Beyond Conventional: Recent Advancement on Floating Drug Delivery Systems: An Approach to Oral Controlled and Sustained Drug Delivery Via Gastric Retention

The oral administration route has always assumed a role of prominence in therapy due to its well-established advantages. Several factors make this route preferable to patients, and these formulations are also less expensive, easy to transport and store, flexible in terms of the constituents, and ready to administer. However, oral administration faces some physiological constraints due to the heterogeneity of the gastrointestinal system. In addition, several variables change throughout the gastrointestinal tract and greatly influence drug absorption. Among these factors, pH, the commensal flora, gastrointestinal transit time, enzymatic activity and surface area are the most important ^[2]. Conventional systems are not enough to overcome all the difficulties imposed by the gastrointestinal tract. For instance, they are inappropriate for drugs that are preferentially absorbed in the upper part of the digestive system since conventional formulations do not possess the capacity to face gastric emptying; therefore, they cannot be released in the colon where they stay during the final period of their release time. Therefore, the incomplete release of drugs and the concomitant reduction of dose effectiveness are consequences of the incapacity of the conventional systems to be retained at the stomach level ^[3]. In order to overcome these adversities, technological researchers have developed pharmaceutical systems that control drug release and the residence time, some of which are already available on the market. The failure in gastric retention with conventional systems has led to the development of oral gastroretentive systems. Such delivery systems were designed to be retained in the upper gastrointestinal tract for a prolonged period of time, during which they release the drug on a controlled basis ^[2]. The extended contact of gastroretentive systems with the absorbing membrane allows an increase in drug bioavailability. Additional advantages of these systems include (i) an improvement in therapeutic effectiveness, (ii) a reduction in drug loss, (iii) an increase in drug solubility in cases with low solubility in a high pH environment, and (iv) benefits due to the delivery of drugs that act locally in the stomach and duodenum ^[4]. Several strategies have been studied to formulate successful controlled drug delivery systems that increase the gastric residence time such as bio adhesive or mucoadhesive systems, expandable systems, high-density systems, floating systems, super porous hydrogels, and magnetic systems. This review compiles relevant information about the drugs that can benefit from gastroretention strategies, the factors that influence their gastric retention time, the mechanism of action of gastroretention, as well as their presentation as single and multiple unit systems ^[4]. In most of the cases, the conventional oral delivery systems show limited bioavailability because of fast gastric-emptying time among many other reasons involved. However, the recent technological development has resulted to many novel pharmaceutical products, mainly the controlled release drug delivery systems to overcome this problem. Gastro-retentive drug delivery system (GRDDS) is one such example where the attribute like gastric retention time coupled with the drug release for extended time has significantly improved patient compliance ^[4]. Some inherent limitations of the conventional oral drug delivery systems have ignited the interest to this new delivery system. Fast gastric emptying associated with conventional oral medications leads to a bioavailability issue for many drug molecules (e.g., pranlukast hydrate, metformin HCl, baclofen, etc.), of which the main principal site of absorption is the stomach or the proximal part of the small intestine, or have the absorption issue in the distal part of the intestine ^[5]. Solubility can also be improved by prolonging the gastric retention of drugs that are less soluble in an elevated pH environment of the intestine ^[2]. There are many drugs (e.g., captopril, metronidazole, ranitidine HCl, etc.) that are prone to degradation in the colonic area ^[2]. To attain required therapeutic activity, recurrent dosing is needed for the drugs with short half-lives as they have the tendency of getting eliminated quickly from the systemic circulation. However, an oral sustained-controlled release formulation with additional gastric retention property can avoid these limitations by releasing the drug slowly in the stomach along with maintaining an effective drug concentration in the systemic circulation for an extended period of time. Apart from the systemic action, GRDDS has proved to be effective locally to treat gastric and duodenal ulcers, including esophagitis, by eradicating the deeply buried Helicobacter pylori from the sub-mucosal tissue of the stomach ^[8,10]. The history of GRDDS formulations dates back to almost three decades ^[11]. The basic fabrication techniques, including their in vitro characterizations, are also well established. Even in recent times, quite a few reviews have been published on GRDDS ^[5,12]. These reviews are more focused on the formulation aspects or in vitro characterization studies done by various researchers or overall GRDDS. The industrial aspects covering physicochemical, biopharmaceutical and regulatory considerations of GRDDS ^[19].

1.  Stomach physiology

The stomach is the most dilated part of the GIT and is situated between the lower end of the oesophagus and the small intestine. Its opening to the duodenum is controlled by the pyloric sphincter ^[17]. To act as a temporary reservoir for ingested food and to deliver it to the duodenum at a controlled rate. To reduce the ingested solids to uniform creamy consistency, known as chime, by the action of acid and enzymatic digestion. This enables better contact of the ingested material with the mucous membrane of the intestines and they’re by facilitates absorption. Another perhaps less obvious, function of stomach is its role in reducing the risk of noxious agents reaching intestine ^[20].

Success of GRDDS relies on the understanding of stomach physiology and related gastric emptying process. Structurally the human stomach is composed of three anatomical regions: fundus, body and antrum (pylorus), as depicted in Fig. 1. After a meal, the average volume of a stomach is about 1.5 l, which varies from 250 to 500 ml during the inter-digestive phases ^[18]. The part made of the fundus and the body acts as a reservoir of any undigested material, while the antrum performs as the principal site for the mixing action. Being the lower part, the antrum works as a pump for gastric emptying by a propel- ling action. Pylorus acts to separate the stomach from the duodenum and plays a major role in gastric residence time of the ingested materials. However, the pattern of the gastric motility is different for the fasting and fed state ^[20]. The gastric motility pattern is systematized in cycles of activity as well as quiescence. The duration of each cycle is 90–120 min and it contains four phases, as mentioned in Table 1. The motility pattern of the stomach is usually called migrating motor complex (MMC) ^[17].

1. 1. 1. Phase I (Basal Phase): This phase lasts about 30-60 min with rare contraction.
2. Phase II (Pre-burst Phase): This phase lasts about 20-40 min with intermittent action potential and contraction that moderately increase in intensity and frequency as the phase progresses. Later in this phase, there is gastric discharge of fluids and small particles ^[7].
3. Phase III (Burst phase): This phase lasts about 10-20 min, with intense and large, regular contractions that last for a short period of 4-6 min. This results in “sweeping” (moving) the undigested materials out of the stomach and down into the small intestine. Thus, these contractions are also known as the “housekeeper wave.”
4. Phase IV: This phase lasts for a very brief (transitory) period of about 0-5 min in which the contraction between phase III and phase I disperses. This is the transitory period between two different cycles ^[7].

2. Advantages and Disadvantages of FDDS

1. Advantages of FDDS

• Improves patient compliance by decreasing dosing frequency.
• Better therapeutic effect of short half-life drugs can be achieved.
• Gastric retention time is increased because of buoyancy.
• Drug releases in a controlled manner for a prolonged period.
• Site-specific drug delivery to stomach can be achieved.
• Enhanced absorption of drugs which solubilize only in the stomach ^[5,6,7].
• Superior to single unit floating dosage forms as such microspheres release drug uniformly and there is no risk of dose dumping ^[5,6,7].

2. Dis-Advantages of FDDS

• Drugs which have stability and solubility problem in acidic pH cannot be used for GRDDS
• Drugs which are irritant to gastric mucosa. NSAIDs and Aspirin cause gastric lesions.
• Drugs that have absorption throughout GIT are not beneficial for this system
• Variability in gastric emptying time and rate is a major disadvantage. 
• Longer time for swelling in hydrogel-based system.
• This system varies with the position of the person ^[5,6,7].

3. Drug selection criteria for GRDDS:

1. A number of considerations should be made while selecting drugs for Gastro-retentive Drug Delivery Systems (GRDDS) to ensure that the medication is suitable for this kind of delivery system ^[6].
2. GRDDS are especially useful for drugs that are poorly soluble and have low permeability in the gastrointestinal tract. These drugs often have limited absorption in the upper GI tract; therefore, prolonging their residence duration can increase their bioavailability.
3. For drugs with a restricted window of absorption in the stomach or upper small intestine, GRDDS is advantageous. These systems can increase the chance of absorption by making sure the drug remains in the absorption site for a longer period of time.
4. The stability or solubility of some drugs changes with pH. GRDDS can be designed to release the medication in response to the pH of the stomach, ensuring optimal absorption.
5. Medication that undergoes significant first pass metabolism in the liver may benefit from gastro-retentive delivery. By remaining exposed in the stomach for an extended length of time, the medicine can initially bypass the liver by decreasing metabolism and increasing systemic bioavailability.
6. Medication with a mechanism of action unique to the stomach, like antacids or those used to treat peptic ulcers or gastro esophageal reflux disease (GERD), is a good fit for GRDDS.
7. Certain drugs may interfere with meals or respond adversely to pH changes in the stomach. GRDDS can be designed to control the drug's release while food is present or to reduce interactions with food ^[6].

4. Factors controlling the gastroretentive drug delivery system

The gastric retention time can affect drug absorption. Absorption is often limited to areas between the stomach and duodenum, and the residence time in this area limits the absorption of drugs. Therefore, the longer the drug stays in contact with the absorbing membrane, more is the rate and extent of absorption. However, the time in the upper part of the gastrointestinal tract is short due to the fast gastric emptying time and generally lasts about 2–3 h. The gastric retention time is, therefore, an important parameter in drug absorption ^[4]. There are various factors to be considered for the development of gastroretentive dosage forms formulation to prolong the dosing intervals and thus improve patient compliance ^[9]. They are shown below.

4.1. Factors related to the dosage forms

• Size of the dosage form

To allow the dosage form to pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm. In most cases, the larger the dosage form the greater will be the GRT. Due to the larger size of the dosage form, it could not quickly pass through the pyloric antrum into the intestine. Small-size tablets leave the stomach during the digestive phase while the large-sized tablets are emptied during the housekeeping waves.

• Shape of dosage form

Ring-shaped and tetrahedron-shaped devices have a better gastric residence time as compared to other shapes ^[9].

• Density of dosage form

Dosage forms having a density lower than the gastric contents can float to the surface, while high density systems sink to the bottom of the stomach. Both positions may isolate the dosage system from the pylorus. A density of b1.0 g/cm 3 is required to exhibit floating property. However, the floating tendency of the dosage form usually decreases as a function of time, as the dosage form gets immersed into the fluid, as a result of the development of hydrodynamic equilibrium ^[9].

4.2. Food intake and its nature

• Fed & unfed state-under fasting condition

Under fasting conditions, the gastrointestinal motility is characterized by periods of strong motor activity or MMC that occurs every 1.5 to 2 h. The MMC sweeps the 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 ^[9].

• Food intake & nature of food

Food intake, viscosity and volume of food, caloric value and frequency of feeding have a profound effect on the gastric retention of dosage forms. The presence or absence of food in the gastrointestinal tract influences the gastric retention time of the dosage form. Usually, the presence of food in the gastrointestinal tract improves the gastric retention time of the dosage form & thus, the absorption of drugs increases by allowing its stay at the absorption site for a longer period ^[9].

• Calorie content

The rate of gastric emptying primarily depends on the caloric contents of the ingested meal. It does not differ for proteins, fats, carbohydrates as long as their caloric content is the same. Generally, an increase in acidity, osmolarity, and caloric value slows down gastric emptying. GRT can be increased between 4 and 10 h with a meal that is high in proteins and fats ^[9].

• Frequency of feed

The GRT can increase by over 400 min when successive meals are given compared with a single meal due to the low frequency of MMC ^[9].

4.3. Patient related factors

• Gender

Gastric emptying rate may differ in male & female. Generally, the gastric emptying in women was slower than in men ^[9].

• Age

Elderly people, especially those over 70 years have a longer gastroretentive time. Thus, gastric emptying time is slowed down ^[9].

• Posture

The effect of posture on GRT, found no significant difference in the mean GRT for individuals in upright, ambulatory and supine state. In the upright position, the floating systems floated to the top of the gastric contents and remained for a longer time, showing prolonged GRT. But the non-floating units settled to the lower part of the stomach and underwent faster emptying as a result of peristaltic contractions, and the floating units remained away from the pylorus. However, in supine position, the floating units are emptied faster than the non- floating units of similar size ^[9].

• Concomitant drug administration

Administration of drugs with impact on gastrointestinal transit time for example drugs acting as anticholinergic agents (e.g. atropine, propantheline), Opiates (e.g. codeine) and prokinetic agents (e.g. metoclopramide, cisapride) can alter gastro retention of oral dosage forms. Anticholinergics like atropine and propantheline increase gastric residence time. Drugs like metoclopramide and cisapride decrease gastric residence time ^[9].

4.4. Disease state

In gastric ulcer, diabetes, and hypothyroidism there is an increase in gastric residence time. In the case of hyperthyroidism and duodenal ulcers there is a decrease in gastric residence time ^[9].

4.5. Volume of the GI fluid

The resting volume of the stomach is 25 to 50 ml. The volume of liquids administered affects the gastric emptying time. When the volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids ^[9].

4.6. Effect of gastrointestinal fluid

On comparison of the floating and non-floating units, it was concluded that regardless of their sizes the floating units remained buoyant on the gastric contents throughout their residence in the GIT, while the non-floating units sink and remained in the lower part of the stomach. Floating units away from the gastro-duodenal junction were protected from the peristaltic waves during the digestive phase while non-floating forms stayed close to the pylorus and were subjected to propelling and retro Pelling waves of the digestive phase ^[9].

5. Approaches to fabricate gastro-retentive systems

There has been a large development of oral control release and sustain release drug delivery system for gastrointestinal diseases, for prolong absorption of drug. This system improv the bioavailability in Gastroretentive track and maintain an effective drug concentration for prolong time in stomach (GIT). As oral drug (Tablet, Capsule, Pellets) administered orally in stomach there is retention of drug in stomach and release drug in controlled manner. Due to controlled and sustained release the drug will supplied continuously to its absorption site or targeted site ^[12]. It also a pH base drug delivery system i.e., drug release at the certain pH there is heavy coating of metal which prevent it dissolving from gastric fluid and dissolved at targeted site. Current review deals with various gastro retentive drug delivery system approaches that have been recently become leading methodology in the field of site-specific drug delivery, controlled release drug delivery ^[8].

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include introducing floating dosage forms (gas generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying drugs. Among these, the floating dosage forms have been most commonly used ^[12]. Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents given in the Figure, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration ^[12]. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal ^[12]. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if F is on the higher positive side. This apparatus helps in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations ^[12].

F = F buoyancy - F gravity

= (Df - Ds) gv--- (1)

Where, F= total vertical force, Df = fluid density, Ds = object density, v = volume and

  g =acceleration due to gravity   

1. Non-effervescent FDDS

1. Hydrodynamically balance system

These are single-unit dosage forms, containing one or more gel-forming hydrophilic polymers. The polymer is mixed with drug and usually administered in a gelatin capsule. The capsule rapidly dissolves in the gastric fluid, and hydration and swelling of the surface polymers produces a floating mass ^[13]. Drug release is controlled by the formation of a hydrated boundary at the surface. Continuous erosion of the surface allows water penetration to the inner layers, maintaining surface hydration and buoyancy. Hydro dynamically balanced systems (HBS) are designed to prolong the stay of the dosage form in the gastro intestinal 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 ^[13].

To increase the GRT of the dosage form micro balloons or hollow microspheres with medications in their other polymer displays were made using a straight forward solvent evaporation or solvent diffusion technique. Polycarbonate, cellulose acetate, calcium alginate, Eudragit, agar, low methoxylated pectin, and other polymers are frequently utilized to create these systems ^[13]. Polymer amount, plasticizer polymer ratio, and formulation solvent all affect buoyancy and medication release from dosage forms. For more than 12 hours, these tiny balloons floated nonstop on the surface of an acidic dissolving medium containing surfactant. Because hollow microspheres combine the benefits of superior floating and multiple-unit systems, they are now regarded as one of the most promising buoyant systems ^[13].

Multi-unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of 2.5 mm diameter may be prepared by dropping sodium alginate solution into aqueous calcium chloride solution, resulting in precipitation of calcium alginate resulting in the formation of a porous system capable of maintaining a floating force of more than 12 h. Compared to solid beads, they have a longer period of stay of more than 5.5 h ^[14].

2. Effervescent FDDS

This approach provides floating drug delivery systems based on the formation of CO₂ gas. It utilizes effervescent components such as sodium bicarbonate (NaHCO₃) or sodium carbonate, and additionally citric or tartaric acid. Alternatively, matrices containing chambers of liquids that turns into gas at body temperature could be used. Upon contact with the acidic environment, a gas is liberated, which produces an upward motion of the dosage form and maintains its buoyancy ^[14]. A decrease in specific gravity causes the dosage form to float on gastric contents. These buoyant systems utilize matrices prepared with swellable polymers such as methocel, polysaccharides (e.g., chitosan), and effervescent components (e.g., sodium bicarbonate, citric acid or tartaric acid). The system is so prepared that upon arrival in the stomach, carbon dioxide is released, causing the formulation to float in the stomach. Other approaches and materials that have been reported are a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating mini capsules with a core of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxyl propyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology, etc. The various types of this system are as:

Gas generating system

1. Gas Generating Systems:

These are matrix type of systems prepared with the help of swellable polymers such as Methyl cellulose and chitosan and various effervescent compounds, eg, sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO₂ is liberated and gets entrapped in swollen hydrocolloids, which provide buoyancy to the dosage forms. In single unit systems, such as capsules or tablets effervescent substances are incorporated in the hydrophilic polymer and CO₂ bubbles are trapped in the swollen matrix ^[14]. In vitro, the lag time before the unit floats is <1>2. The main difficulty of such formulation is to find a good compromise between elasticity, plasticity and permeability of the polymer ^[14].

2. Volatile liquid containing system:

These have an inflatable chamber that holds a liquid, such as ether or cyclopentane, which gasifies at body temperature and causes the chamber in the stomach to inflate. These systems osmotically regulate a floating system with a specified hollow unit. The system has two chambers, the first containing the medicine and the second containing the volatile system. These systems are further classified as follows:

• Intra gastric floating gastrointestinal drug delivery system-

This method includes a flotation chamber filled with vacuum or an inert, harmless gas, as well as a micro porosity compartment containing a medication reservoir ^[14].

At body temperature, an inflatable chamber holding liquid ether gasifiers to inflate the stomach. The inflatable chamber contains bio erodible polymer filament (e.g., a copolymer of polyvinyl alcohol and polyethylene) that gradually dissolves in gastric fluid, causing the inflated chamber to release gas and collapse ^[14].

It is made up of an inflatable floating capsule and an osmotic pressure regulated medication delivery system. The inflatable capsule disintegrates in the stomach, releasing the osmotically regulated drug delivery system, which is made up of two parts: a drug reservoir compartment and an osmotically active compartment. Working on this method, super porous hydrogels are a good example ^[14]. The dose form expands to several times its original volume when it comes in contact with gastric fluid. Due to the dose form's bigger size, the gastric contraction slips over the system's surface, pushing the dosage form back into the stomach after the gastric contraction has pushed it to the pylorus ^[14].

The high-density frameworks density is going from2.5 to 3.0 g/mL to withstand in vivo peristaltic development and stayed flawless notwithstanding the GIT unsettling influence. The density of the measurements structures is expanded with barium sulfate, iron powder, titanium oxide, and zinc oxide fuse. The significant downside of this framework is expanded portion size to accomplish high density ^[10,55].   

In these frameworks, by the use of the attractive outer field the structure of the measurement washed inside the stomach. The dose structure would contain attractively dynamic components. One outer magnet was needed to position on the midsection over the area of the stomach to hold the controlled dose structure set up (Figure no.10). The significant downside of this framework is the absence of patient consistence. The lozenge form would contain magnetically active rudiments. One external attraction was needed to place on the tummy over the position of the stomach to retain the administered medicine in place (Figure no. 10). Though innovative in design, lack of patient compliance was one of the major lapses for in vivo design of this delivery system ^[10,55].

Lozenge form to attain sustained- release specific. farther advancement with the preface of swelling and expanding system (Figure no. 11), GRDDS managed to achieve significant success both in vitro and in vivo in order to retain the lozenge form in the stomach. one similar system that was designed to increase in size bigger than the periphery of pyloric sphincter and remain logged there (Figure no. 11). Alternately, the system was named as ‘draw type systems’ due to their pyloric sphincter blocking trait ^[55]. Once the polymer came in contact with the gastric fluid, it absorbed water and swelled. The selection of a suitable polymer (or combination of polymers) with an applicable molecular weight/ density grade and swelling parcels enabled the of similar kind of lozenge form has taken place with the preface of new polymers with super-porous nature, causing them to swell to an equilibrium size within a nanosecond. This characteristic rapid-fire lump property (swelling rate is 1100 or further) of the polymer with an average severance size of further than 100 ?m occurs due to capillary wetting through several interrelated open pores when the lozenge form comes in contact with GI fluid ^[10,55].

Bio adhesive or muco-tenacious medicine delivery systems were also tried as gastro-forgetful systems. The lozenge form was made to be attached inside the lumen of the stomach wall and survive the gastrointestinal motility for a longer period (Figure no. 12). It was also salutary as a point specific design to promote original medicine immersion in an infected area of the stomach. Muco- tenacious excipients like polycarbophil, lectins, Carbopol, chitosan, carboxymethylcellulose (CMC), pectin and gliadin were reported as expression compositions for this kind of design ^[55]. The combination of macho- adhesion and floating or swelling medium is being espoused as another new approach for bettered gastro- retention attributes. In- situ gelling fashion (also known as raft forming system) in combination with carbon dioxide bubble ruse was also reported as another case compliance design for gastroretention. This type of delivery system, originally as a result form, contains sodium alginate as in situ gel forming polymer along with carbonates or bicarbonates as bouncy agents. When they come in contact with the gastric fluid, they swell and induce a thick cohesive gel that contains entrapped carbon dioxide bubbles, causing the medicine delivery systems to float. For gastroesophageal influx treatment, raft forming systems are constantly used because of their tendency to produce a subcaste on the upper part of the gastric fluid ^[10,55].

7. Raft forming systems

These are in situ gelling system gotten by blend with carbon dioxide bubble ensnarement. At first, it is an answer, contains sodium alginate (in situ gel previous) alongside carbonates or bicarbonate’s as bubbly specialists. At the point when they interact with the GIFs, sodium alginate grows and produce a thick, strong gel that captures carbon dioxide bubbles, making it skim. They are significantly suggested for the treatment of gastroesophageal reflux ^[54].

6. Applications of floating drug delivery systems:

• Enhance bioavailability:

The bioavailability of CR-GRDF is significantly enhanced in comparison to the administration of non-GRDF CR polymeric formulations. There are several different processes, related to absorption and transit of the drug in the gastrointestinal tract, that act concomitantly to influence the magnitude of drug absorption ^[37].

• Sustained drug delivery:

In this systems dose large in size and passing from the pyloric opening is prohibited. New sustained release floating capsules of nicardipine hydrochloride were developed and were evaluated in vivo. Plasma concentration time curves showed a longer duration for administration (16 hours) in the sustained release floating capsules as compared with conventional MICARD capsules (8 hours). Similarly, a comparative study between the Madopar HBS and Madopar standard formulation was done it shown the drug was released up to 8 hours in vitro in the former case and the release completed in less than 30 minutes in the latter case ^[37].

• Site–specific drug delivery systems:

These systems are particularly advantageous for drugs those are specifically absorbed from the stomach or the proximal part of the small intestine. The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug. It reduces the side effects which are caused by the drug in the blood circulation. In addition, the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency ^[37].

• Absorption enhancement:

Drugs which are having poor bioavailability because of site specific absorption from the upper part of the GIT are potential candidates to be formulated as floating drug delivery systems, there by maximizing their absorption ^[37].

• Minimize adverse activity at the colon:

Retention of the drug in the HBS systems at the stomach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This pharmacodynamic aspect provides the rationale for GRDF formulation for beta-lactam antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganism’s resistance ^[37].

• Reduce fluctuations of drug concentration:

Continuous input of the drug following controlled release gastro-retentive dosage form administration produces blood drug concentrations within a narrower range compared to the immediate release dosage forms. Thus, fluctuations in drug effects are minimized and concentration dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index ^[37].

7. Recent studies on various gastro-retentive technologies:

8. ---

   Natural gums

Natural polymers, in addition to manufactured cellulose ethers, have been employed as hydrocolloids to successfully control drug release from swellable systems ^[7]. Natural polymers contain beneficial properties such as biocompatibility and safety, and so have valuable pharmaceutical and biological applications. Natural gums-gellan gum, guar gum, carrageenan’s, and xanthan gum along with other polysaccharides like alginates and chitosan and natural polymers like pectin and gelatin are natural hydrocolloids or gel-forming agents that can swell in contact with gastric fluid, maintain relative shape integrity, and have a bulk density less than the gastric content ^[15,18].

Natural polymers

Natural gums are polysaccharides consisting of multiple sugar units linked together to create large molecules. Gums are frequently produced by higher plants as a result of their protection mechanisms following injury. They are heterogeneous in composition. Upon hydrolysis they yield simple sugar units such as arabinose, galactose, glucose, mannose, xylose or uranic acids, etc. The linear polysaccharides occupy greater volume than branched polymers of comparable molecular weight. Hence, at the same concentration, comparable linear polysaccharides exhibit greater viscosity ^[22]. Therefore, it is difficult for the heterogeneous gum molecules to move freely without becoming entangled with each other. Also, the natural gums are often known for their swelling properties. This is due to entrapment of large amounts of water between their chains and branches ^[22]. The polysaccharide gums represent one of the most abundant industrial raw materials and have been the subject of intensive research due to their sustainability, biodegradability and bio-safety. Many natural gums form three dimensional interconnected molecular networks known as “gels”. The strength of the gel depends on its structure and concentration, as well as on factors such as ionic strength, pH and temperature. Natural gums are used in pharmaceuticals for their diverse properties and applications. They have good adhesive and laxative properties and are used in dental preparations. They are used as binders and disintegrants in solid dosage forms. In liquid oral and topical products, they are used as suspending, and stabilizing agents ^[22].