BY MITHILA PARIKH

flotting drug delivary system

NEED FOR GASTRO RETENTIVE DOSAGE FORMS:

Existing oral control release delivery systems are useful only for drugs having good absorption throughout the gastrointestinal (GI) tract. But such systems may fail for certain drugs due to: 1] Uncertainties of gastrointestinal tract with respect to presence of meal, 2] Brief gastric emptying time in humans (10-30 mins for liquid to 2-3 hours for solids), 3] Gradient pH condition throughout GIT and 4] Presence of narrow absorption window i.e. absorption from a particular region of GIT. Polar compounds and those that rely on active transport process generally display good absorption from the upper GI tract, but are poorly absorbed in the large intestine (or colon). As a consequence, their oral bioavailability diminishes. In addition, the development of a modified release product, such as those designed to provide once-daily dosing will be difficult, if not impossible. Hence, the concept of ‘absorption window’ has come up. Gastroretentive dosage forms can provide solution for this problem. After oral administration, such a dosage form would be retained in the stomach and release the drug there in a controlled and prolonged manner, so that the drug could be supplied continuously to its absorption sites in the upper gastrointestinal tract.

APPROACHES TO GASTRIC RETENTION:
Several approaches have been attempted to formulate gastroretentive dosage forms (GRDFs) which rely on one or more of the following principles:
1] Floating delivery systems: These are low density dosage forms that remain buoyant above the gastric fluid.
2] Sinking delivery systems: The density of system is larger than that of the gastric juice, the device settles down to the bottom of the stomach, remaining located below the pylorus.
3] Bioadhesive delivery systems: These systems adhere to the stomach mucosa.
4] Swelling and expanding delivery systems: The dosage form by swell or unfold to a size which limits its emptying through pyloric sphincter.
5] Use of Prokinetic agents: These compounds reduce motility of GI tract thereby increasing gastric residence of systems.
6] Superporous hydrogels: They expand dramatically (swell hundreds of times than their dehydrated form) within in the stomach while drug being released slowly from it to the intestine.

BIOLOGICAL ASPECTS OF GRDFs:
1) Role of the gastro intestinal tract:
The GI tract is essentially a tube about 9 m long that runs from the mouth to the anus and includes the throat , esophagus , stomach , small intestine and large intestine. Stomach is a J shaped dilated portion of alimentary canal situated in the epigastric , umbilical, and left hypochondriac regions of the abdominal cavity. Its size varies with the amount of food it contains. The volume is 1500ml or more in an adult and after food has emptied a collapsed state is obtained with a resting volume of only 25-30 ml. [2] [3] The stomach is composed of fundus ( part which faces opening of esophagus into the stomach ), the body ( central part ) and the antrum . The pylorus is an anatomical sphincter situated between the most terminal antrum and duodenum. The fundus and the body store food temporarily, secrete digestive juices and propel chyme, a milky mixture of food and gastric juices into the antrum. The antrum grinds and triturates the food particles and regulates the secretion of hydrochloric acid and emptying of food. [4]
2) Gastric emptying:
The process of gastric emptying is characterized by a distinct cycle of electromechanical activity known as the interdigestive migrating myoelectric complex. This series of events that cycle through the stomach and small intestine every 1.5 – 2 hrs is divided into four consecutive phases: [5]
• Phase I (45 – 60 min), known as basal phase, which develops few or no contractions;
• Phase II (30 – 45 min), known as preburst phase, consists of intermittent action potentials and contractions, which gradually increase in intensity and frequency as the phase progresses;
• Phase III (5 – 15 min) is a bust phase wherein short period of intense contractions and peristaltic waves, involving both the proximal and distal gastric regions (‘housekeeper waves’) are generated. In this phase, indigestible solids are removed from the fasted stomach;
• Phase IV (0 – 5 min) is a transition period of decreasing activity until the next cycle begins.
During fed state, onset of MMC is delayed & hence there is slowing of gastric emptying rate.

FLOATING DRUG DELIVERY SYSTEMS:
This approach has recently become one of the leading methodologies in gastroretentivity. It is convenient and utilizes simple technique to prolong gastric residence time (GRT). All floating DDS have the common property of possessing density lower than that of gastric fluids so that they can float in the stomach for prolonged period of time. While the system is floating on gastric contents, the drug is released slowly at the desired rate from the system. The intragastric position of the DDS, far distant from the gastroduodenal junction, protects them from a random, early and erratic emptying during their digestive phase even if their size is smaller than pylorus opening. The mechanisms by which a drug delivery can float are illustrated as below:

APPILICATION OF FDDSs:
Floating drug delivery is used to deliver drugs that
1. act locally in the stomach eg. Cytoprotective agent (Misoprostol), Antacids (Aluminum hydroxide), Antibiotics against helicobacter pylori (Ciprofloxacin, Ofloxacine) etc.
2. have an ‘absorption window’ in the stomach and/or the upper part small intestine eg. L-Dopa, p-Aminobenzoic acid, Furosemide, Metformin etc.
3. are unstable in the intestinal and colonic environment eg. Captopril.
4. exhibit low solubility at higher pH values eg. Diazepam, Chlordiazepoxide, Verapamil.

FACTORS AFFECTING GASTRIC RETENTION OF FLOATING DOSAGE FORMS:
A number of factors affect the efficacy of FDDSs, which are schematically represented as follows [6, 7]:

1) Food related factors:
• Fasted or fed state – under fasting conditions, the GI motility is characterised by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and, if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer.
• Type & frequency of feed – feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release while the GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.
2) Biological factors:
• Age & gender– elderly people, especially those over 70, have a significantly longer GRT. Mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface.
• Posture – GRT can vary between supine and upright ambulatory states of the patient.
• Disease state – diabetes and Crohn’s disease.
3) Formulation related factors:
• Density – GRT is a function of dosage form buoyancy that is dependent on the density.
• Shape of dosage form – tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilopounds per square inch (KSI) are reported to have better GRT ≈ 90% to 100% retention at 24 hours compared with other shapes.
• Size of dosage form – dosage form units with a diameter of more than 7.5mm are reported to have an increased GRT compared with those with a diameter of 9.9mm.
• Single or multiple unit formulation – multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co-administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.
The bulk density of a dosage form is not a sole measure to describe its buoyant capabilities because the magnitude of floating strength may vary as a function of time and gradually decreases after immersion of dosage form in fluid due to development of its hydrodynamic equilibrium.


FORMULATION CONSIDERATIONS:
While formulating FDDS, three major conditions must be met viz.
1. It must have sufficient structure to form a cohesive gel barrier.
2. It must maintain an overall specific gravity lower than that of gastric contents.
3. It should dissolve slowly enough to serve as a reservoir for delivery system.
From the studies it is found that high molecular weight polymers and lower rates of polymer hydration are usually associated with enhanced floating behaviour. The different dosage forms developed are tablets (single layered, bilayered, trilayered) capsules, granules, powders, laminated films, hollow microspheres, microballons etc. Single unit and multiple units are two types of FDDS that have come up. Single unit dosage forms are more popular but have a disadvantage owing to their “all or nothing” emptying process leading to high variability of GI transit time. The multiple unit dosage forms may be better suited because they are claimed to reduce the intersubject variability in absorption and lower the probability of dose dumping. Such a dosage form can be distributed widely throughout the GI tract providing the possibility of a longer lasting and more reliable release of drug from dosage form.
Based on the mechanism of buoyancy, two different systems have been developed. They are effervescent and non-effervescent dosage form.