Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
ONTARGET
Targeted Drug Delivery Systems
Dr. Gajanan S. Sanap M.Pharm.,Ph.D
Department of Pharmaceutics
Ideal College of Ph...

 Introduction
 Anatomy of colon
 Criteria of drug selection
 Approaches of colon targeting
 EVALUATION
Reference
C...
INTRODUCTION
Targeted drug delivery systems:
 The major goal of any drug delivery system is to supply a therapeutic
amoun...
Definition:-
Colon drug delivery system refers to targeted delivery of drug in to the
lower parts of GI tract , mainly lar...
 Oral route is considered to be most convenient for administration of
drug to patient.
 Colon is used as site of Targete...
As most of the conventional drug delivery systems for treating colon
disorders such as inflammatory bowel diseases, infec...
In recent times the colon-specific delivery systems(CSDDS) are also
gaining importance for the systemic delivery of prote...
ADVENTAGES
 The site specific delivery of drug to lower part of GIT, for
localized treatment of several colonic diseases....
Multiple manufacturing steps.
Microflora affects activity of drug via metabolic degradation of the
drug.
Bioavailabilit...
 Substantial variation in gastric retention time may
affect drug delivery.
 Diseased condition may affect the colonic tr...
Application
In local colonic pathologies
Systemic delivery of protein and peptide
Potential site for the treatment of d...
Table 1. Colon targeting diseases, drugs and sites
Targetsites Disease conditions Drugand activeagents
Topical action Infl...
Inflammatory
bowels
disease
Ulcerative
colitis
Crohn’s disease
Colon Cancer
Colon and rectum cancer - 10% in men and 11% women
 >55,000 Total Colorectal Cancer Deaths
Anatomy & physiology of colon
The GI tract is divided into stomach, small intestine & large
intestine.
The colon itself ...
Function of colon
 Formation of suitable environment for colonic
microorganism.
 Act as storage reservoirs of waste matt...
 Gastrointestinal Transit --
 Gastric emptying of various dosage form is highly
inconsistant & depends primary on whethe...
Factors to be considered for colonic drug delivery
1. pH in the colon:
 pH of the GI tract is subjected to both inter & i...
2. Gastrointestinal transit:
Gastric emptying of dosage forms is highly variable &
depends primarily on whether the subje...
3. Colonic microflora:
Many compounds taken orally are metabolized by gut
bacteria.
Drug release depends on enzymes that...
Drug absorption in the colon
Drugs are absorbed passively by either paracellular or
transcellular route.
Transcellular a...
Role of absorption enhancers
The permeability of drugs can be modified by the use of
chemical enhancers.
These enhancers...

 Drugs used for local effects in colon against GIT diseases.
 Drugs poorly absorbed from upper GIT.
 Drugs for colon ...
Pharmaceutical Approaches for Targeting Drugs
to Colon
 pH sensitive systems
 Microbially triggered system
◦ Prodrugs
◦ ...
Approaches to colon specific drug delivery
1. Coating with pH dependent polymers:
 The underlying principle of this appro...
Examples: Cellulose Acetate Phthalate (CAP)
CAP is a white free-flowing powder. It is insoluble in water, alcohols,
and ch...
 Cellulose Acetate Phthalate:
 Methacrylic Acid Copolymers:
 These are anionic copolymers and are very commonly utilize...
Shellac:
 Shellac is a material of natural origin used for enteric coatings. It is
a purified resinous secretion of the i...
EudracolTM
 The microflora of the colon is in the range of 1011 -1012 CFU/ mL,
consisting mainly of anaerobic bacteria, e.g. bactero...
 A Prodrug is a pharmacologically inactive derivative of a parent
molecule that require some form of transformation in vi...
 The azo linkage exhibits a wide
range of thermal, chemical,
photochemical and pharmaceutical
properties.
 The azo compo...
40
Prodrugs
Drug Carrier Molecule
Enzymatic stimuli in the biological
environment of the GIT breaks the bond
Concept
of
pr...
41
Bacteria in
colon
Hydrolysis of sulphasalazine (A) into 5-aminosalicylic acid (B) and
sulfapyridine (C).
(
A
)
(
B
)
(
...
Prodrugs: Example,
Sulfasalazine is mainly used for the treatment of inflammatory
bowl diseases.
Chemically it is 5-amin...
Azo polymeric new drug
 In which use of polymers as drug carriers for drug
delivery to colon .
 Synthetic, naturally, su...
1)Azo bond conjugate:-
Azoreductase enzyme produced in colon by colonic
bacteria which degrades azo bond.
This principle i...
Carrier moiety conjugated
with 5-amino salicylic acid
Prodrug of 5-amino
salicylic acid
p-aminohippurate (4-amino
benzoyl ...
Polysaccharide based delivery system
Polysaccharides offer an alternative substrate for the
bacterial enzymes present in ...
Polysaccharides as carriers:
The colonic microflora secretes a number of enzymes that are
capable of hydrolytic cleavage ...
63
Polysaccharides used for Colon Drug
Delivery
• Chitosan
• Pectin
• Guar gum
• Chondroitin sulphate
• Dextran
• Cyclodex...
49
Different bacterial species acting on
Polysaccharides in colon
Polysaccharides Bacterial species
Amylose
Chitosan
Chond...
Polysaccharides Drug targeted to colon
Guar gum
Pectin
Inulin
Amylase
Cyclodextrin (β)
Dextran
Chitosan
Eudragits
Rofecoxi...
MARKETED PREPERATION
MARKETED PRODUCTS
51
Time release dosage forms:
Nonbiodegradable polymers are used.
They are generally nonspecific with respect to pH-solubil...
Lag phase
of
~ 5 h is
observed.
This system, first described by Shah & co-workers, uses lag time to
achieve colon delivery.
System consist of 3 main par...
PULSINCAP
OROS-CT
CODES™
PORT® SYSTEM
TIME CLOCK® SYSTEM
COLAL-PRED™
Pulsincap:
Hydrogel capsule
Pulsincap and Hydrophilic Sandwich Capsules
Erodible plug time-delayed capsule:
 OROS-CT
 CODES™
 PORT® SYSTEM
TIME CLOCK® SYSTEM
 Solid dosage form coated
with lipid barriers containing
carnauba wax and bees wax
along with surfact...
COLAL-PRED™
Pellets containing the drug (prednisolone
metasulphobenzoate) with a coating of
ethylcellulose and a specifi...
Patient compliance and treatment efficacy
Useful in treatment of ulcerative colitis, crohn's disease,
irritable bowel sy...
Disadvantages
There is less fluid in colon than in small intestine and
hence, dissolution is a problem for water soluble...
Applications
LOCALACTIONS
1. Ulcerative colitis.
2. CHRON'S disease.
3. Irritable bowel syndrome.
4. Metastatic human col...
The OROS-CT (Alza corporation) can be used to target the drug
locally to the colon for the treatment of disease or to ach...
Delivery port
Osmet pump
Depend up on the osmotic pressure
exerted by osmogens on drug
compartment with which though drug
...
OROS-CT (Alza corporation)
Immediately after the OROS-CT is swallowed, the gelatin capsule
containing the push-pull units...
MARKETED PRODUCTS
Sr.
no.
Marketed
name
Company
name
Disease Drug content
1) Mesacol tablet Sun pharma,
India
Ulcerative
c...
For evaluation, not any standardized evaluation technique is available
for evaluation of CDDS because an ideal in vitro mo...
1. In vitro methods:
 The ability of the coats/ carriers to remain in the physiological
environment of the stomach and sm...
IN-VITRO DISSOLUTIONTEST
 Dissolution of CDDS is usually complex, dissolution
Describe in USP
 Disso. Carried out by con...
BioDis-III (Apparatus III)
• Ideal for the dissolution profiling of extended release
dosage forms.
• It is designed to mee...
Bio-Dis III
• Capable of running unattended upto 6 days and can store upto 25
programms.
• 7 sample tubes which automatica...
In vitro enzymatic degradation test
Method 1:
Drug release in buffer medium containing enzymes(e.g.pectinase, dextranase) ...
2 In vivo methods:
Animal models
Rats, mice, pigs and dogs animal models were reported for colon
targeted drug delivery ...
Techniques which are used for monitoring the in vivo behavior of
colon targeted drug delivery are
String technique,
Endos...
Endoscope technique:
It is an optical technique in which a fiber scope (gastro scope) is
used to directly monitor the beh...
Reoentgenography :
The inclusion of a radio-opaque material into a solid dosage form
enables it to be visualized by the u...
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Colon targeted drug delivery systems
Upcoming SlideShare
Loading in …5
×

Colon targeted drug delivery systems

4,853 views

Published on

Colon targeted drug delivery systems

Published in: Health & Medicine
  • Be the first to comment

Colon targeted drug delivery systems

  1. 1. ONTARGET Targeted Drug Delivery Systems Dr. Gajanan S. Sanap M.Pharm.,Ph.D Department of Pharmaceutics Ideal College of Pharmacy and Research Kalyan 421- 306 COLON TARGETED DRUG DELIVERY
  2. 2.   Introduction  Anatomy of colon  Criteria of drug selection  Approaches of colon targeting  EVALUATION Reference CONTENTs
  3. 3. INTRODUCTION Targeted drug delivery systems:  The major goal of any drug delivery system is to supply a therapeutic amount of drug to a target site in a body.  Targeted drug delivery implies selective and effective localization of drug into the target at therapeutic concentrations with limited access to non target sites.  A targeted drug delivery system is preferred in drugs having instability, low solubility and short half life,
  4. 4. Definition:- Colon drug delivery system refers to targeted delivery of drug in to the lower parts of GI tract , mainly large intestine. Targeted delivery of drugs to the colon is usually to achieve one or more of four objectives. To reduce dosing frequency To delay delivery to the colon to achieve high local concentrations in the treatment of diseases of the distal gut, To delay delivery to a time appropriate to treat acute phases of disease (chronotherapy), To deliver to a region that is less hostile metabolically, e.g., to facilitate absorption of acid and enzymatically labile materials, especially peptides.
  5. 5.  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.
  6. 6. As most of the conventional drug delivery systems for treating colon disorders such as inflammatory bowel diseases, infectious diseases and colon cancer are failing as the drugs don't reach the site of action in appropriate concentration. Thus an effective and safe therapy of these colonic disorders using site specific drug delivery system.  The therapeutic advantages of targeting drug to the diseased organ include, a)Delivery of drug in its intact form as close as possible to the target site. b)The ability to cut down the conventional dose. c) Reduced incidence of adverse side effects. WHY COLON TARGETED DRUG DELIVERY IS NEEDED?
  7. 7. In recent times the colon-specific delivery systems(CSDDS) are also gaining importance for the systemic delivery of protein and peptide drugs . This is because, i)as the peptide and protein drugs are destroyed and inactivated in acidic environment of stomach or by pancreatic enzymes (or) by parenteral route which is inconvenient and expensive. ii) Due to the negligible activity of brush border membrane peptidase activity and less activity of pancreatic enzymes the colon is considered as the most suitable site.
  8. 8. ADVENTAGES  The site specific delivery of drug to lower part of GIT, for localized treatment of several colonic diseases. (ulcerative colitis, Chron's disease, carcinomas and infections)  Prevent drug from degradation  Ensure direct treatment at disease site.  Suitable absorption site for Protein & Peptide drug.  Used to prolong the drug therapy.  Improved drug utilization.
  9. 9. Multiple manufacturing steps. Microflora affects activity of drug via metabolic degradation of the drug. Bioavailability of drug may be low due to potentially binding of drug in a nonspecific way to dietary residues, intestinal secretions, mucus or faecal matter. Non availability of an appropriate dissolution testing method to evaluate the dosage form in-vitro. Drug should be in solution form before absorption and there for rate limiting step for poor soluble drugs. Limitations / Challenges/Difficulties
  10. 10.  Substantial variation in gastric retention time may affect drug delivery.  Diseased condition may affect the colonic transit time and drug release profile.  pH level of colon may vary between individuals due to disease, state and temperature of food consumed.
  11. 11. Application In local colonic pathologies Systemic delivery of protein and peptide Potential site for the treatment of diseases sensitive to circadian rhythms (asthma, angina and arthritis) For the drugs that are absorbed through colon such as steroids (….efficacy..) For the treatment of disorders like IBS, colitis, crohn’s disease (…where it is necessary to attain high concentration of drugs)
  12. 12. Table 1. Colon targeting diseases, drugs and sites Targetsites Disease conditions Drugand activeagents Topical action Inflammatory Bowel Diseases, Irritable bowel disease and Crohn’s disease. Chronic pancreatitis Hydrocortisone, Budenoside, Prednisolone, Sulfaselazine, Olsalazine, Mesalazine, Balsalazide Local action Pancreatactomy and cystic fibrosis, Colorectal cancer Digestive enzyme supplements 5-Flourouracil Systemic action To prevent gastric irritation To prevent first pass metabolism of orally ingested drugs Oral delivery of peptides Oral delivery of vaccines NSAIDS Steroids Insulin
  13. 13. Inflammatory bowels disease
  14. 14. Ulcerative colitis
  15. 15. Crohn’s disease
  16. 16. Colon Cancer Colon and rectum cancer - 10% in men and 11% women  >55,000 Total Colorectal Cancer Deaths
  17. 17. Anatomy & physiology of colon The GI tract is divided into stomach, small intestine & large intestine. The colon itself is made up of the caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon. It is about 1.5 m long. Although it varies in diameter from approx 9 cm in caecum & 2 cm in sigmoid colon. The wall of colon is composed of 4 layers: serosa, muscularis externa, sub mucosa & mucosa. Serosa consists of areolar tissue, muscularis externa composed of an inner circular layer of fibers, sub mucosa is layer of connective tissue, mucosa is divided into epithelium lamina propria & muscularis mucosae
  18. 18. Function of colon  Formation of suitable environment for colonic microorganism.  Act as storage reservoirs of waste matter.  Removal of content of colon at proper time.  Absorption of potassium ion & water from lumen, concentrating fecal content & secretion & excretion of potassium & bicarbonates.
  19. 19.  Gastrointestinal Transit --  Gastric emptying of various dosage form is highly inconsistant & depends primary on whether the subject is fed or fasting & properties of dosage form.  The arrival of dosage form in colon is determined by rate of gastric emptying & intestine transit time. Intestinal transit time Organ Transit time (hrs) Stomach <1 (fasting) >3 (fed) Small intestine 3-4 Large intestine 20-30
  20. 20. Factors to be considered for colonic drug delivery 1. pH in the colon:  pH of the GI tract is subjected to both inter & intra subject variation.  On entry in to the colon, the pH dropped to 6.4 . The pH in the mid colon & the left colon is 6.0- 7.6 Location pH Oral cavity 6.2-7.4 Esophagus 5.0-6.0 Stomach Fasted condition 1.5-2.0 Fed condition 3.0-5.0 Small intestine Jejunum 5.0-6.5 Ileum 6.0-7.5 Large intestine Right colon 6.4 Mid & left colon 6.0-7.6
  21. 21. 2. Gastrointestinal transit: Gastric emptying of dosage forms is highly variable & depends primarily on whether the subject is fed or fasted. The arrival of an oral dosage form at the colon is determined by the rate of gastric emptying & the small intestinal transit time. The transit time of dosage form in GIT: Organ Transit time (hrs) Stomach <1 (fasting), >3 (fed) Small intestine 3-4 large intestine 20-30
  22. 22. 3. Colonic microflora: Many compounds taken orally are metabolized by gut bacteria. Drug release depends on enzymes that are derived from microflora present in colon. These enzymes are used to degrade coatings/matrices as well as to break bonds between an inert carrier and an active agent resulting in the drug release from the formulation. Important metabolic reactions carried out by intestinal bacteria : hydrolysis, reduction, dehydroxylation, decarboxylation, dehalogenation, deamination, acetylation, esterification.
  23. 23. Drug absorption in the colon Drugs are absorbed passively by either paracellular or transcellular route. Transcellular absorption involves the passage of drugs through cells.(Lipophilic drug) Paracellular absorption involves the transport of drug through tight junction between cells. ( Hydrophilic drug) The colon may not be the best site for drug absorption since the colonic mucosa lacks well defined villi as found in the small intestine. The colon contents become more viscous with progressive absorption of water as one travels further through the colon. This causes a reduced dissolution rate, slow diffusion of drug through the mucosa.
  24. 24. Role of absorption enhancers The permeability of drugs can be modified by the use of chemical enhancers. These enhancers increase transcellular & paracellular transport through one of the following mechanism: 1. By modifying epithelial permeability via denaturating membrane proteins. 2. By reversibly disrupting the integrity of lipid bilayer of colon. Category Example NSAIDs Indomethacin Calcium ion chelating agent EDTA Surfactants Polyoxyethylene lauryl ether Bile salts Glycocholate Fatty acids Sodium caprylate Mixed micelles Oleic acid glycocholate
  25. 25.   Drugs used for local effects in colon against GIT diseases.  Drugs poorly absorbed from upper GIT.  Drugs for colon cancer.  Drugs that degrade in stomach and small intestine.  Drugs that undergo extensive first pass metabolism.  Drugs for targeting. Criteria of drug selection
  26. 26. Pharmaceutical Approaches for Targeting Drugs to Colon  pH sensitive systems  Microbially triggered system ◦ Prodrugs ◦ Polysaccharide based systems  Timed release systems  Osmotically controlled drug delivery systems  Pressure dependent release systems  An oral colonic delivery system should retard drug release in the stomach and small intestine but allow complete release in the colon.  A variety of strategies has been used and systems have been developed for the purpose of achieving colonic targeting .
  27. 27. Approaches to colon specific drug delivery 1. Coating with pH dependent polymers:  The underlying principle of this approach has been employment of polymers that are able to withstand the lower pH values of the stomach, but that disintegrate and release the drug as the pH in the small bowel increases. Selection of enteric polymer dissolving at pH 7 is likely to cause drug release in terminal small bowel. The pH in the transverse colon is 6.6 and 7.0 in the descending colon. Use of pH dependent polymers is based on these differences in pH levels. The polymers described as pH dependent in colon specific drug delivery are insoluble at low pH levels but become increasingly soluble as pH rises. These processes distribute the drug throughout the large intestine and improve the potential of colon targeted delivery systems.
  28. 28. Examples: Cellulose Acetate Phthalate (CAP) CAP is a white free-flowing powder. It is insoluble in water, alcohols, and chlorinated hydrocarbons, but soluble in acetone and its mixtures with alcohols, ethyl acetate–IPA mixture. Enteric polymers Optimum pH for dissolution Polyvinyl acetate phthalate (PVAP) 5.0 Cellulose acetate trimelitate (CAT) 5.5 Hydroxypropyl methyl cellulose phthalate (HPMCP) >5.5 Methacrylic acid copolymer, Type C (Eudragit L100-55) >6.0 Cellulose acetate phthalate (CAP) (Aquateric) 6.0 Shellac 7.0 Table. pH of commonly used enteric polymers.
  29. 29.  Cellulose Acetate Phthalate:  Methacrylic Acid Copolymers:  These are anionic copolymers and are very commonly utilized for enteric coating, including application in colonic delivery.   Eudragit L
  30. 30. Shellac:  Shellac is a material of natural origin used for enteric coatings. It is a purified resinous secretion of the insect Laccifer lacca. Hydroxypropyl Methylcellulose Phthalate (HPMCP):  HPMCP is a white powder or granular material. It is a more flexible polymer than CAP. Commercially, the available forms are HPMCP-50 and HPMCP-55.
  31. 31. EudracolTM
  32. 32.  The microflora of the colon is in the range of 1011 -1012 CFU/ mL, consisting mainly of anaerobic bacteria, e.g. bacteroides, bifidobacteria, eubacteria, clostridia, enterococci, enterobacteria and ruminococcus etc.  Microflora produces a vast number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase, deaminase, and urea dehydroxylase.  Presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-specific drug delivery.  These polymers shield the drug from the environments of stomach and small intestine, and are able to deliver the drug to the colon. Microbially Triggered Drug Delivery to Colon
  33. 33.  A Prodrug is a pharmacologically inactive derivative of a parent molecule that require some form of transformation in vivo to release the active drug at the target site.  This approach involves covalent linkage between the drug and its carrier.  Biotransformation is carried out by a variety of enzymes, mainly of bacterial origin, present in the colon. The enzymes that are mainly targeted for colon drug delivery include azoreducatase-galactosidase, β- xylosidase, nitroreductase, glycosidase deaminase, etc. PRODRUG For colonic delivery , prodrug is designed to undergo minimal hydrolysis in upper tracts of GIT & undergo enzymatic hydrolysis in colon there by releasing the active drug moiety from drug moiety. Metabolism of azo compound by intestinal bacteria is one of most extensively studied bacterial metabolic process.
  34. 34.  The azo linkage exhibits a wide range of thermal, chemical, photochemical and pharmaceutical properties.  The azo compounds are extensively metabolized by the intestinal bacteria.  Sulphasalazine, which was used for the treatment of rheumatoid arthritis. This compound has an azo bond between 5-ASA and sulphapyridine.  Include naturally occurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotin sulphate), algal (alginates) or microbial (dextran) origin.  The polysaccrides can be broken down by the colonic microflora to simple saccharides. Therefore, they fall into the category of “generally regarded as safe” (GRAS). AZOREDUCTASES POLYSACCHARIDASES Of the multitude of bacterial enzymes that are produced in colon, 2 main classes are:-
  35. 35. 40 Prodrugs Drug Carrier Molecule Enzymatic stimuli in the biological environment of the GIT breaks the bond Concept of prodrug s Prodrugs Drug Carrier Molecule Concept of prodrug s Prodrugs Drug Carrier Molecule Concept of prodrug s Prodrugs Drug Carrier Molecule Concept of prodrug s
  36. 36. 41 Bacteria in colon Hydrolysis of sulphasalazine (A) into 5-aminosalicylic acid (B) and sulfapyridine (C). ( A ) ( B ) ( C )
  37. 37. Prodrugs: Example, Sulfasalazine is mainly used for the treatment of inflammatory bowl diseases. Chemically it is 5-amino salicylic acid (5-ASA) coupled with sulphapyridine by azo bonding. On reaching the colon, the azo bond is reduced by azoreductases to 5-ASA & sulphapyridine. The active moiety is 5-ASA & sulphapyridine acts as carrier to deliver 5-ASA in colon.
  38. 38. Azo polymeric new drug  In which use of polymers as drug carriers for drug delivery to colon .  Synthetic, naturally, sub-synthetic polymers used form colon targeted polymeric prodrug with azo linkage between polymer & drug moiety.  The various azo polymers are evaluated for coating materials over drug core. These are susceptible to cleavage by azo reductase enzyme.  Coating of protein & peptide drug capsules crosslinked with azoaromatic group Polymer to protect drug from degradation in stomach & small intestine. In colon azo bonds reduced & drug is released 43
  39. 39. 1)Azo bond conjugate:- Azoreductase enzyme produced in colon by colonic bacteria which degrades azo bond. This principle is utilized in preparation of prodrug derivative of active drug for targeting in colon. Sulphasalazine(SASP) is prodrug of 5-ASA. It is conjugated with sulphapyridine through azo bond. Sulphasalazine was introduced for the treatment of rheumatoid arthritis and anti-inflammatory disease.
  40. 40. Carrier moiety conjugated with 5-amino salicylic acid Prodrug of 5-amino salicylic acid p-aminohippurate (4-amino benzoyl glycine) ipsalazine, p- 4-amino benzoyl-β- alanine balsalazine p-aminobenzoate HB-313 nonabsorbable sulphanilamide ethylene polymer poly-ASA a dimer representing two molecules of 5-ASA that are linked via an azo bond olsalazine (OSZ) 45
  41. 41. Polysaccharide based delivery system Polysaccharides offer an alternative substrate for the bacterial enzymes present in the colon. Most of them are hydrophilic in nature. Natural polysaccharides are either modified or mixed with water insoluble polymers. 46
  42. 42. Polysaccharides as carriers: The colonic microflora secretes a number of enzymes that are capable of hydrolytic cleavage of glycosidic bonds. These include β-d-glucosidase, β-dgalactosidase, amylase, pectinase, xylanase, α-d-xylosidase, and dextranases. Natural polysaccharides like pectin & inulin are not digested in stomach & small intestine but are degraded in colon by resident bacteria. The bacteria converts polysaccharides to gases such as methane, carbon dioxide, hydrogen & to short chain fatty acids. These polysaccharides thus have the potential as non-toxic carriers for colon specific drug delivery.
  43. 43. 63 Polysaccharides used for Colon Drug Delivery • Chitosan • Pectin • Guar gum • Chondroitin sulphate • Dextran • Cyclodextrins • Almond gum • Locust bean gum • Inulin • Boswellia gum • Karaya gum
  44. 44. 49 Different bacterial species acting on Polysaccharides in colon Polysaccharides Bacterial species Amylose Chitosan Chondroitin sulphate Cyclodextrins Dextran Guar gum Bacteriodes Bifidobacterium Bacteriodes Bacteriodes Bacteriodes Bacteriodes Bacteriodes Ruminococccus
  45. 45. Polysaccharides Drug targeted to colon Guar gum Pectin Inulin Amylase Cyclodextrin (β) Dextran Chitosan Eudragits Rofecoxib , Tinidazole Naproxen Azathioprine 5-Amino salicylic acid Albendazole Ibuprofen Satranidozole 5-fluorouracil List of few studies on Polysaccharides 50
  46. 46. MARKETED PREPERATION MARKETED PRODUCTS 51
  47. 47. Time release dosage forms: Nonbiodegradable polymers are used. They are generally nonspecific with respect to pH-solubility characteristics and the employment of these polymers as carrier matrices for colonic delivery often utilizes a time-dependent mechanism.  This provides an initial lag phase of low or no release during transit through the upper gastrointestinal tract.  The lag time usually starts after gastric emptying because most of the time- controlled formulations are enteric coated.  The enteric polymer coat prevents drug release in the stomach.  Drug release from these systems is not pH dependent.  Various polymers used are: polyacrylates, methylcellulose, HPMC, CMC etc.
  48. 48. Lag phase of ~ 5 h is observed.
  49. 49. This system, first described by Shah & co-workers, uses lag time to achieve colon delivery. System consist of 3 main parts: An outer enteric coat, inner semipermeable polymer membrane, and a central core having swelling excipients and an active component. The outer enteric coating prevents drug release until the tablet reaches the small intestine. In the small intestine, the enteric coating dissolves allowing gastrointestinal fluids to diffuse through the semipermeable membrane into the core. The core swells until after a period of 4–6 h, when it bursts, and releases the active component in the colon.
  50. 50. PULSINCAP OROS-CT CODES™ PORT® SYSTEM TIME CLOCK® SYSTEM COLAL-PRED™
  51. 51. Pulsincap: Hydrogel capsule
  52. 52. Pulsincap and Hydrophilic Sandwich Capsules
  53. 53. Erodible plug time-delayed capsule:
  54. 54.  OROS-CT
  55. 55.  CODES™
  56. 56.  PORT® SYSTEM
  57. 57. TIME CLOCK® SYSTEM  Solid dosage form coated with lipid barriers containing carnauba wax and bees wax along with surfactants.  Further coated with enteric coating polymer to prevent premature drug release, but the release is independent of pH or digestive state of the gut Enteric coating Wax coating with surfactant Drug core
  58. 58. COLAL-PRED™ Pellets containing the drug (prednisolone metasulphobenzoate) with a coating of ethylcellulose and a specific form of amylose (derived from starch). After completion of succsesful phase I and II trials ‘Alizyme’ obtained approval for Phase III clinical trial of COLAL-PREDTM in maintenance of remission of ulcerative colitis.
  59. 59. Patient compliance and treatment efficacy Useful in treatment of ulcerative colitis, crohn's disease, irritable bowel syndrome and carcinomas Low dose is required ,so less side effect Used for local and systemic action Gastric irritation can be avoided
  60. 60. Disadvantages There is less fluid in colon than in small intestine and hence, dissolution is a problem for water soluble drugs. Binding of drug to dietary residues, intestinal secretions etc., reduce concentration of free drugs. Some micro flora may degrade the drug. Small luminal surface area and relative tightness of tight Junctions in colon, delay the systemic absorption. Onset of action is slow.
  61. 61. Applications LOCALACTIONS 1. Ulcerative colitis. 2. CHRON'S disease. 3. Irritable bowel syndrome. 4. Metastatic human colon cancer. SYSTEMIC ACTIONS 1. Molecules degraded/poorly absorbed from upper G.I.T such as peptides and proteins are better absorbed from colon. 2. For achieving chemotherapy for diseases that are sensitive to circadian rhythm such as Asthma, angina, arthritis.
  62. 62. The OROS-CT (Alza corporation) can be used to target the drug locally to the colon for the treatment of disease or to achieve systemic absorption. The OROS-CT system can be a single osmotic unit or may incorporate as many as 5-6 push-pull units, each 4 mm in diameter, encapsulated within a hard gelatin capsule. For treating ulcerative colitis, each push pull unit is designed with a 3-4 h post gastric delay to prevent drug delivery in the small intestine. Drug release begins when the unit reaches the colon. OROS-CT units can maintain a constant release rate for up to 24 hours in the colon or can deliver drug over a period as short as four hours. Osmotic Controlled Drug Delivery (ORDS-CT)
  63. 63. Delivery port Osmet pump Depend up on the osmotic pressure exerted by osmogens on drug compartment with which though drug get released slowly through the orifice.
  64. 64. OROS-CT (Alza corporation) Immediately after the OROS-CT is swallowed, the gelatin capsule containing the push-pull units dissolve  Because of its enteric coating, each push-pull unit is prevented from absorbing water in the acidic environment. As the unit enter the small intestine, the coating dissolve in this higher pH (pH >7), water enters the unit, causing the osmotic push compartment to swell and concomitantly creates a flowable gel in the drug compartment. Swelling of the osmotic push layer forces drug gel out of the orifice.
  65. 65. MARKETED PRODUCTS Sr. no. Marketed name Company name Disease Drug content 1) Mesacol tablet Sun pharma, India Ulcerative colitis Mesalamine 2) SAZO Wallace , India Ulcerative colitis, crohn’s disease Sulphasalazin e 3) BUSCOPAN German remedies Colonic motility Hyoscine butyl bromide 4) Entofoam Cipla, India Ulcerative colitis Hydrocortison e acetate
  66. 66. For evaluation, not any standardized evaluation technique is available for evaluation of CDDS because an ideal in vitro model should posses the in-vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes, enzyme activity, and other components of food. These conditions are influenced by the diet, physical stress, and these factors make it difficult to design a standard in-vitro model. EVALUATION 1. In vitro dissolution study 2. In vitro enzymatic degradation test 3. Relative colonic tissue exposure 4. Relative systemic exposure to drugs 5. -Scintigraphy 6. Magnetic moment imaging study 7. Drug delivery index 8. High frequency capsule
  67. 67. 1. In vitro methods:  The ability of the coats/ carriers to remain in the physiological environment of the stomach and small intestine is generally assessed by conducting drug release studies in, • Drug release study in 0.1 N HCl for 2 hours (mean gastric emptying time) • Drug release study in phosphate buffer for 3 hours (mean small intestine transit time PH 6.8) These dissolution studies can be carried out by using paddle or basket or flow through dissolution apparatus.
  68. 68. IN-VITRO DISSOLUTIONTEST  Dissolution of CDDS is usually complex, dissolution Describe in USP  Disso. Carried out by conventional basket method.  Dissolution tests for CDDS in different media simulating pH condition & times likely to be encountered at various location in GI tract.  Following media were used- pH 1.2 to simulate gastric fluid. pH 6.8 to simulate jejunal region of small intestine. pH 7.2 to simulate ileum segment. Enteric coated CDDS studied in gradient disso. Study in 3 buffer systems. 2 hr at pH 1.2, then 1 hr at pH 6.8& finally at pH 7.4 75
  69. 69. BioDis-III (Apparatus III) • Ideal for the dissolution profiling of extended release dosage forms. • It is designed to meet or exceed current USP specification. • It used a reciprocating motion to dip the inner tube into media. • At the designated time, the entire row of inner tubes raises and moves to the next row of media.
  70. 70. Bio-Dis III • Capable of running unattended upto 6 days and can store upto 25 programms. • 7 sample tubes which automatically traverse upto 6 rows of corresponding outer tubes filled with different media. • With accessories, the appropriate media volume can vary from 100, 300 ml (USP) or 1000 ml. BioDis III
  71. 71. In vitro enzymatic degradation test Method 1: Drug release in buffer medium containing enzymes(e.g.pectinase, dextranase) or rat or guinea pig or rabbit decal contents Amount of drug release in particular time directly proportional to the rate of degradation of polymer carrier. Method 2: Incubating carrier drug system in fermenter Suitable medium containing colonic bacteria (streptococcus faecium or B.ovatus) Amount of drug released at different time intervels determined. B R Nahata College of Pharmacy Mandsaur (M.P.)
  72. 72. 2 In vivo methods: Animal models Rats, mice, pigs and dogs animal models were reported for colon targeted drug delivery systems. For simulating the human physiological environment of the colon, appropriate animal model selection is depends on its approach and design of system. For example, guinea pigs have glycosidase and glucuronidase activities in the colon and digestive anatomy and physiology is similar to that of human, so they are appropriate in evaluating prodrugs containing glucoside and glucuronate conjugated for colonic delivery.
  73. 73. Techniques which are used for monitoring the in vivo behavior of colon targeted drug delivery are String technique, Endoscopy, Radiotelemetry, Roentegenography, Gamma scintigraphy. String technique : In these studies, a tablet was attached to a piece of string and the subject swallowed the tablet, leaving the free end of the string hanging from his mouth. At various time points, the tablet was withdrawn from the stomach by pulling out the string and physically examining the tablet for the signs of disintegration.
  74. 74. Endoscope technique: It is an optical technique in which a fiber scope (gastro scope) is used to directly monitor the behavior of the dosage form after ingestion. This method requires administration of a mild sedative to facilitate the swallowing of the endoscopic tube. The sedative alter the gastric emptying and GI motility. Radiotelemetry : This technique involves the administration of a capsule that consist of a small pH probe interfaced with a miniature radio transmitter which is capable of sending a signal indicating the pH of the environment to an external antenna attached to body of the subject. So it is necessary to physically attach the dosage form to the capsule which may effect the behaviour of the dosage form being studied.
  75. 75. Reoentgenography : The inclusion of a radio-opaque material into a solid dosage form enables it to be visualized by the use of X-rays. By incorporating Barium sulphate into a pharmaceutical dosage form, it is possible to follow the movement, location, and the integrity of the dosage form after oral administration by placing the subject under a fluoroscope and taking a series of X-rays at a various time points. Gamma scintigraphy The most useful technique, to evaluate the in vivo behavior of dosage forms in animals and humans is external scintigraphy or gamma scintigraphy It requires the presence of a gamma emitting radio active isotope in the dosage form that can be detected in vivo by an external gamma camera. The dosage form can be radio labeled using conventional labeling or neutron activation methods.

×