum; an impairment to the MMC typically results in
small intestinal bacterial overgrowth.

16. • The MMC originates mainly in the stomach—
while ~25% will arise from the duodenum or
proximal jejunum-and can travel to the distal
end of the ileum.
• They consist of four distinct phases:
• Phase I – A prolonged period of quiescence
(40–60% of total time);
MIGRATING MOTOR COMPLEX PHASES
• Phase II – Increased frequency of action potentials and smooth muscle
contractility (20–30% of total time);
• Phase III – A few minutes of peak electrical and mechanical activity (5–10
minutes);
• Phase IV – Declining activity which merges with the next Phase I.

17. FLOATING DRUG DELIVERY SYSTEMS
• Floating drug delivery systems have
a bulk density lower than gastric
fluids and thus remain buoyant in the
stomach for prolonged period of
time, without affecting the gastric
emptying rate.
• While the system is floating on the
gastric contents, the drug is released
slowly at a desired rate from the
system.

18. FLOATING DRUG DELIVERY SYSTEMS
The major requirements for floating drug delivery system are:
• Release contents slowly to serve as a reservoir.
• Maintain specific gravity lower than gastric contents (1.004 – 1.01
gm/mL).
• Form a cohesive gel barrier.
• The inherent low density can be provided by the entrapment of
air (e.g. hollow chambers) or by the incorporation of low density
materials, e.g. fatty materials or oils, or foam powder.
• Multiple-unit floating system preferred over Single-unit dosage
because of dose dumping.

19. FLOATING TECHNIQUES
• Effervescent floating drug delivery system
• Volatile liquid containing systems
• CO2 gas generating systems
• Non-Effervescent floating drug delivery system
• Colloidal gel barrier systems
• Alginate beads
• Hollow Microspheres
• Microporous Compartment System
• Raft forming system / Magnetic systems

20. EFFERVESCENT SYSTEM
• These systems produce gases within the system, On gas
production their density becomes less and they start
floating.
1. Volatile oil containing systems
❖These systems consists of two chambers and a shell
1. Reservoir for drug
2. Reservoir for volatile oil
3. Coating of these chambers with a porous membrane (polymers)

21. • The volatile oil chamber expands on reaching body
temperature (ingestion) due to conversion to gas and become
low density as volume of system increases than its weight.
• The bio-erodible polymeric plug placed in the volatile oil
chamber degrades after 24 h or any set time period and
system sinks.
• The sinked system will be evacuated from the body.

22. CO2 GAS GENERATING SYSTEMS
• This systems contains four layers
• A central sustained/controlled release layer of drug
• Surrounding is a layer of sodium bicarbonate NaHCO3 (a salt of base)
• Surrounding is another layer of Tartaric acid (an acid to react base)
• Coated with a polymer membrane that swells and occupy gas CO2
generated
• Upon ingestion water penetrates and acid reacts with bicarbonate to
generate CO2
• The system will opt high volume that will cause floating

23. NON-EFFERVESCENT FLOATING DRUG
DELIVERY SYSTEM
• This type is also called as hydro dynamically balanced system
(HBS).
• The formulation involves the mixing of the drug with gel forming
hydrocolloids.
• These gel forming hydrocolloids are swellable cellulose type
hydrocolloids, polysaccharide, matrix forming polymer like
polycarbonate, polystyrene and polymethacrylate.
1. COLLOIDAL GEL BARRIER SYSTEM
These system don’t produce gases by reacting or activating
rather these form low density due to already available gas
entrapped within systems or swelling mechanisms.

24. This hydrocolloids swell in contact with gastric fluid after oral
administration and maintains integrity of shape and a bulk density
barrier, the air trapped by swollen polymer confer buoyancy to the
dosage forms.
The polymer layer gets hydrated and swells up. The swelling develops a
colloidal gel barrier enabling controlled release of the drug by diffusion
and erosion

25. (a)
Multiple
unit
floating
system
(b)
CO2
Generating
System
(c)
Osmotic
Pump
(d)
Microporous
compartment
system
(e)
HBS
(f)
Hollow
Microspheres

26. 2. ALGINATE BEADS
• These multi-unit systems are prepared by freeze-drying of the
beads prepared after ionic gelation of sodium alginate with
calcium chloride solution.
• If sodium alginate solution is added dropwise into calcium
chloride solution, calcium alginate precipitates.
• Spherical beads (~2.5 mm) are obtained in the precipitate.
• Now, the beads are separated for snap-freezing in liquid nitrogen,
followed by freeze-drying (40 °C, 24 h).
• As reported by Garg et al. 2008, a porous floating system is
developed, which has the ability to maintain floatation for over 12 h
and GRT greater than 5.5 h

27. HOLLOW MICROSPHERES
• Micro-balloons or hollow microspheres are multiple-unit floating
systems.
• The hollow central part of the drug delivery system is enclosed by a
drug-loaded polymer matrix.
• These are prepared by either simple solvent evaporation technique or
solvent diffusion method.
• Polymers frequently used in these systems are Eudragit S, polycarbonate,
agar, calcium alginate, low methoxylated pectin, etc.
• In-vitro studies in aqueous medium showed floatation for 12 h. When
administered orally, radio-graphical studies showed dispersion of these
systems occurred in the upper portion of the stomach region with a
retention of 3 h

28. RAFT-FORMING SYSTEMS
• These systems work by forming viscous cohesive gel.
• When the system comes in contact with the GI fluid, formation of the gel
occurs by swelling of the solid to colloid occurs at its every portion,
creating a continuous layer.
• This layer is called raft that contains calcium carbonate and sodium
alginate.
• When it comes in contact with the GI fluid, sodium alginate complexes
with the Ca+2 ions resulting in the formation of a low-density gel which
floats and forms a plank or a barrier-like structure on the GI fluid.
• NaHCO3 can also be used in these systems for providing buoyancy by
producing CO2 gas.

29. • Different approaches for this system are based
on physical mechanism and physiological
stimuli.
• The former consists of swelling, cross-linking,
and diffusion, whereas the latter mainly
comprises of pH and temperature-dependent
swellings.
• Polymers present in these systems are alginic
acid, chitosan, carbopol, gellan gum, etc.
• These systems show a sustained-release of the
drug by remaining in the stomach region for
several hours

30. MUCOADHESIVE OR BIOADHESIVE
TECHNOLOGIES
• The systems which have the capability to adhere or attach with
the mucous membrane of stomach or buccal cavity are known
as mucoadhesive/bucoadhesive DDS.
• Bio/muco-adhesive are those which bind to the gastric
epithelial cell surface or mucin and serve as a potential means
of extending the GRT of drug delivery system (DDS) in the
stomach, by increasing the intimacy and duration of contact of
drug with the biological membrance.
• The basis of adhesion in that a dosage form can stick to the
mucosal surface by different mechanism.

31. • Mucoadhesive technologies are also known as bioadhesive
systems.
• These are designed to increase the GRT of the system by
getting bound to the epithelium of the GI wall.
• It does so by increasing the contact time of the system with
the GI wall membrane.
• A mucoadhesive agent along with the drug simply
constitutes the system.
• The adhesive interaction between the system and the GI
membrane is formed through bonding, hydration, or through
receptors

32. MUCOUS MEMBRANE
• It’s a protective layer inside the stomach wall that is sticky in
nature.
• The mucous layer consists of water (95%w/w), mucin (less than
5%w/w), salts (1%w/w), carbohydrates, and lipids.
• Mucin is a glycoprotein (0.2 to > 50 MDa) which is coded by MUC
genes and classified as membrane-bound and secreted.
• Mucins MUC1, MUC2, MUC4, MUC6, MUC5AC, and MUC7 are
commonly secreted from transmembrane proteins, goblet cells,
tracheobronchioles, primary lining of stomach, and saliva,
respectively.
• Over secretion of mucin cause cancer (MUC1 & MUC4),
Inflammation (MUC2), asthma and COPD (MUC1-MUC4).

33. • Mucoadhesion consists of
several complex
processes, which mainly
consists of two stages or
mechanisms, namely
contact stage and
consolidation stage as
depicted in Figure.
• a) Stages of mucoadhesion
• b) Mucoadhesive joint.
• c) Wetting theory
• d) Effect of contact angle
on wetting and adhesion
• e) Fracture theory.
• f) Diffusion interlocking
theory

34. MECHANISM OF ADHESION
• The moisture activates the mucoadhesive particles by
plasticizing the particles, allowing them to become free, and
get combined by weak Van der Waal’s force and hydrogen
bond (Hydration).
• Cationic materials (e.g. chitosan) interact with negatively
charged groups (e.g. sulphate) on the cell surfaces or on the
mucin through electrostatic interactions (Bonding).
• In the diffusion theory, the mucoadhesive particles and
glycoproteins present in the mucous interact by inter-
penetrating with each of their chains and by building
secondary bonds.

35. • Three types of polymers are used as binding to mucous.
• Anionic Polymers: Carboxyl and sulphate functional group polymers
produce –ve charge at pH exceeding pKa. E.g. Poly Acrylic Acid, Na
Carboxy Methyl Cellulose.
• Cationic Polymers: Produce +ve charge, e.g. Chitosan
(polysaccharide, chitin source)
• Covalent binding: Carbonyl Di Imidazole (CDI) functional groups
have high covalent binding to mucin, e.g. Lectins, Thiolated polymers,
PAA, Antibodies (aminoacidic sequence)
• Receptor binding: Functional groups of polymers react with receptors
present on mucous membrane e.g. muscarinic, histamine, serotonin, G-
protein.

36. EXPANDABLE SYSTEMS
• These have the nature of expanding in size when coming in
contact with the GI fluid.
• They increase in size to such a limit that they do not pass out
through the pyloric sphincter.Thus, they remain in the
stomach region for a sustained period of time and therefore
also called as ‘plug type systems’.
• The polymer network is hydrophilic in nature which is cross-
linked, and this leads to the high expansion/swelling of the
polymer.This cross-linking helps in maintaining physical
integrity of the system.

37. MAGNETIC SYSTEMS
• These systems consist of a small magnet placed internally in
the dosage form along with the drug and the excipients.
• A magnet is to be placed on the external environment of the
abdomen in such a precise way that the system inside the
stomach stays intact in that position.
• Thus, these systems provide enhanced GRT depending on
the duration the magnet is kept. The placement of the
external magnet in an accurate position outside the
abdomen for a long duration of time sometimes may affect
patient compliance .

39. ION-EXCHANGE RESIN SYSTEMS
• These systems consist of hydrophobic polymers which are cross-
linked in nature and contain ions inside them.
• The resin contains ions which are exchangeable and this nature
categorizes the resin into anionic and cationic. Anionic and
cationic resins can be both classified into organic and inorganic
resins.
• The inorganic resins of both the types can be further classified
into natural and synthetic.
• Under the cationic resins, the organics can be further divided into
natural, synthetic, and semi-synthetic. Under the anionic resins,
the organics can be divided into semi-synthetic and synthetic.
The drug-loaded resin is called as resinate.

40. • When this resinate reaches the GI fluid, it gets encountered with a huge
number ions present in the GI fluid. Here, the drug ions (D+) present in
the resinate get exchanged with the H+ ions present in the GI fluid,
thus making the D+ ions available in the GI environment. The left-out
resin particle is then eliminated from the body through faeces or
through biodegradation.
Organic Inorganic
Natural Semi-synthetic Synthetic Natural Synthetic
Cation Lignite Zeocarb Tannin
formaldehyde
Clay Zeolites
Anion – Sephadex Amine
formaldehyde
Dolomite Silicates

41. • Ion exchange resins are insoluble polymers that contain acidic or
basic functional groups and have the ability to exchange counter-
ions within aqueous solutions surrounding them.
• Available normally in the form of small (1-2 mm diameter) beads,
usually white or yellowish, fabricated from an organic polymer
substrate backbone
• Ion exchange is an adsorption phenomenon where the
mechanism of adsorption is electrostatic
• Electrostatic forces hold ions to charged functional groups on the
surface of the ion exchange resin. The adsorbed ions replace ions
that are on the resin surface on a 1:1 charge basis.

42. PREPARATION OF RESINATE