INTRODUCTION:

The Oral route is considered as the most preferable route of drug delivery due to the ease of administration, low cost of therapy, patient compliance and flexibility in formulation etc. Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms. The gastric emptying of dosage forms in human is affected by several factors because of which wide inter and intra subject variations are observed. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastro intestinal tract. Drug absorption from the gastro intestinal tract is a complex procedure and is subjected to many variables¹.

The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, floating, sedimentation, expansion, modified shape systems, or by the simultaneous administration of pharmacological agents that delay gastric emptying. The hydro dynamic balanced systems (HBS) are also called as floating drug delivery system (FDDS) which is an oral dosage form (capsule or tablet) designed to prolong the gastric residence time².

Advantages of floating drug delivery systems^{2, 3}

1. FDDS dosage forms are advantageous for drugs meant for local action in stomach e.g.: Antacids

2. Floating dosage forms such as tablets or capsules will remains in the solution for prolonged time even at the alkaline ph of the intestine.

3. The efficacy of the medicaments administered utilizing the sustained release principle of HBS been found to be independent of the site of absorption of the particular medicaments.

4. Gastric retention will provide advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region.

Disadvantages of floating drug delivery systems^{2, 3}

1. One of the disadvantages of floating systems is that they require a sufficiently high of fluids in the stomach, so that the drug dosages form float therein and work efficiently.

2. These systems also require the presence of food to delay their gastric emptying.

3. There are certain situations where gastric retention is not desirable. Aspirin and non-steroidalanti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in the stomach is unwanted.

4. Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well throughout the GI tract will not benefit from incorporation into a gastric retention system.

Basic anatomy and physiology of stomach^{3, 4}:

The stomach is J-shaped organ located in the upper left hand portion of the abdomen, just below the diaphragm. It occupies a portion of the epigastria and left hydrochondriac region. The main function of the stomach is to store the food temporarily, grind it and then release it slowly into the duodenum. Due to its small surface area very little absorption takes place from the stomach. It provides barrier to the delivery of drugs to small intestine (figure 1).

Figure 1: Anatomy of Stomach Gastric motility and transit time:

During the fasting state an interdigestive series of electrical events take place which cycle both through stomach and intestine every 2-3 hrs, which is called as interdigestive myloelectric cycle or migrating myloelectric cycle (MMC) which is further divided in to four phases After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state which is also termed as digestive motility pattern^{5, 6}.

A. Phase 1-(Basic phase)- last from 30-60 minutes with rare contractions.

B. Phase 2-(Pre burst phase)- last for 20-40 minutes with intermittent action potential and contractions.

C. Phase 3-(Burst phase) - last for 10-20 minutes which includes intense and regular contractions for short period.

D. Phase 4- last for 0-5 minutes and occurs between phase 2 and 1 of 2 consecutive cycles (Fig1).

Phase 3 is the housekeeping role and serves to clear all indigestible materials from the stomach and small intestine⁶. Consequently, a controlled-release gastrointestinal drug delivery system must be capable of resting the housekeeping action of phase 3.

Factors affecting gastric retention⁷:

Gastric residence time of an oral dosage form is affected by several factors. To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2mm.the ph of the stomach in fasting state is 1.5 to 2 and in fed state is 2.0 to 6.0. The rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However increase in acidity and caloric value slows down gastric emptying time.

The rate of gastric emptying depends on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time.

Ø Size – dosage form units with a diameter of more than 7.5 mm are reported to have an increased GRT compared with those with a diameter of 9.9 mm

Ø Shape of dosage form – tetrahedron and ring shaped devices with a flexural modulus of 48 and22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes

Ø Age – elderly people, especially those over 70, have a significantly longer GRT.

Ø Biological factors – diabetes and Crohn’s disease, etc.

Approaches to gastric retention^{8, 9 10}:

A number of approaches have been used to increase the GRT of a dosage form in stomach by employing a variety of concepts. These include:

1. Single unit dosage forms:

In low density approaches the globular shells apparently having lower density than that of gastric fluid can be used as a carrier like popcorn, poprice, polystrol for the drug for its controlled release. The polymer of choice can be either Ethyl cellulose (S.D.Fine Chem. Ltd., Mumbai) or HPMC (Loba Chemie Pvt. Ltd; Mumbai), depending on type of release desired. Finally the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration.

· Hydro dynamically balanced systems (HBS):

Hydro dynamically balanced systems (HBS) are designed to prolong the stay of the dosage form in the gastrointestinal tract and aid in enhancing the absorption. Such systems are best suited for drugs having a better solubility in acidic environment and also for the drugs having specific site of absorption in the upper part of the small intestine. To remain in the stomach for a prolonged period of time the dosage form must have a bulk density of less than 1. It should stay in the stomach, maintain its structural integrity, and release drug constantly from the dosage form.

Fluid- filled floating chamber type of dosage forms includes incorporation of a gas-filled floatation chamber into a micro porous component that houses a drug reservoir.

Single-unit formulations are associated with problems such as sticking together or being obstructed in the gastrointestinal tract, which may have a potential danger of producing irritation.

2. Multiple unit dosage forms:

To overcome the problems of single unit dosage form is to develop a these multiple dosage forms. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of 12 to 18 mm in their expanded state is exceeded.

Most Multi particulate pulsatile delivery systems are reservoir devices coated with a reputable polymeric layer. Upon water ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure build-up within the system. The pres-sure necessary to rupture the coating can be achieved with swelling agents, gas producing effervescent excipients or increased osmotic pressure.

Classification of floating drug delivery systems^{11, 12}:

Floating drug delivery systems are classified depending up on the two formulations variables Effervescent and Non-effervescent systems (Vedha hari b.n.et al, 2010, Drs Jose Gutierrz Rocca et al, 2003).

1. Effervescent Systems:

These effervescent systems further classified into two types.

I. Gas generating systems

II. Volatile Liquid/Vacuum Containing Systems

· Gas generating systems:

These are matrix type of systems prepared with the help of swellable polymers such as methylcellulose and Chitosan and various effervescent compounds, e.g. sodium bi carbonate, tartaric acid, and citric acid. They are formulated in such a way that when contact with the acidic gastric contents, co₂is liberated and gets entrapped in swollen hydro colloids, which provides buoyancy to the dosage forms (figure 2).

Figure 2: Buoyancy mechanism of Gas generating systems

These systems are again classified into 3 categories:

1. Intra gastric single layer floating tablets

2. Intra gastric bi layer floating tablets

3. Multiple unit type floating pills.

1. Intra gastric single layer floating tablets:

These are formulated by intimate mixing of drugs with gel forming hydro colloids which swells in contact with gastric fluids and maintains a relatively integrity of shape and bulk density lesser than gastric environment (figure 3). The drug slowly released at a desired rate from the floating system and after the complete release the residual system is expelled from the stomach. This leads to an increase in the GRT and a better control over fluctuations in plasma drug concentration.

Figure 3: Intra gastric single layer floating tablet.

2. Intra gastric bi layer floating tablets:

These are also compressed tablets containing two layers (figure 4):

Ø Immediate release layer

Ø Sustained release layer

Figure 4: Intra gastric bi layer floating tablet

3. Multiple unit type floating pills:

Multiple unit type of floating pills composed of inner effervescent layer containing sodium bicarbonate and tartaric acid and outer swellable polymeric membrane made up of polyvinyl acetate and purified shellac. The inner layer was further divided into two sub layers to avoid physical contact between sodium bicarbonate and tartaric acid. When the pill was immersed in buffer solution at 37 °C, it settled down at the bottom, buffer solution entered in to the effervescent layer through the outer swellable membrane. Which floats as they have lower density? This lower density is due to generation and entrapment of co₂ within system (figure 5).

Figure 5: Multi- unit oral floating dosage forms.

II. Volatile Liquid/Vacuum Containing Systems:

Ø Intra gastric floating gastrointestinal drug delivery system

Ø Inflatable gastro intestinal delivery system

Ø Intra gastric osmotically controlled drug delivery system

· Intra gastric floating gastrointestinal drug delivery system:

These systems can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a microspores compartment. The peripheral walls of the reservoir compartment were completely sealed to prevent any physical contact of the undissolved drug with walls of the stomach (figure 6).

Figure 6: Intragastric floating drug delivery system

· Inflatable gastro intestinal delivery system:

In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach. After oral admistration of the capsules, the shell dissolves to release the drug reservoir together with the inflatable chamber. The drug continuously released from the gastric fluid (figure 7).

It is observed that the system start floating within 10 min over the water level for period of 5hr, independent of the ph and viscosity of medium.

Figure 7: Inflatable gastrointestinal delivery system

· Intra gastric Osmotically Controlled Drug Delivery System:

It is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule (figure 8). In the stomach, the capsule quickly disintegrates to release the intra gastric osmotically CDDS. The inflatable support inside forms hollow polymeric bag that contain liquids that gasified at body temperature to inflate the bag¹³.

These osmotic pressure CDDS consists of 2 components: drug reservoir compartment and osmotically active compartment. Drug reservoir compartment is impermeable to vapor and liquids and hence drug delivery orifice and osmotically active compartment have osmotically active salt .which imbibes water from gastro intestinal tract and release drug.

Figure 8: Intragastric osmotically controlled drug delivery system

2. Non-Effervescent Systems:

The non-effervescent FDDS works on the mechanism of polymer swelling, bioadhesion of the polymer to mucosal layer of GI tract. The most commonly used excipients for the preparations of non-effervescent FDDS are gel forming or swellable type hydrocolloids, poly-saccharides and matrix forming polymers like poly methacrylates, polycarbonates, poly acrylates polystyrenes and bioadhesion polymers like chitosan and carbopols^{14, 15}.

The various types of these systems are as follows

· Single layer floating tablet

· Bi layer floating tablet

· Hydro dynamically balanced capsule

· Casein gelatin floating beads

· Hollow microsphere or micro balloons

Ø Single layer floating tablet

They are formulated by intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than unity.

Ø Bi layer floating tablet

A bi layer tablet contain two layer one immediate release layer which release initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach.

Ø Alginate Beads

Spherical beads of approximately 2.5 mm diameter can be prepared by dropping solution of sodium alginate into aqueous solution of calcium chloride, emulsifying property and thus causes air bubbles incorporation that act as air reservoir in floating system.

Ø Hollow Microspheres

Hollow microspheres (micro balloons) loaded with drug in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ethanol dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated aqueous solution of PVA that was thermally controlled at 400C.

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Received on 27.03.2013 Modified on 19.04.2013

Research J. Pharm. and Tech 6(7): July 2013; Page 706-710