INTRODUCTION:

The main goal of any drug delivery system is to achieve desired concentration of the drug in blood or tissue, which is therapeutically effective and non toxic for a prolonged period. The pointing of the goal is towards the two main aspects regarding drug delivery, namely spatial placement and temporal delivery of a drug. Spatial placement means targeting a drug to a specific organ or a tissue while temporal delivery refers to controlling the rate of drug delivery to that specific organ or a tissue [1]. Oral delivery of drugs is by farther most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. Many of the drug delivery systems, available in the market are oral drug delivery type systems[2].

Oral drug delivery systems have progressed from immediate release to site-specific delivery over a period of time. Every patient would always like to have a ideal drug delivery system possessing the two main properties that are single dose or less frequent dosing for the whole duration of treatment and the dosage form must release active drug directly at the site of action[3]. The GIT is the most preferred and most commonly used route for the delivery of drugs [4]. Physiological properties of the GIT which favor absorption are the relatively large volume of fluid available, the peristaltic movements of the stomach and intestines, the large mucosal area over which absorption can occur, and the extensive blood flow through the mesenteric circulation [5]. Drugs that are easily absorbed from gastrointestinal tract (GIT) and have short half-lives are eliminated quickly from the systemic circulation. Frequent dosing of these drugs is required to achieve suitable therapeutic activity[6]. To avoid this limitation, the development of oral sustained-controlled release formulations is an attempt to release the drug slowly into the gastrointestinal tract (GIT) and maintain an effective drug concentration in the systemic circulation for a long time. After oral administration, such a drug delivery would be retained in the stomach and release the drug in a controlled manner, so that the drug could be supplied continuously to its absorption sites in the gastrointestinal tract (GIT) [7].

Gastro retentive drug delivery is an approach to prolong gastric residence time, thereby targeting site-specific drug release in the upper gastrointestinal tract (GIT) for local or systemic effects. Over the last few decades, several gastro retentive drug delivery approaches being designed and developed, including: high density (sinking) systems that is retained in the bottom of the stomach[8], low density (floating) systems that causes buoyancy in gastric fluid [9, 10, 11], mucoadhesive systems that causes bioadhesion to stomach mucosa [12], unfoldable, extendible, or swellable systems which limits emptying of the dosage forms through the pyloric sphincter of stomach [13,14], super porous hydrogel systems [15], magnetic systems [16]etc. The current review deals with various gastro retentive approaches that have recently become leading methodologies in the field of site-specific orally administered controlled release drug delivery systems.

Bioadhesion may be defined as the state in which two materials, at least one of which is of biological nature, are held together for extended periods of time by interfacial forces [17]. For drug delivery purposes, the term bioadhesion implies attachment of a drug carrier system to a specific biological location[18]. The biological surface can be epithelial tissue or the mucous coat on the surface of a tissue. If adhesive attachment is to a mucous coat, the phenomenon is referred to as mucoadhesion [19]. Mucous coat includes the mucosal linings of the nasal, rectal, oesophageal, vaginal, ocular, and oral cavity.

Mucoadhesive controlled release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site. Mucoadhesion also increase the intimacy and duration of contact between a drug-containing polymer and a mucous surface [20]. The combined effects of the direct drug absorption and decrease in excretion rate (due to prolonged residence time) allow for an increased bioavailability of the drug with a smaller dosage and less frequent administration (Vyas and Khar, 2002)

Need for Mucoadhesive Nanoparticles

A Sustained drug delivery system with prolonged residence time in the stomach is of particular interest for drugs

· Are locally active in the stomach (misoprostol, antacids antibiotics against H.pylori).

· Have an absorption window in stomach or in the upper small intestine (L-dopa, P-aminobenzoic acid, furosemide). [21]

· Are unstable in the intestine or colonic environment (captopril).

· Exhibit low solubility at high pH values (diazepam, verapamil).

· Alter normal flora of the colon (antibiotics).[22,23]

· Absorbed by transporter mechanism (paclitaxel).

Advantages of Gastro retentive mucoadhesive Drug Delivery Systems

1. Enhanced first-pass biotransformation

2. Enhanced bioavailability

3. Sustained drug delivery/reduced frequency of dosing

4. Reduced fluctuations of drug concentration

5. Improved selectivity in receptor activation

6. Targeted therapy for local ailments in the upper GIT

7. Reduced counter-activity of the body

8. Site specific drug delivery

9. Minimized adverse activity at the colon[24,25]

Disadvantages of Gastro retentive Drug Delivery System

· Floating system is not feasible for those drugs that have solubility or stability problem in G.I. tract.

· These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently-coat, water.

· The drugs that are significantly absorbed through out gastrointestinal tract, which undergo significant first pass metabolism, are only desirable candidate.

· Some drugs present in the floating system causes irritation to gastric mucosa.(26)

Limitations of Gastro retentive mucoadhesive drug Delivery Systems [4,5]

1. Bioadhesion in the acidic environment and high turnover of mucus may raise questions about the effectiveness of this technique. Similarly retention of high density system in the antrum part under the migrating waves of the stomach is questionable.

2. Not suitable for drug that may cause gastric lesions eg. Non- steroidal anti-inflammatory drug. Drug that are unsuitable in the strong acidic environment, these system do not offer significant advantages over the conventional dosage forms for drugs, that are absorbed through out the gastrointestinal tract.

3. The mucus on the walls of the stomach is in a state of constant, resulting in unpredictable adherence.

4. The bioadhesion system in patients with achlorhydria can be questionable in case of swellable system, faster swelling properties are required and complete swelling of the system should be achieved well before the gastric emptying time.[27]

5. Drugs that are irritant to gastric mucosa are not suitable for GRDDS.

Table 1: Different drugs use in formulation of gastro retentive dosage forms[28,29]

S.No.	Dosage Form / Drug Delivery System	Drug
1.	Floating tablets and pills	Acetaminophen, acetylsalicylic acid, ampicillin, amoxycillin trihydrate, atenolol, diltiazem, fluorouracil, isosorbide mononitrate, p- aminobenzoic acid, theophylline and verapamil
2.	Floating capsules	Chlordiazepoxide hydrogen chloride, diazepam, furosemide, misoprostol, L-dopa, benserazide, ursodeoxycholic acid and pepstatin
3.	Floating granules	Diclofenac sodium, indomethacin and prednisolone
4.	Films	Cinnarizine, Albendazole
5.	Floating microspheres	Aspirin, griseofulvin, p-nitroaniline, ibuprofen, terfinadine and Tranilast
6.	Floating nanoparticles	Amoxycillin,
7.	Floating Powders	Several basic drugs

Nanoparticulate dosage forms that can be retained in the stomach by adhering to the mucosal layer of the stomach can be called as stomach specific mucoadhesive nanoparticles (SSMN). SSMN greatly improve stomach pharmacotherapy through local drug release, which leads to high drug concentrations at the gastric mucosa (eradicating Helicobacter pylori from sub mucosal tissue of the stomach), making it possible to treat duodenal ulcers, gastritis and oesophagitis, and reduce the risk of gastric carcinoma[30].

Nanoparticles are defined as solid, submicron-sized drug carriers that may or may not be biodegradable [31,32]. The term nanoparticle is a collective name for both nanospheres and nanocapsules. Nanospheres have a matrix type of structure. Drugs may be absorbed at the sphere surface or encapsulated within the particle. Nanocapsules are vesicular systems in which the drug is confined to a cavity consisting of an inner liquid core surrounded by a polymeric membrane [33]. The literature emphasizes the advantages of nanoparticles over microparticles [34] and liposomes. The submicron size of nanoparticles offers a number of distinct advantages over microparticles, including relatively higher intracellular uptake compared with microparticles. In terms of intestinal uptake, apart from their particle size, nanoparticle nature and charge properties seem to influence the uptake by intestinal epithelia. Uptake of nanoparticles prepared from hydrophobic polymers seems to be higher than that of particles with more hydrophilic surfaces [35,36], thus more hydrophilic particles may be rapidly eliminated. In contrast, nanoparticles based on hydrophilic polymers, negatively charged, show a strong increase in bioadhesive properties and are absorbed by both M cells and absorptive enterocytes. A combination of both nano-particle surface charges and increased hydrophilicity of the matrix material seem to affect the gastrointestinal uptake in a positive sense.

Nanoparticles are one of the attractive research areas for sustained release formulations because they are able to deliver drugs with the right dose at the appropriate time which increases patient compliance and reduces toxicity. Nanoparticles are nanosized colloidal structures composed of synthetic or semi-synthetic polymers. The colloidal carriers are based on biodegradable and biocompatible polymeric systems which have largely influenced the sustained and targeted drug delivery concepts with a size range of 1 to 1000 nm (Mohanraj et al. 2006).

Factors Affecting Gastric Retention of Dosage Forms [37-42]

1. Density: GRT is a function of dosage form buoyancy that is dependent on the density.

2. Size: 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.

3. Shape of dosage form: Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo 90% to 100% pounds per square inch (KSI) are reported to have better GRT retention at 24 hours compared with other shapes.

4. 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.

5. Fed or unfed state/under fasting conditions: GI motility is characterized 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.

6. Nature of meal: 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.

7. Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats.

8. Frequency of feed: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.

9. Gender: 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.

10. Age: Elderly people, especially those over 70, have a significantly longer GRT.

11. Posture: GRT can vary between supine and upright ambulatory states of the patient.

12. Concomitant drug administration: Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride.

13. Biological factors: Diabetes and Crohn’s disease.

14. Physiological factors:

Method of preparation of nanoparticulate (nanospheres) system

NPs have been prepared mainly by two methods: (i) dispersion of the preformed polymers; and (ii) polymerization of monomers.

1. Solvent evaporation method

In this method, the polymer is dissolved in an organic solvent like dichloromethane, chloroform or ethyl acetate. The drug is dissolved or dispersed into the preformed polymer solution, and this mixture is then emulsified into an aqueous solution to make an oil (O) in water (W) i.e., O/W emulsion by using a surfactant/emulsifying agent like gelatine, poly(vinyl alcohol), polysorbate-80, poloxamer-188, etc. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. The effect of process variables on the properties of NPs was discussed earlier [43]. The W/O/W method has also been used to prepare the water-soluble drug-loaded NPs [44]. Both the above methods use a high-speed homogenization or sonication. However, these procedures are good for a laboratory-scale operation, but for a large-scale pilot production, alternative methods using low-energy emulsification are required. In this pursuit, following approaches have been attempted.

2. Spontaneous emulsification/solvent diffusion method

In a modified version of the solvent evaporation method [45-47] the water-soluble solvent like acetone or methanol along with the water insoluble organic solvent like dichloromethane or chloroform were used as an oil phase. Due to the spontaneous diffusion of water-soluble solvent (acetone or methanol), an interfacial turbulence is created between two phases leading to the formation of smaller particles. As the concentration of water-soluble solvent (acetone) increases, a considerable decrease in particle size can be achieved.

3. Salting out/ emulsification diffusion method

The methods discussed above require the use of organic solvents, which are hazardous to the environment as well as to the physiological system [48]. The US FDA has specified the residual amount of organic solvents in injectable colloidal systems [49,50]. In order to meet these requirements, Allemann and co-workers have developed two methods of preparing NPs. The first one is a salting-out method [51,52] while the second one is the emulsification-solvent diffusion technique [53,54].

Preparation of Mucoadhesive nanoparticles drug delivery system

Mucoadhesive PLGA nanoparticles were prepared by the solvent deposition method. Drugs was dissolved at 35–40°C in neutral water containing a hydrophilic surfactant at various concentrations. A mucoadhesive polymer, polycarbophil, was dispersed in this aqueous phase. Organic phase was prepared by solubilizing PLGA in acetone at various concentrations. The organic phase was poured into the aqueous solution drop wise, under stirring (RPM 5000) for 2 h, thus forming a milky colloidal suspension. The organic solvent was then evaporated by using a Rota evaporator. The resultant dispersion was dried using a freeze drying method [55,56].

Characterization of Mucoadhesive Nanoparticle

1. Particle Size Analysis

The drug loaded Nanoparticles were subjected to Scanning Electron Microscope (SEM) for determining its size and shape [57].

2. Morphological Study

Morphological examination, surface morphology (roundness, smoothness, and formation of aggregates) of Nanoparticles was performed using Scanning Electron Microscopy[58].

3. % Entrapment

2.5 ml sample of nanosuspensions was taken in dialysis bag. Both the ends of dialysis bag were tied. Then dialysis bag containing nanosuspension was kept in100 ml disilled water under stirring for 1 hour. After 1 hour dialysis bag was removed and 1 ml solution was taken from 100 mlouter solution. 1ml of this solution was diluted with 5ml distilled water. And absorbance was measured on UV spectrophotometer . Calculated by formula

% Entrapment = Drug Concentration in outer solution

Total Drug Concentration

4. Loading efficiency

The Nanosuspensions with known amount of drug (10mg/20ml) incorporated was centrifuged at 5000 rpm for 15 minutes. The supernatant solution was separated.5ml of supernatant was distributed with 100 ml of 2% w/v tween 80 solutions and the absorbance was measured using UV spectrophotometer at 306 nm using 2% w/v tween 80 as blank. The amount of drug unentrapped in the supernatant was calculated. The amount of drug entrapped and percentage entrapment was determined from drug unentrapped. Standard deviation was determined for 3 trials.

Loading efficiency

= Total amount of drug - Amount of unbound drug ×100

Nanoparticles weight

5. In vitro drug release

The dissolution medium used was freshly prepared phosphate buffer Solution (PBS) of pH 6.5. Dialysis membrane, previously soaked in distilled water was tied to one end and 5 ml of formulation was accurately placed into it. Bag was tied at both the ends. And then it was attached to a paddle and suspended in 400 ml of dissolution medium maintained at 37°C±0.5°C. The speed of dissolution apparatus Type-II was 100 rpm. Aliquots, each of 5 ml volume were withdrawn at 15 min interval and each time fresh buffer were replaced by an equal volume of PBS pH 6.5. The aliquots were suitably diluted with PBS pH6.5 and analyzed by UV-Vis Spectrophotometer[59].

6. Drug Content

10 mg of Spray dried material was crushed and suspended in 100 ml distilled water. After 24 hour the filtrate was diluted with 10ml distilled water and final solution was assayed spectrophotomatically at particulate nm for drug content.

7. Differential Scanning Calorimetry

Samples of drug, polymers and nanoparticles were accurately weighed and put into separate aluminium pans and the DSC thermo grams were recorded at a heating rate of 10ºC/min in the range 50ºC to 300ºC. Nitrogen gas was purged at the rate of 10 ml/min. to maintain inert atmosphere [60].

8. X-ray Diffraction Study

X-ray diffraction patterns of drug loaded polymeric nanoparticles were compared with that of the plain drug. The Powder X-ray diffraction pattern of drug was carried out by X-ray Diffract meter.

9. Mucoadhesive Test

A piece of goat nasal mucosa was cleaned and placed in Krebs solution in Petri plate. It was washed with distilled water, and then accurately weighed drug loaded polymeric Nanoparticles equivalent to 10 mg were spreaded on to it. The mucosa was kept aside for 5 min. Then surface was washed with phosphate buffer pH 6.5. This solution was filtered and absorbance was recorded by making dilutions. Nanoparticles retained on mucosal surface after first washing were removed with rinsing thoroughly by phosphate buffer 6.5. The solution was stirred to dissolve drug, filtered and absorbance was recorded. Percentage mucoadhesion was measured by calculating drug present in retained nanoparticles[61].

10. In vitro evaluation of intestinal mucoadhesion of nanoparticles

In vitro evaluation of intestinal mucoadhesion of nanoparticles approved the protocol for the study. Male Sprague Dawley rats weighing 200–250 g were fasted overnight before the experiments, but allowed free access to water. A part of intestine (duodenum and jejunum) was excised under anesthesia and perfused with physiological saline to remove the contents of stomach. The cleaned portion was used immediately after preparation. A 50 mg quantity of mucoadhesive nanoparticle sample that was suspended in phosphate buffer (pH 6.8) was filled into the cleaned intestine, ligated and then incubated in physiological saline at 37°C for 30 min. The liquid content of separated portion of intestine was then removed by injecting the air and the same was perfused with phosphate (pH 6.8) for 2 h, at a flow rate of 1 ml/min. The intestine was cut open and the nanoparticles that remained in it were recovered with phosphate buffer (pH 6.8). The final volume of washing solution was mixed with 10 ml of acetone solution and kept for 2 h for complete digestion of nanoparticles. After filtration through a 0.45‑mm filter paper, absorbance was determined spectrophotomatically at particulate nm, drug and gastric mucoadhesion was determined as the % of nanoparticles remaining in intestine after perfusion.[62]

In vivo techniques

GI transit using radio-opaque technique

It involves the use of radio-opaque markers, e.g.,barium sulfate, encapsulated in bioadhesive DDS to determine the effects of bioadhesive polymers on GI transit time. Faeces collection (using an automated faeces collection machine) and x-ray inspection provide a non-invasive method of monitoring total GI residence time without affecting normal GI motility. Mucoadhesives labelled with Cr-51, Tc-99m , In-113m, or I-123 have been used to study the transit of the DDS in the GI tract [63].

Gamma scintigraphy technique

It is a valuable tool used in the development of pharmaceutical dosage forms. With this methodology, it is possible to obtain information non-invasively. This technique gives information in terms of oral dosage forms across the different regions of GI tract, the time and site of disintegration of dosage forms, the site of drug absorption, and also the effect of food, disease, and size of the dosage form on the in vivo performance of the dosage forms.

Specific Sites for Mucoadhesive Drug Delivery Systems

Buccal cavity: - At this site, first-pass metabolism is avoided, and the non-keratinized epithelium is relatively permeable to drugs. Due to flow of saliva and swallowing, materials in the buccal cavity have a short residence time and so it is one of the most suitable areas for the development of bioadhesive devices that adhere to the buccal mucosa and remain in place for a considerable period of time

Vagina:- The vagina is a highly suitable site for bioadhesive formulations and it is here that the success of the concept can be seen convincingly. The bioadhesion increases the retention time (up to 72 h) and a smaller amount of the active ingredient can be used, reducing any adverse effects [27].

Nasal cavity:- Ease of access, avoidance of first-pass metabolism and a relatively permeable and well-vascularised membrane, contribute to make the nasal cavity an attractive site for drug delivery. Although the surface area is not large (between 150-200 cm²), one major disadvantage of nasal mucosa is the rapid removal of substances by mucociliary action (with a residence time half-life of 15 - 30 min) [47]. This makes it a prime target for bioadhesive formulations to prolong the residence time to allow drug release and absorption.

Eye:- One major problem for drug administration to the eye is rapid loss of the drug and or vehicle as a result of tear flow, and so it is a target for prolonging the residence time by bioadhesion. The bioadhesive polymers are finding increasing use in ophthalmic formulations, but often as viscosity enhancers rather than as bioadhesives per se [27].

Gastrointestinal tract :- Oral route is undoubtedly most favored route of administration, but hepatic first-pass metabolism, degradation of drug during absorption, mucus covering GI epithilia, and high turnover of mucus are serious concerns of oral route. In recent years, the gastrointestinal tract (GIT) delivery emerged as a most important route of administration. Bioadhesive retentive system involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the GIT. Using bioadhesive would be achieved increase GI transit time and increase in bioavailability. Salman aimed to develop polymeric nanoparticulate carriers with bioadhesive properties and to evaluate their adjuvant potential for oral vaccination. Thiamine was used as a specific ligand–nanoparticle conjugate (TNP) to target specific sites within the gastrointestinal tract, namely enterocytes and Peyer’s patches. The affinity of nanoparticles to the gut mucosa was studied in orally inoculated rats. The authors concluded that thiamine-coated nanoparticles showed promise as particulate vectors for oral vaccination and immunotherapy.

Rectal :- The function of the rectum is mostly concerned with removing water. Surface area without villi gives it a relatively small surface area for drug absorption.[54] Most rectal absorption of drugs is achieved by a simple diffusion process through the lipid membrane. Drugs that are liable to extensive first-pass metabolism can benefit greatly if delivered to the rectal area, especially if they are targeted to areas close to the anus. Furthermore, addition of bioadhesive polymer the migration distance in the rectum decreased. Kim [108] aimed to develop a thermoreversible flurbiprofen liquid suppository base composed of poloxamer and sodium alginate for the improvement of rectal bioavailability of flurbiprofen.

Formulation Development in Gastro retentive Mucoadhesive drug delivery system

Umamaheshwari et al. formulated mucoadhesive gliadin nanoparticles (GNP) containing amoxicillin by desolvation method and evaluated their effectiveness in eradicating H. pylori. To evaluate in vivo gastric mucoadhesive property in albino rats Rhodamine isothiocyanate-entrapped GNP formulations were prepared. It was reported that on increasing gliadin concentration, the mucoadhesive property of GNP increased. In vitro antimicrobial activity of GNP containing amoxicillin on an isolated H. pylori strain shown that the time required for complete eradication was higher in GNP containing amoxicillin than in amoxicillin because of the controlled drug delivery of amoxicillin from GNP containing amoxicillin. They concluded that GNP containing amoxicillin eradicated H. pylori from the gastrointestinal tract more effectively than amoxicillin because of the prolonged gastrointestinal residence time attributed to mucoadhesion [19].

Liu et al. prepared mucoadhesive microspheres of amoxicillin by an emulsification/evaporation method, using ethyl cellulose as matrix and carbopol 934P as a mucoadhesive polymer. They found that free amoxicillin was rapidly degraded in acidic medium; however, amoxicillin entrapped in the microspheres kept stable. The in vitro release test showed that about 90% of the amoxicillin was released in the pH 1.0 HCl solution within 4 h. Finally, studies on the in vivo clearance of H. pylori revealed that, in a single-dosage administration (4 mg/kg to 14.8 mg/kg), the mucoadhesive microspheres had a better effectiveness (expressed by the ratio of colony counts between amoxicillin powder and microspheres) compared to amoxicillin powder (3.2 to 9.7, respectively). In parallel, a multi dosage administration regimen (3.5 mg/kg, twice a day for 3 consecutive days) showed a complete eradication of H. pylori with microspheres in five of six rat stomachs, whereas amoxicillin powder showed four times less effectiveness [21].

Makhlof et al. developed mucoadhesive particulate system for the oral delivery of peptide drugs by combining safe permeation enhancers by ionic interaction of spermine (SPM) with polyacrylic acid (PAA) polymer. Cytotoxicity studies in Caco-2 monolayers revealed the safety of the delivery system in the concentration range used for permeation enhancement. The cellular transport of fluorescein isothiocyanate dextran (FD4) showed higher permeation enhancing profiles of SPM–PAA NPs, as compared to SPM solution or PAA NPs prepared by ionic gelation with MgCl2 (Mg-PAA NPs). The permeation enhancing properties of SPM– PAA NPs were further evaluated in vivo after oral administration to rats, using FD4 and calcitonin as models of poorly permeating drugs. Confocal microscopy images of rat's small intestine confirmed previous findings in Caco-2 cells and revealed a strong and prolonged penetration of FD4 from the mucosal to the basolateral side of the intestinal wall [25].

Irache et al. developed bioadhesive nanoparticles for the oral delivery of poorly available drugs. The bioadhesive potential of Gantrez nanoparticles fluorescently labeled with rhodamine B isothiocyanate was determined. The adhesive potential of Gantrez was found to be stronger when formulated as nanoparticles than in the solubilized form. Conventional nanoparticles displayed a tropism for the upper areas of the gastrointestinal tract, with a maximum of adhesion 30 min post-administration and a decrease in the adhered fraction along the time depending on the given dose. Finally, nanoparticles were coated with either gelatin or albumin. In the first case, the presence of gelatin dramatically decreased the initial capacity of these carriers to interact with the gut mucosa and the intensity of these phenomenons. In the latter, bovine serum albumin coated nanoparticles (BSA-NP) showed an important tropism for the stomach mucosa without further significant distribution to other parts of the gut mucosa [27].

Suwannateep et al. developed mucoadhesive drug carriers for the gastro-intestinal tract (GIT). Here, a monopolymeric carrier made from ethyl cellulose (EC) and a dipolymeric carrier made from a blend of methylcellulose (MC) and EC (ECMC) were prepared through a self-assembling process and yielded the highest reported curcumin loading of 48 to 49%. The in vivo evaluation of their adherence to stomach mucosa and their ability to release curcumin into the circulation were carried out through quantification of curcumin levels in the stomach tissue and in blood of mice orally administered with the two spheres. Direct evidence of the adherence of the C-EC and C-ECMC particles along the mucosal epithelia of the stomach is also presented for the first time through SEM images [26].

Katayama et al. prepared a sustained release liquid preparation using sodium alginate. To evaluate the gastric retention time of the preparation, the remaining percent of ampicillin when an aqueous ampicillin solution vs. the sodium alginate preparation were administrated in isolated perfused rat stomachs was compared, With calcium pretreatment, the total remaining percent of ampicillin at 120 min was 0.3% and 8% for the aqueous ampicillin solution and the sodium alginate preparation, respectively. Moreover, it was observed that the sodium alginate preparation remained mainly on the gastric mucus [20].

Mitragotri et al. invented a novel intestinal mucoadhesive patch system for oral drug delivery. The patch system comprises an impermeable backing layer, a drug reservoir and a mucoadhesive layer. The drug reservoir and the mucoadhesive layer may be combined into a single layer. When the patches are introduced into the gastrointestinal tract, the mucoadhesive layer sticks to the lumenal wall due to its mucoadhesive properties, then the drug releases from the reservoir in a unidirectional way through the mucoadhesive layer into the intestine mucosa. This improved method is advantageous in enhancing bioavailability of poorly absorbed drugs such as polar molecules or bioactive peptides and proteins [24].

Park et al. stated that highly charged carboxylated polyanions are good potential bioadhesives for drug delivery. They described a new, simple experimental technique that can quantitatively measure bioadhesive properties of various polymers. The technique consists of labeling the lipid bilayer of cultured human conjunctival epithelial cells with the fluorescent probe pyrene. Addition of polymers to this substrate surface compresses the lipid bilayer causing a change in fluorescence as compared to control cells. The fluorescent probe, pyrene, provides information on membrane viscosity, which is proportional to polymer binding. In addition to the use of pyrene, membrane proteins were labeled with fluorescein isothiocyanate, and depolarization of probe labeled proteins was measured before and after polymer treatment. By using these fluorescent probes, it was possible to ompare charge sign. Charge type and density, and backbone structure as to their influence on polymer adhesion [29].

Sakuma et al. investigated the mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal (GI) tract in rats. Radio labeled nanoparticles were synthesized by adding hydrophobic 3-(trifluoromethyl) - 3-(m-[125I]iodophenyl)diazirine in the final process of nanoparticle preparation. The radioiodonated diazirine seemed to be incorporated in the hydrophobic polystyrene core of nanoparticles. The change in blood ionized calcium concentration after oral administration of salmon calcitonin (SCT) with nanoparticles showed that the in vivo enhancement of SCT absorption by radio labeled nanoparticles was the same as that by non-labeled nanoparticles. The GI transit rates of nanoparticles having surface poly (N-isopropylacrylamide), poly (vinylamine) and poly (methacrylic acid) chains, which can improve SCT absorption, were slower than that of nanoparticles covered by poly (N-vinylacetamide), which does not enhance SCT absorption at all. These slow transit rates were probably the result of mucoadhesion of nanoparticles. The strength of mucoadhesion depended on the structure of the hydrophilic polymeric chains on the nanoparticle surface. The mucoadhesion of poly (N-isopropylacrylamide) nanoparticles, which most strongly enhanced SCT absorption, was stronger than that of ionic nanoparticles, and poly (N-vinylacetamide) nanoparticles probably did not adhere to the GI mucosa. These findings demonstrated that there is a good correlation between mucoadhesion and enhancement of SCT absorption [35].

Patel and Chavda developed mucoadhesive amoxicillin microspheres for anti-Helicobacter pylori therapy using emulsion-solvent evaporation technique. They used carbopol-934P as mucoadhesive polymer and ethyl cellulose ascarrier polymer. Preliminary trials indicated that quantity of emulsifying agent, time of stirring, drug-to-polymers ratio and speed of rotation affected the characteristics of microspheres. The morphological characteristics of the mucoadhesive microspheres were studied under a scanning electron microscope. Microspheres were discrete, spherical, free flowing showing a good percentage of drug entrapment efficiency and adhered strongly to the gastric mucous layer and could retain in the gastrointestinal tract for an extended period of time. A 3² full factorial design was employed to study the effect of independent variables; drug-to-polymer-to-polymer ratio and stirring speed on percentage mucoadhesion, drug entrapment efficiency, particle size and time for 80% dissolution. The best batch exhibited a high drug entrapment efficiency of 56%; mucoadhesion percentage of 80% after 1 h particle size of 109 µm. A sustained drug release was obtained for more than 12 h. In vitro release test showed that amoxicillin released slightly faster in pH 1.2 hydrochloric acid than in pH 7.8 phosphate buffer. In-vivo H. pylori clearance tests carried out by administering in H. pylori infectious Wistar rats under fed conditions at single dose or multiple oral dose(s) showed that amoxicillin mucoadhesive microspheres had a betterclearance effect than amoxicillin powder.

Narkar et al. developed amoxicillin-loaded mucoadhesive gellan beads. The beads were prepared by the cation-induced ionotropic gelation method using acidic and alkaline cross-linking media. The authors used a 3² randomized factorial design to evaluate the effect of the two variables; concentration of gellan gum (X1) and quantity of drug (X2) on both yield and entrapment efficiency. Each factor was used at three different levels. The results revealed a positive effect for the polymer concentration and a negative effect for the drug quantity. In addition, the beads prepared in alkaline cross-linking medium showed higher yield entrapment efficiency than the acidic cross-linking medium. Therefore, batches with lowest, medium, and highest drug entrapment obtained using alkaline cross linking medium were selected to be coated with chitosan in order to obtain controlled drug release. The prepared beads were also evaluated for micromeritic properties, scanning electron microscopy (SEM), thermal properties, swelling behavior, in vitro drug release, in- vivo and in-vitro mucoadhesive properties, and in-vitro growth inhibition study. Chitosan-coated gellan beads exhibited in-vitro drug release up to 7 hours in a controlled manner. They also showed good mucoadhesivity and complete growth inhibition of H. pylori.

Yao et al developed a novel gastro-mucoadhesive delivery system for Riboflavin-5’- phosphate sodium salt (RF5P), which is site-specifically absorbed from the upper gastrointestinal tract, based on ion-exchange fiber. Gastrointestinal transit studies of the RF5P fiber complexes in rats and gamma imaging study in volunteer was carried out to evaluate the gastro-retentive behavior of the fiber. The pharmacokinetic profile and parameters of riboflavin via analysis of urinary excretion of riboflavin on man were measured. Study on rat and man provide evidence for the validity of the hypothesis that the drug fiber provided good mucoadhesive properties in vivo and should therefore be of considerable interest for the development of future mucoadhesive oral drug delivery dosage forms [42]

12. Application of gastro retentive mucoadhesive Nanoparticles

I. Sustained Drug Delivery SSMN can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral controlled release formulation, hence, can be overcome with these systems.

II. Site Specific Drug Delivery These systems are particularly advantageous for drugs that are specifically absorbed from stomach or proximal part of the small intestine e.g., riboflavin, furosemide and misoprostal.

III. Absorption Enhancement Drugs that have poor bioavailability because of site specific absorption from the upper part of the GIT are potential candidate to be formulated as floating drug delivery systems, thereby maximizing their absorption.

IV. Maintenance of Constant Blood Level These systems provide an easy way of maintaining constant blood level by once a day administration and constant release of drug.

V. Patient Compliance Once a day administration of dosage form provides better patient compliance.

VI. Improved Therapeutic Efficacy Once a day administration and continuous release of drug at specified place for prolonged period, improve therapeutic efficiency of drug.

SUMMARY AND CONCLUSION:

To develop an efficient gastro retentive mucoadhesiv dosage form is a real challenge to pharmaceutical technology. Indeed, the drug delivery system must remain for a sufficient time in the stomach, which is not compatible with its normal physiology and present their own advantages and disadvantages. Now, a lot of work is running to develop different types of gastro retentive delivery systems of various drugs. In the future, it is expected that they will become of increasing importance, ultimately leading to improved efficiencies of various types of pharmacotherapies. It can be concluded that the therapeutic potential of colloidal drug carriers after oral administration is probably not to deliver the drug directly in the blood flow, but to increase bioavailability by protecting the drug from denaturation in the gastro-intestinal lumen or by increasing the drug concentration for a prolonged period of time directly at the surface of the mucous membrane. Improvements in all aspects of this delivery system are required, so that efficient systems will emerge.

REFERENCES:

1. Patil C, Baklilwal S ,Rane B ,Gujrathi N , Pawar S. Floating Microspheres : A Promising Approach For Gastric Retention. Int. J. of Pharm. Res. and Dev. 2011; 12(2): 26-38.(38)

2. Dhole A, Gaikwad P, Bankar V, Pawar S. A Review on Floating Multiparticulate Drug Delivery System: A Novel Approach to Gastric Retention. Int. J. Pharm. Sci. Rev. and Res. 2011; 6(2): 205-211.

3. Siddhapara M, Tikare V, Ramana M, Sutariya B, Vaghasiya B. Gastroretentive Drug Delivery System: Stomach Specific Mucoadhesive Tablet. Int. Res. J. Pharmacy. 2011; 12(2): 90-96.

4. Gruber P, Longer MA, Robinson JR. Some biological issues in oral, controlled drug delivery. Adv Drug Delivery Rev 1987;1:1-18.

5. Wade A. (Ed.) Drug absorption. In: Pharmaceutical handbook, The Pharmaceutical Press, London, 1980;19:294-334.

6. Streubel A, Siepmann J, Bodmeier R. Gastro retentive drug delivery system. Expert Opin Drug Deliv 2006; 3(2):217-33.

7. Garg R, Gupta GD. Progress in controlled gastro retentive delivery systems. Trop. J Pharm Res 2008; 7(3): 1055-66.

8. Rouge N, Allemann E, Gex-Fabry M, Balant L, Cole ET, Buri P, Doelker E. Comparative pharmacokinetic study of a floating multiple-unit capsule, a high density multiple-unit capsule and an immediate-release tablet containing 25 mg atenolol. Pharm Acta Helbetiae 1998; 73: 81-7.

9. Streubel A, Siepmann J, Bodmeier R. Multiple unit Gastroretentive drug delivery: a new preparation method for low density microparticles. J Microencapsul 2003; 20: 329-47.

10. Goole J, Vanderbist F, Aruighi K. Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms. Int J Pharm 2007; 334: 35-41.

11. Shrma S, Pawar A. Low density multiparticulate system for pulsatile release of meloxicam. Int J Pharm 2006; 313: 150-58.

12. Santus G, Lazzarini G, Bottoni G, Sandefer EP, PageRC, Doll WJ, Ryo UY, Digenis GA. An in vitro- in vivo investigation of oral bioadhesive controlled release furosemide formulations. Eur J Pharm Biopharm 1997;44: 39-52.

13. Klausner EA, Lavy E, Friedman M, Hoffman A. Expandable gastroretentive dosage forms. J Control Release 2003; 90: 143-62.

14. Deshpande AA, Shah N, Rhodes CT, Malik W. Development of a novel controlled-release system for gastric retention. Pharm Res 1997; 14: 815-19.

15. Park K. Enzyme-digestible swelling as platforms forlong-term oral drug delivery: synthesis and characterization. Biomaterials 1988; 9: 435.

16. Fujimori J, Machida Y, Nagai T. Preparation of a magnetically-responsive tablet and configuration of its gastric residence in beagle dogs. STP Pharma Sci 1994; 4: 425-30.

17. Good WR. Transdermal nitro-controlled delivery of nitroglycerin via the transdermal route. Drug Dev Ind Pharm. 1983;9:647–70.

18. 2. Henriksen I, Green KL, Smart JD, Smistad G, Karlsen J. Bioadhesion of Hydrated Chitosans: An in vitro and in vivo Study. Int J Pharm. 1996;145:231–40.

19. 3. Leung SH, Robinson JR. The Contribution of anionic polymer structural features related to mucoadhesion. J Control Release. 1988;5:223–31.

20. Vyas SP, Khar RK. Gastroretentive systems. In: Controlled drug Delivery. Vallabh Prakashan, Delhi, India. 2006. p. 197-217.

21. Chowdary K.P.R., Srinivas L., Mucoadhesive drug delivery systems: A review of current status, Indian Drugs,2000,37(9), 400-406.

22. G.P. Andrews et al., Mucoadhesive polymeric platforms for controlled drug delivery, Eur. J. Pharm. Biopharm,71,2009,505-518.

23. Feng SS, Mu L, Win KY, Huang G. Nanoparticles of biodegradable polymers for clinical administration of paclitaxel. Curr Med Chem 2004;11:413‑24

24. Garg S., Sharma S., Gastroretentive Drug Delivery System, Business Briefing: Pharmatech., 2003; 160‐166.

25. Babu V. B. M., Khar R. K., In vitro and In vivostudies of sustained release floating dosage forms containing salbutamol sulphate, Pharmazie, 1990; 45:268-270.

26. Allemann E, Gurny R, Doekler E. Drug-loaded nanoparticles-preparation methods and drug targeting issues. Eur J Pharm Biopharm 1993;39:173-91.

27. R Garg, GD Gupta, Progress in Controlled Gastroretentive Delivery Systems. Trop J Pharm Res, 2008; 7 (3): 1055-1066.

28. Arrora S, Ali J, Khar RK, Baboota S. Floatng drug delivery systems: A review. AAPS Pharm Sci Tech 2005; 6(3): 372-90.

29. Vyas SP, Khar RK. Gastroretentive systems. In: Controlled drug Delivery. Vallabh Prakashan, Delhi, India. 2006; 197-217

30. Makhlof A, Werle M et al., A mucoadhesive nanoparticulate system for the simultaneous delivery of macromolecules and permeation enhancers to the intestinal mucosa. J Control Release 2011;149:81-8.

31. Couvreur P, Dubernet C, Puisieux F. Controlled drug delivery withnanoparticles: current possibilities and future trends. Eur J Pharm Biopharm 1995;41:2-13.

32. Couvreur P. Polyalkylcyanoacrylates as colloidal drug carriers. Crit Rev Ther Drug Carrier Syst 1988;5:1-20.

33 McClean S, Prosser E, Meehan E, O’Malley D, Clarke N, Ramtoola Z, et al. Binding and uptake of biodegradable poly-lactide micro-and nanoparticles in intestinal epithelia. Eur J Pharm Sci 1998;6:153-63.

34. Benoit JP, Couvreur P, Devissaguet J-P, Fessi H, Puisieux F, Roblot-Treupel L. Les formes vectorise´es ou distribution module, nouveuax siste`mes d’administration medicaments. J Pharm Belg 1986;41:319-29.

35. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release 2001;70:1-20.

36. Jung T, Kamm W, Breitenbach A, Kaiserling E, Xiao JX, Kissel T. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to affect mucosal uptake? Eur J Pharm Biopharm 2000;50:147-60.

37. Katakam V, Somagoni J, Reddy S, Eaga,C. Floating Drug Delivery Systems: A Review. Current Trends in Biotech. and Pharmacy. 2010 ; 4(2): 610-647.

38. Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Contro.Rel. 2000; 63: 235-259.

39. Sharma S, Prashar M, Sahu RK. Floating Drug Delivery System: Incredible Revolution. Pharmacologyonline. 2011 ; 3: 1039-1054

40. Gattani YS. Floating Multiparticulate Drug DeliverySystems: An Overview. Int.J.Pharma Bio Sciences.2010 ; 2(1): 1-14.

41. Jain K, Rajput R, Dhamal S, Patel K, Agarwal P. Hydrodynamically Balanced Systems (HBS): Innovative Approach of Gastroretention: A Review. Int. J.PharmTech Res.2011; 3(3): 1495-1508.

42. Nayak AK, Maji R, Das B. Gastroretentive drug delivery systems: a review. Asian J. Pharma. Clinical Res.2010; 1(3): 1-10.

43. P.D. Scholes, A.G.A. Coombes, L. Illum, S.S. Davis, M. Vert, M.C. Davies, The preparation of sub-500 nm poly(lactide- co-glycolide) microspheres for site-specific drug delivery, J. Control. Rel. 25 (1993) 145-153.

44. M.F. Zambaux, F. Bonneaux, R. Gref, P. Maincent, E. Dellacherie, M.J. Alonso, P. Labrude, C.Vigneron, Influence of experimental parameters on the characteristics of poly(lac- tic acid) nanoparticles prepared by double emulsion method, J. Control. Rel. 50 (1998) 31-40.

45. T. Niwa, H. Takeuchi, T. Hino, N. Kunou, Y. Kawashima, Preparations of biodegradable nanospheres of water-soluble and insoluble drugs with D,L-lactide/glycolide copolymer by a novel spontaneous emulsification solvent diffusion method and the drug release behavior, J. Control. Rel. 25 (1993) 89-98.

46. P. Wehrle, B. Magenheim, S. Benita, The Influence of process parameters on the PLA nanoparticle size distribution evaluated by means of factorial design, J. Pharm. Biopharm. 41 (1995) 19-26.

47. H. Murakami, H. Yoshino, M. Mizobe, M. Kobayashi, H. Takeuchi, Y. Kawashima, Preparation of poly(D,L-lactide-co- glycolide) latex for surface modifying material by a double coacervation method, Proced. Intern. Symp. Control. Rel. Bioact. Mater. 23 (1996) 361-362.

48. D.T. Birnbaum, J.D. Kosmala, D.B. Henthorn, L.B. Peppas Controlled release of b-estradiol from PLAGA microparti- cles: The effect of organic phase solvent on encapsulation and release, J. Control. Rel. 65 (2000) 375-387.

49. R. Bodmeier, J.W. McGinity, Solvent selection in the preparation of poly(D,L-lactide) microspheres prepared by the solvent evaporation method, Int. J. Pharm. 43 (1988) 179186.

50. R. Arshaday, Preparation of porous and nonporous biodegradable polymeric hollow microspheres, J. Control. Rel. 17 (1991) 1-22.

51. E. Allemann, R. Gurnay, E. Doelker, Preparation of aqueous polymeric nanodispersions by a reversible salting-out process: influence of process parameters on particle size, Int. J. Pharm. 87 (1992) 247-253.

52. E. Allemann, J.C. Leroux, R. Gurnay, E. Doelker, Invitro extended-release properties of drug-loaded poly(D,L-lactic) acid nanoparticles produced by a salting-out procedure, Pharm. Res. 10 (1993) 1732-1737.

53. J.C. Leroux, E. Allemann, E. Doelker, R. Gurnay, New approach for the preparation of nanoparticles by an emulsifi- cation-diffusion method, Eur. J. Pharm. Biopharm. 41 (1995) 14-18.

54. G.D. Quintanar, Q.A. Ganem, E. Allemann, H. Fessi, E. Doelker, Influence of the stabilizer coating layer on the purification and freeze drying of poly (DL-lactic acid) nanoparticles prepared by emulsification-diffusion technique, J. Microencapsulation 15 (1998) 107-119.

55. Kamath KR, Park K. In Encyclopedia of Pharmaceutical Technology. Vol. 10. New York: Marcel Dekker; vol.10, 1988. p. 133‑64.

56. Phutane P, Shidhaye S, Lotlikar V, Ghule A, Sutar S, Kadam V.In vitro evaluation of novel sustained release microspheres of glipizide prepared by the emulsion solvent diffusion‑evaporation method. J Young Pharma 2010;2:35‑4

57. Krishna R.S.M, Shivakumar H.G, Gowda D.V, and Banerjee S., Nanoparticles: a novel colloidal drug delivery system, Indian J Pharm Edu Res, 2006,40(1), 15-21.

58. Vyas S.P. and Khar R.K., Controlled drug delivery-concepts and advances, Vallabh Prakashan, New Delhi, 2002, 1st ed, p.331-81.

59. Pandey R, Ahmad Z, Sharma S and Khullar G.K., Nanoencapsulation of azole antifungals, Potential applications to improve oral drug delivery, Int J Pharm. 2005, 301, 268-276.

60. Adlin Jino Nesalin J., Gowthamarajan K and Somashekhara C.N., formulation and evaluation of nanoparticles containing flutamide, Int.J. ChemTech Res.2009,1(4): 1331-1334.

61. Sagar S. Jadhav* and Aparna V. Bhalerao. Formulation and characterization of chitosan nanoparticles loaded with rizatriptan benzoate. Scholar Research Library ,2013, 5 (4):218-223

62. Ramteke S, Umamaheshwari RB, Jain NK. Clarithromycin based oral sustained release nanoparticulate system. Indian J Pharm Sci 2006; 68:479‑84.

63. Mathiowitz E, Chickering D, Jacob JS, Santos C. Bioadhesive drug delivery systems. Mathiowitz E(ed). In: Encyclopedia of Controlled Drug Delivery, vol.1. Wiley, New York, 1999, pp. 9–44.

64. Salman HH, Gamazo C, Agueros M, Irache JM. Bioadhesive capacity and immunoadjuvant properties of thiamine-coated nanoparticles. Vaccine. 2007; 48:8123–32.

65. Woodley J. Bioadhesion: New Possibilities for Drug Administration. Clin Pharmacokinet, 2001; 40 (2): 77-84.

66. Umamaheshwari RB, Ramteke S et al., Anti–Helicobacter Pylori effect of mucoadhesive nanoparticles bearing amoxicillin in experimental gerbil’s model. AAPS Pharm SciTech 2004;5(2):1-9.

67. Liu Z, Lu W et al., In-vitro and in-vivo studies on mucoadhesive microspheres of amoxicillin. J Control Release 2005;102(1):135-44.

68. Makhlof A, Werle M et al., A mucoadhesive nanoparticulate system for the simultaneous delivery of macromolecules and permeation enhancers to the intestinal mucosa. J Control Release 2011;149:81-8.

69. Irache JM, Huici M., et al., Bioadhesive properties of Gantrez nanoparticles. Molecules 2005;10:126-45.

70. Suwannateep N, Banlunara W et al., Mucoadhesive curcumin nanospheres: Biological activity, adhesion to stomach mucosa and release of curcumin into the circulation. J Control Release 2011;151:176-82.

71. Katayama H, Nishimura T et al., Sustained release liquid preparation using sodium alginate for eradication of Helicobacter Pylori. Biol Pharm Bull 1999;22(1):55-60.

72. Mitragotri S, Shen Z. Methods for oral drug delivery. US patent 20030017195; 2003.

73. Park K, Robinson JR. Bioadhesive polymers as platforms for oral-controlled drug delivery: method to study bioadhesion. Int J Pharm 19844;19:107-27.

74. Sakuma S, Sudo R et al., Mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal tract. Int J Pharm 1999;177:161-72.

75. Patel JK, Chavda JR, Formulation and evaluation of stomach-specific amoxicillin-loaded carbopol-934P mucoadhesive microspheres for anti-Helicobacter pylori therapy, J Microencapsul, 1-12, (2008).

76. Narkar M, Sher P, Pawar A, Stomach-specific controlled release gellan beads of acid-soluble drug prepared by ionotropic gelation method, AAPS PharmSciTech, 11(1):267-77, (2010).

77. Yao H, Xu L et al., A novel riboflavin gastro-mucoadhesive delivery system based on ion-exchange fiber. Int J Pharm 2008; 364: 21-6

77. Mohanraj, VJ and Chen, Y., Nanoparticles – A review , tropical journal of pharmaceutical research 2006; 5(1): 561-573.

78. Garima Gupta, Amit Singh, A Short Review on Stomach Specific Drug Delivery System. International Journal of PharmTech Research, 2012; 5(4): 1527-1547.

79. Chandrashekhar B. Borase, Floating systems for oral Controlled Release Drug Delivery . Int J App Pharm,2012; 4( 2) :1-13

80. Mathur P ,Saroha K ,Syan N, Verma S , Nanda S, Valecha V. An overview on recent advancements and developmentsin gastroretentive buoyant drug delivery system. Pelagia Res. Lib. 2011; 2 (1): 161-169

81. Kadam SM, Kadam SR, Patil U, Ratan G, Jamkandi V. Review on Floating Drug Delivery Systems: An Approach To Oral Controlled Drug Delivery Via Gastric Retention. Int. J. Res. Ayur. Pharm. 2011; 6 (2): 1752-1755.

82. Katakam V, Somagoni J, Reddy S, Eaga,C. Floating Drug Delivery Systems: A Review. Current Trends in Biotech. and Pharmacy. 2010 ; 4(2): 610-647.

83. Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Contro.Rel. 2000; 63: 235-259.

84. Sharma S, Prashar M, Sahu RK. Floating Drug Delivery System: Incredible Revolution. Pharmacologyonline. 2011 ; 3: 1039-1054

85. Gattani YS. Floating Multiparticulate Drug Delivery Systems: An Overview. Int.J.Pharma Bio Sciences.2010 ; 2(1): 1-14.

86. Jain K, Rajput R, Dhamal S, Patel K, Agarwal P. Hydrodynamically Balanced Systems (HBS): Innovative Approach of Gastroretention: A Review. Int. J.PharmTech Res.2011; 3(3): 1495-1508.

87. Nayak AK, Maji R, Das B. Gastroretentive drug delivery systems: a review. Asian JPharma. Clinical Res.2010; 1(3): 1-10.

Received on 05.04.2014 Accepted on 18.05.2014

Asian J. Pharm. Res. 4(2): April-June 2014; Page 55-64

*Corresponding Author E-mail: manuiopresearch@gmail.com