These have various advantages,
which include, a reproducible gastric residence time, no risk of dose dumping and the flexibility to blend with different compositions or release patterns e.g., pellets.
However, drug loading in these systems is
excipients (e.g. sugar cores). Multiparticulate with pulsatile release profiles are usually reservoir-type devices with a coating, which either ruptures or changes its permeability.
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Figure 1.3: Different stages in drug release from pulsincap
Swellable materials coated with insoluble, but permeable polymers (e.g.,
Erodible compressed materials (e.g., HPMC, polyvinyl alcohol, polyethylene oxide) Congealed melted polymers (e.g., saturated polyglycoated glycerides or glyceryl
2) Multiparticulate Pulsatile Drug Delivery Systems:
These have various advantages, when compared to single unit dosage forms, which include, a reproducible gastric residence time, no risk of dose dumping and the flexibility to blend with different compositions or release patterns e.g., pellets.
However, drug loading in these systems is low because of higher need of excipients (e.g. sugar cores). Multiparticulate with pulsatile release profiles are usually
type devices with a coating, which either ruptures or changes its permeability.
141414 14 Different stages in drug release from pulsincap
Swellable materials coated with insoluble, but permeable polymers (e.g.,
materials (e.g., HPMC, polyvinyl alcohol, polyethylene oxide) Congealed melted polymers (e.g., saturated polyglycoated glycerides or glyceryl
when compared to single unit dosage forms, which include, a reproducible gastric residence time, no risk of dose dumping and the flexibility to blend with different compositions or release patterns e.g., pellets.
low because of higher need of excipients (e.g. sugar cores). Multiparticulate with pulsatile release profiles are usually type devices with a coating, which either ruptures or changes its permeability.
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1.6 COLON SPECIFIC DRUG DELIVERY SYSTEMS (CSDDS) 16, 17
The colonic region of the gastrointestinal tract is one area that would benefit from the development and use of such modified release technologies. Although considered by many to be an innocuous organ that has simple functions in the form of water and electrolyte absorption and the formation, storage and expulsion of faecal material, the colon is vulnerable to a number of disorders including ulcerative colitis, crohn’s disease IBS and carcinomas. In addition, systemic absorption from the colon also be used as a means of achieving chronotherapy for diseases that are sensitive to circadian rhythms such as asthma, angina and arthritis.
Structure and function of the Colon16
The colon forms the lower part of the gastrointestinal tract and extends from the ileocecal junction at the anus. The colon is upper five feet of the large intestine and the rectum is the lower six inches. While the colon is mainly situated in the abdomen, the rectum is primarily a pelvic organ. As shown in the Fig 1.4, the first portion of the colon is spherical and is called cecum. The appendix hangs off the cecum. The next portion of the colon, in the order in which contents flow, is the ascending (proximal) colon, just under the liver, the angle or bend is known as the hepatic flexure, located just beneath the rib cage. The colon then turns to a long horizontal segment, the transverse colon. Beneath the left rib cage, the colon turns downward at the haustra, to become the descending (distal) colon. In the left lower portion of the abdomen, the colon makes an S-shaped curve from the hip over the midline known as the sigmoid colon. The colon and rectum have an anatomic blood supply. Along these blood vessels are lymph nodes. Lymph
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and store cells that fight infection, inflammation, foreign proteins and cancer.
pH in colon:7,16
Radiotelemetry shows the highest pH levels (7.5 entry into the colon, the pH drops to 6.4
the left colon 7.0±0.7. There is a fall in pH on entry into the colon due to the presence of short chain fatty acids arising from bacterial fermentation polysaccharide
Location Oral cavity Oseophagus Stomach Small intestine Large intestine
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nodes are structures found in the circulating lymphatic system of the body that produce and store cells that fight infection, inflammation, foreign proteins and cancer.
Figure 1.4: Structure of colon
Radiotelemetry shows the highest pH levels (7.5±0.5) in the terminal ileum. On entry into the colon, the pH drops to 6.4±0.6. The pH in the mid colon is 6.6
0.7. There is a fall in pH on entry into the colon due to the presence of short chain fatty acids arising from bacterial fermentation polysaccharide
Table 1.2: Average pH in the GI tract
pH 6.2-7.4 5.0-6.0
Fasted condition:1.5-2.0, Fed condition: 3.0 Jejunum:5.0-6.5, Ileum: 6.0-7.5 Right colon: 6.4, Mild colon and left colon:6.0
161616 16 lymphatic system of the body that produce and store cells that fight infection, inflammation, foreign proteins and cancer.
0.5) in the terminal ileum. On 0.6. The pH in the mid colon is 6.6±0.8 and in 0.7. There is a fall in pH on entry into the colon due to the presence of short chain fatty acids arising from bacterial fermentation polysaccharides.
Fed condition: 3.0-7.5
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Gastrointestinal transit:7
Gastric emptying of dosage form is highly variable and depends primarily on whether the subject is fed or fasted and on the properties of the dosage forms such as size and density. The arrival of an oral dosage form at the colon is determined by the rate of gastric emptying and the small intestinal transit time. Although the surface area in the colon is low compared to the small intestine, this is compensated by the markedly slower rate of transit.
Table 1.3: Average GI transit time
Oral Transit time (hr)
Stomach <1(fasting);>3(fed)
Small intestine 3-4
Large intestine 20-30
1.7 METHODS FOR TARGETING DRUG INTO THE COLON7,14,16,19,20
These applications are either drug specific (prodrug) or formulations specific (coated or matrix preparations). The most commonly used targeting mechanisms are:
1 pH-dependent delivery 2 Time dependent delivery 3 Pressure dependent delivery 4 Bacteria- dependent delivery
The possibility of exploiting delayed release to perform chronotherapy, is quite appealing for those diseases, the symptoms of which recur mainly at night time or in the early morning, such as bronchial asthma, angina pectoris and rheumatoid arthritis.21,22,23,24.
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Table 1.4: Summary of colon-specific drug delivery strategies16,19,20
Design strategy
Drug release triggering
mechanisms Advantages Disadvantages
Prodrugs
Cleavage of the linkage bond between drug and carrier via reduction and hydrolysis by enzyme from colon bacteria. Typical enzymes include azoreductase, glycosidase, and glucuronidase. Able to achieve site specificity. It will be considered as a new chemical entity
from regulatory prespective. So far this
approch has been primarily constricted to
achives releated to the treatment of IBD. pH- depedent systems Combination of polymers with pH-dependent solubility to take advantage of the pH changes along the GI tract. Formulation well protected in the stomach Unpredictable site- specificity of drug release because of inter/intra subject variation of pH between
small intestine and the colon.
Time- dependent system
The onset of drug release is aligned with positioning the delivery system in the colon by incorporating a time factor simulating the system transit in upper GIT.
Small intestine transit time
fairly consistent.
Substantial variation in gastric retention times make it complicated in predicting the accurate location of drug release.
Microfloro activated system
Primarily fermentation of non-starch polysaccharides by colon anaerobic bacteria. The polysaccharides are incorporated into the delivery system via film coating and matrix formation.
Good site specificity with
prodrugs and polysaccharides.
Diet and disease can affect colonic microflora; enzymatic
degredation may be excessively slow. In this work Flurbiprofen was selected for dosage development. Flurbiprofen [1,1’-biphenyl]-4-acetic acid, 2-fluoro-alpha-methyl-, is an important analgesic and non-steroidal anti-inflammatory drug (NSAID) also with anti-pyretic properties whose mechanism of action is the inhibition of prostaglandin synthesis. It is used in the therapy of rheumatoid disorders. The drug must be administered approximately 150- 200mg daily by oral in divided doses.25
Department of Pharmaceutics, Bharathi College of Pharmacy. Department of Pharmaceutics, Bharathi College of Pharmacy. Department of Pharmaceutics, Bharathi College of Pharmacy.
Department of Pharmaceutics, Bharathi College of Pharmacy. 1919 1919
To design and characterize an oral, drug delivery system of Flurbiprofen intended to approximate the chronobiology of arthrities, proposed for colonic targeting. It is a chronopharmaceutical approach for the better treatment of rheumatoid arthritis. Based on the concept that a formulation on leaving the stomach, arrives at the ileocaecal junction in about 6 hours after administration and difference in pH throughout GIT, a time and pH dependent pulsatile (or modified pulsincap), controlled drug delivery system was designed. This capsule consists of a non-disintegrating body and a soluble cap. The drug formulations is contained within the capsule body and separated from the water-soluble cap by a hydrogel polymer plug. The entire capsule is enteric coated to prevent variable gastric emptying. The enteric coating prevents disintegration of the soluble cap in the gastric fluid. On reaching the small intestine the capsule will lose its enteric coating and the polymer plug inside the capsule swells to create a lag phase that equals the small intestinal transit time. This plug ejects on swelling and releases the drug from the capsule in the colon.
2.1 PLAN OF RESEARCH WORK
Preformulation studies:
• Selection of polymer and its combinations suitable for the colonic drug delivery • Preparation of standard graph of Flurbiprofen using spectrometric methods. • Drug-polymer Interaction
Experimental designing for formulation and evaluation of Flurbiprofenmicrospheres: • Preparation of Flurbiprofen microspheres by emulsification-solvent evaporation.