PHARMACEUTICAL APPROACHES FOR TARGETING DRUGS TO COLON

1. RECENT ADVANCES IN COLON TARGETED
DRUG DELIVERY
Presentedby
VarunM. Girme
M. PHARM
(PHARMACEUTICS)SEM- III

2. CONTENTS
• INTRODUCTION
• ANATOMY & PHYSIOLOGY OF COLON
• COLON ABSORPTION
• PHARMACEUTICAL APPROACHES FORTARGETING DRUGS TO COLON
• EVALUATION OF COLON TARGETED DRUG DELIVERY SYSTEM
• CASE STUDY
• REFERENCES
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3. Oral route is considered to be most convenient for
administration of drug to patient.
Colon is used as site of Targeted drug delivery.
Colon was considered as a BLACK-BOX , as most of
the drug are absorbed from the upper part of the GI tract.
Prime objective-Beneficial in the treatment of colon
diseases.
Increase the pharmacological activity.
Reduce dosing & side effects.
Prevent drug from degradation.
INTRODUCTION
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4. Layers:
•Serosa
•Muscularis externa
•Submucosa
•mucosa
ANATOMY & PHYSIOLOGY OF COLON
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6. DRUG ABSORPTION IN THE COLON
Drug molecules pass from the apical to
basolateral surface of the epithelial cell by
1.Transcellular - Passing through colonocytes.
2. paracellular - Passing between adjacent
colonocytes.
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7. l. COVALENT LINKAGE OFDRUG WITH CARRIER
ll. APPROACHESTODELIVER INTACTMOLECULE TOCOLON
lll . CURRENT APPROACHES
PHARMACEUTICAL APPROACHES TO DELIVER A
DRUG TO COLON
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8. 12/9/2015 8
APPROACHES
Covelent linkage of
drug with carrier
Azo bond
conjugates
Glycoside
conjugates
Glucuronide
conjugates
Cyclodextrin
conjugates
Dextran
conjugates
Amino acid
conjugates
Polymeric
prodrugs
Deliver the intact
molecules to colon
Coating with polymers
Coating with pH
sensitive polymers
Embedding in
matrices
Embedding in biodegradable
matrices and hydrogels
Time dependent
Bioadesive systems
Osmotic controlled drug
delivery
Current Approaches
Pulsinicap
Port system
Chronotropic system
CODES
COLAL-PRED System
Multi particulate
Ticking capsule
Enterion capsule technology
Probiotic approach
Nanoparticulate system

9. l. COVALENT LINKAGE OF DRUG WITH CARRIER
Prodrug approaches
1.Azo bond conjugate
2.Glycoside conjugation
3.Glucoronide conjugates
4.Cyclodextrin conjugate
5.Dextran conjugate
6.Amino acid conjugation
7.Polymericprodrugs
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10. 1.Azo bond conjugate
Complex and relatively stable community of
microorganism.
Show various metabolic reactions including reduction of
azo and nitro group.
Hydrolysis of sulfasalazine by azo reductase into
sulfapyridine and 5-aminosalicylic acid
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11. 2.Glycoside conjugation
Hydrophilic in nature so they are not absorbed by the
small intestine.
But when they reach in the colon they are hydrolyzed
by the enzyme bacterial glycosidase.
Dexamethasone-21-Dglucoside (Arrow shows site of
action of glycosidase)
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12. 3.Glucoronide conjugates
The major mechanism for the inactivation and
preparation for clearance of a variety of drugs.
Bacteria of the lower GIT however secrete β-
glucuronidase and can deglucuronidate a variety of drugs
in the intestine.
Utilized to improve certain properties of drugs such as
solubility, stability and bioavailability.
The interior of these molecules is relatively lipophilic
and the exterior relatively hydrophilic, they tend to form
inclusion complexes with various drug molecules.
4.Cyclodextrinconjugate
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13. 5.Dextran conjugate
These linkages are hydrolyzed by moulds, bacteria, and
mammalian cells.
In the colon, dextran’s glycosidic bonds are hydrolyzed
by dextranases to give shorter prodrug oligomers, which
are further split by the colonic esterases to release the drug
free in the lumen of the colon
6.Aminoacid conjugation
Made up by two hydrophilic groups like -NH2 and –
COOH they reduce the cell membrane permeability.
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14. conjugates of salicylic acid. (a) Salicyluric acid. (b)
Salicylglutamic acid conjugate (Dotted line shows the site
of cleavage)
7.Polymericprodrugs.
Both synthetic as well as naturally occurring polymers
are used for this purpose.
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15. ll. APPROACHESTODELIVERINTACTMOLECULETOCOLON
1.Coating with polymers
2.Coating with pH-sensitive polymers
3.Coating with biodegradable polymers
4.Embedding in matrices
5.Embedding in biodegradable matrices and hydrogels
6.Time dependent approach
7.Bioadhesive systems
8.Osmotic controlled drugdelivery
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16. 1.Coating with polymers
•The drug molecule is intact with the suitable polymer in
that manner that the drug release only in the colon instead
of other part like small intestine and stomach.
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2.Coatingwith pH-sensitive polymers

17. 3.Coating with biodegradable polymers
large number of microorganisms are present in the
colon. they are involved in the reduction of the dietary
components.
The micro organisms present in the colon cause the
cleavage of the polymer at the alkaline ph and in the
colon.
4.Embedding in matrices
The polymers used for this technique should exhibit
degradability in the colon for liberation of entrapped
drug.
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18. 5.Embedding in biodegradable matrices and hydrogels
The matrices of polysaccharides remain intact in the
physiological environment of stomach and small intestine.
once they reach in the colon, they are acted upon by the
bacterial polysaccharidases and results in the degradation
of the matrices.
6.Time dependent approach
•Drug release occur after a certain lag period which is
related to the time spend by the drug in reaching from
mouth to the colon.
•The lag time is depend on the size of the drug and gastric
emptying.
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19. 7. Bioadhesive systems
•Dosage form remains in contact with particular organ for
an period of time.
•Improved absorption characteristics in case of poorly
absorbable drugs
8. Osmotic controlleddrug delivery
•OROS-CT system can be single osmotic unit or may
incorporate as many as 5-6 pushpull units, each 4 mm in
diameter, encapsulated with in a hard gelatin capsule .
• Each bilayer push pull unit contains an osmotic push
layer and a drug layer, both surrounded by a
semipermeable membrane.
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20. CURRENT APPROACHES
1. Pulsincap
2. Port system
3. Chronotropicsystem
4. CODESTM
5. COLAL-PREDsystem
6. Multi particulates
7. Ticking capsules
8. Enterion Capsule Technology
9. Probiotic approach
10. Nanoparticulate system
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21. 1. Pulsincap
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22. 2. Port system
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23. 3. Chronotropic system
Drug release after a particular lag time.
Surrounding with a soluble barrier layer, which consists
of hydrophilic polymer HPMC.
The coating of additional enteric coating film outside
that layer to overcome the gastric empting variability.
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24. 4. CODESTM
Designed to avoid the inherent problems associated with
pH or time dependent systems.
Combined approach of pH dependent and microbially
triggered CDDS.
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25. 5. COLAL-PRED system
Proprietary gastrointestinal product developed by
Alizyme for the treatment of ulcerative colitis (US).
Treatment for ulcerative colitis without the typical side
effects of steroids.
COLAL-PRED has a coating that is broken down only
in the colon by bacteria.
This leads to topical delivery of steroids to the colon
without significant systemic exposure with minimizing
steroid related side effects.
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26. 6. Multi particulates
pH-sensitive, time dependent and microbial control
systems for colon targeting.
Advantage
Fewer adverse effects than single unit dosage form
More predictable gastric emptying
 Frequency of dose required is less
 Increase patient convenience
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27. 7. Ticking capsules
It is electronically programmed to control the delivery of
medicine according to a pre-defined drug release profile.
Determines its location in the intestinal tract by measuring
the local acidity (pH difference) of its environment.
releases medicine from its drug reservoir via a
microprocessor controlled pump, allowing accurate
programmable drug delivery.
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28. 8. Enterion Capsule Technology
 Developed by Phaeton Research, Nottingham, UK.
The capsule can be loaded with either a liquid
formulation or a particulate formulation
The floor of the drug reservoir is the piston face, which
is held back against a compressed spring by a high-tensile
strength polymer filament.
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29. capsule reaches in the gastrointestinal tract ejected by
the external application of an oscillating magnetic field.
This magnetic field induce power in a tuned coil
antenna, embedded in capsule wall. This power is fed to a
tiny heater resistor located in capsule.
This heater resistor increases temperature & releases
the spring & drives the piston.
The resulting increase in pressure within the drug
reservoir forces off the O-ring sealed cap and ejects the
drug or drug formulation into the surrounding GI fluids.
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30. 9. Probiotic approach
In this approach, three components are desirable
namely probiotic strain, microbially digestable carrier and
triggering temperature.
Probiotic strains include inactive microflora like
Bifidobacterium and Lactobacillus species.
At body temperature, these strains triggered to be
active and start digesting the carrier and ultimately
release the drug at desired place.
Success in colon drug delivery system because these
conditions are only available in colon.
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31. 10. Nanoparticulate system
 Size range : 10–100 nm.
drugs given with nanoparticles shows enhanced
solubility, permeability and bioavailability.
The drug is dissolved, entrapped, encapsulated or
attached to a nanoparticle matrix.
Drug Loading is relatively high and drugs can be
incorporated into the systems without chemical reaction.
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32. EVALUATION OF COLON TARGETED DRUG DELIVERY
SYSTEM
• InvitroDissolutiontest
• InVivoEvaluation
• Gammascintigraphy
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33. InvitroDissolution test
•Dissolution for colon-specific drug delivery are
usually complex.
•Methods described in the USP cannot completely vivo
conditions such as pH, bacterial environment and
mixing forces.
•Dissolution studies in different buffers may be
undertaken.
•The media chosen are, for example, pH 1.2 to simulate
gastric fluid, pH 6.8 to simulate the jejunal region of the
small intestine, and pH 7.2 to simulate the ileal segment.
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34. •InVivoEvaluation
•A number of animals such as rats and guinea pigs are
used to evaluate the delivery of drug to colon.
• Resemble the anatomic and physiological conditions as
well as the microflora of human GIT.
•Eg. Guinea pigs are commonly used for experimental
IBD model.
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35. Gamma scintigraphy
Time of arrival of a colon-specific drug delivery
system in the colon.
Time of transit through the stomach and small intestine.
Disintegration can be obtained.
Regional permeability in the colon.
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 5-Fluoro uracil: -active pharmaceutical ingredient.
 Chitosan :- used as polymer.
Eudragit S100:- used for enteric coating
CASE STUDY

37. Method:- solvent emulsification evaporation technique
Different ratios of drug: polymer (1:1, 1:2,1:3, 1:4)
Pellets and Enteric coating of nanoparticles were prepared.
Particle size:- 138 ± 1.01 nm
Entrapment efficiency:- 69.18%
In vitro drug release studies.
5-FU enteric coated nanoparticles with drug: polymer ratio
of 1:3 (5-FU E1) and1:2 (5-FU E2)
Plain chitosan nanoparticles, which were non-enteric
coated (5-FU NE).
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38. 5-FU E1 nanoparticles has shown enhanced drug
release 82 ±0.05% and 71± 1.02% at 24 h and 8 h.
5-FU E2 nanoparticles have shown a slight decrease in
the drug release 73± 0.89% at 24 h and 68± 0.25% at 8 h.
5-FU E1 nanoparticles considered as a potential carrier,
which can release and localize the drug at colonic pH.
Chitosan leads to the sustained release and also
benefitted by its tumor inhibiting property.
Enteric coating with Eudragit-S100 was supported by
preventing drug degradation at gastric pH and allowing it
to release once it enters the neutral and alkaline medium.
5-FU E1 nanoparticles released drug after 4 h once it
enters intestinal fluid and enhancing its drug release at
colonic region.
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39. Formulated nanoparticles improved localization of the
drug at the colon area and also achieved sustained release
over a prolonged period of 24 h.
Decreased toxicity to healthy cells as more amount of
drug is localized in the colon area.
Benefit the patient in decreasing the dosing frequency
and dose that can be administered.
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40. REFERENCES
Shashank Tummala , M.N. Satish Kumar, Ashwati
Prakash (2015), “Formulation and characterization of 5-
Fluorouracil enteric coated nanoparticles for sustained and
localized release in treating colorectal cancer”, Saudi
Pharmaceutical Journal, 308–314.
Cherukuri Sowmya, Reddipalli Sandhya, Komaragiri
Keerthi. (2012), “Colon specific drug delivery system: A
review on pharmaceutical approaches with current trends”,
International research Journal Of Pharmacy, 45-55.
Asha Patel, Nilam Bhatt, Dr.K.R.Patel, (2011), “Colon
Targeted Drug Delivery System: A Review System”,
Journal Of Pharmaceutical Sciences And Bioscientific
Research, Vol1, Issue 1, 37-49
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41. Sunena Sethi, SL Harikumar, Nirmala Rayat, (2012),
“Review On advances in Colon Targeted Drug Delivery
System”, International Journal Of Pharmaceutical Sciences
and Research, Vol. 3, Issue 09, 2989-3000
Dinesh Kumar, Mankaran Singh, Sharma Deepak, (2012),
“Emerging Techniques and Challenges in Colon Drug
Delivery Systems”, Journal of Applied Pharmaceutical
Science, 139-147
Pawar Dhanashree G*, Darekar Avinash B, Saudagar
Ravindra B, (2013), “Colon Targeted Drug Delivery System:
Pharmaceutical Approaches with Current Trends”, Vol2,
Issue 6, 6589-6612
Sardarmal Yadav , Ashish Kumar Pareek, Dr.Shiv Garg,
(2015), “Recent advances in Colon Specific Drug Delivery
System”, World Journal of Pharmaceutical Research, Vol4,
Issue 6, 1380-1394.
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