Oral Delivery Of Drugs Biology Essay

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Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. It is evident from the recent scientific and patent literature that an increased interest in novel dosage forms that are retained in the stomach for a prolonged and predictable period of time exists today in academic and industrial research groups. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT). Dosage forms with a prolonged GRT, i.e. gastro retentive dosage forms (GRDFs), will provide us with new and important therapeutic options. GRDFs extend significantly the period of time over which the drug may be released. Thus, they not only prolong dosing intervals, but also increase patient compliance beyond the level of existing controlled release dosage forms. This application is especially effective in delivery of sparingly soluble and insoluble drugs. It is known that, as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes significant factor affecting drug absorption. To address this, oral administration of sparingly soluble drugs are carried out frequently, often several times per day.

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As a mechanism to override this problem, erodible, gastro retentive dosage forms have been developed that provide continuous, controlled administration of these drugs at the absorption site. In addition, these dosage forms are useful for delivering drugs incorporated into vesicles such as liposomes, nanoparticles, proteinoid mcirospheres and pharmacosomes, etc. compared with other applications, the frequency of dosing may be the same, but the gastro retentive dosage forms will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability.1

Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. 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 gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables. It is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa. Thus, small intestinal transit time is an important parameter for drugs that are incompletely absorbed. Basic human physiology with the details of gastric emptying, motility patterns, and physiological and formulation variables affecting the cosmic emptying are summarized.

Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.

The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, flotation, sedimentation, expansion, modified shape systems, or by the simultaneous administration of pharmacological agent that delay gastric emptying. Based on these approaches, classification of floating drug delivery systems (FDDS) has been described in detail. In vivo/in vitro evaluation of FDDS has been discussed by scientists to assess the efficiency and application of such systems. Several recent examples have been reported showing the efficiency of such systems for drugs with bioavailability problems.2

Pharmaceutical dosage form(DF) with gastro retentive properties would enable an extended absorption phase of these drugs with narrow absorption window. After oral administration, DF would be retained in stomach and release drug there, in a controlled and prolonged manner, so that drug could be supplied continuously to its absorption sites in upper GIT. Another interesting importance for the DF with prolonged residence time in the stomach is :

Drugs are locally active in the stomach e.g. drugs used in the eradication of helicobacter pylori, which is now believed to be the causative bacterium for chronic gastritis and peptic ulcer. e.g. tetracycline;

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Drugs are unstable in the intestinal or colonic environment e.g. ranitidine; and

Drugs have a low solubility at high Ph values e.g. verapamil. 3

MECHANISTIC ASPECTS OF FLOATING DRUG DELIVERY SYSTEM 1

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention tome. These attempts include introducing floating dosage forms (gas-generating systems and swelling or expanding systems), muco adhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and coadministration of gastric-emptying delaying drugs. Among these, the floating dosage forms have been used most commonly. However, most of these approaches are influenced by a number of factors that affect their efficacy as a gastro retentive system.

Basic Gastrointestinal Tract Physiology

Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions. Gastric emptying occurs during fasting as well as fed states.

The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.

Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.

Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.

Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.

Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.

After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.

Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate.

Fig. 2 Intragastric residence positions of floating and non floating units.2

Factors Affecting Gastric Retention

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 2 mm. The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach doesn't get time to produce sufficient acid when the liquid empties the stomach, hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.

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. Biological factors such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chron's disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.

The resting volume of the stomach is 25 to 50 mL. Volume of liquids administered affects the gastric emptying time. When volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves.

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Several formulation parameters can affect the gastric residence time. More reliable gastric emptying patterns are observed for multiparticulate formulations as compared with single unit formulations, which suffer from "all or none concept." As the units of multiparticulate systems are distributed freely throughout the gastrointestinal tract, their transport is affected to a lesser extent by the transit time of food compared with single unit formulation.

Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. The density of a dosage form also affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period.

When subjects were kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention.

A comparison was made to study the affect of fed and nonfed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach. 2

Pharmacokinetic aspects 8

1. Absorption window-validation that the drug is within the category of NAW agents

Currently various experimental techniques are available that permit us to verify the absorption properties of the tested molecule, to determine the mechanism of intestinal absorption and to elucidate the permeability at different regions of the GI tract.

2.Enhanced bioavailability

The bioavailability of riboflavin and levodopa CR-GRDF is significantly enhanced in

comparison to administration of non-GRDF CR polymeric formulation. Several different processes, related to absorption and transit of the drug in the gastrointestinal tract, act concomitantly and influence the magnitude of drug absorption. Therefore, in vivo studies are necessary to determine the release profile of the drug from the dosage form that will provide enhanced bioavailability.

3.Enhanced first pass biotransformation

In a similar fashion to increased efficacy of active transporters exhibiting capacity limited activity, the pre-systemic metabolism of the tested compound may be considerably increased when the drug is presented to the metabolic enzymes (cytochrome P450, in

particular CYP3A4) in a sustained manner, rather than by a bolus input.

4.Improved bioavailability due to reduced P-glycoprotein (P-gp) activity in the duodenum

In apparent contrast to the higher density of CYP3A4 at the upper part of the intestine, P-gp mRNA levels increase longitudinally along the intestine such that the highest levels are located in the colon. Therefore, for drugs that are P-gp substrate and do not undergo oxidative metabolism, such as digoxin, CR-GRDF may elevate absorption compared to the immediate and CR dosage forms.

5.Reduced frequency of dosing

For drugs with relatively short biological half-life, sustained and slow input from CR-GRDF may result in a flip-flop pharmacokinetics and enable reduced dosing frequency. This feature is associated with improved patient compliance, and thereby improves therapy.

6. Targeted therapy for local ailments in the upper GI tract

The prolonged and sustained administration of the drug from the GRDF to the stomach may be advantageous for local therapy in the stomach and the small intestine. By this mode of administration, therapeutic drug concentrations may be attained locally while

the systemic concentrations, following drug absorption and distribution, are minimal.

Pharmacodynamic aspects

1.Reduced fluctuations of drug concentration

Continuous input of the drug following CR-GRDF 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.

2.Improved selectivity in receptor activation

Minimization of fluctuations in drug concentration also makes it possible to obtain certain selectivity in the elicited pharmacological effect of drugs that activate different types of receptors at different concentrations.

3. Reduced counter-activity of the body

In many cases, the pharmacological response which intervenes with the natural physiologic processes provokes a rebound activity of the body that minimizes drug activity. Slow input of the drug into the body was shown to minimize the counter activity leading to higher drug efficiency.

4. Extended time over critical (effective) concentration

For certain drugs that have non-concentration dependent pharmacodynamics, such as beta-lactam antibiotics, the clinical response is not associated with peak concentration, but rather, with the duration of time over a critical therapeutic concentration. The sustained mode of administration enables extension of the time over a critical concentration and thus enhances the pharmacological effects and improves the clinical

outcomes.

5. Minimized adverse activity at the colon

Retention of the drug in the GRDF 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 development of microorganism's resistance.Due complexity of pharmacokinetic and pharmacodynamic parameters, in vivo studies are required to establish the optimal dosage form for a specific drug. For a certain drug, interplay of its pharmacokinetic and pharmacodynamic parameters will determine the effectiveness and benefits of the CR-GRDF compared to the other dosage forms.

APPROACHES TO GASTRIC RETENTION 1

Various approaches have been followed to encourage gastric retention of an oral dosage form. Floating systems have low bulk density so that they can float on the gastric juice in the stomach. The problem arises when the stomach is completely emptied of gastric fluid. In such a situation, there is nothing to float on. Floating systems can be based on the following Hydro dynamically balanced systems (HBS) - incorporated buoyant materials enable the devicto float; Effervescent systems- gas generating materials such as carbonates are incorporated. These materials react with gastric acid and produce carbon dioxide, which allows them to float; Low-density systems have a density lower than that of the gastric fluid so they are buoyant. Raft systems incorporate alginate gels - these have a carbonate component and ,upon reaction with gastric acid, bubbles for min the gel, enabling floating; and Bio adhesive or muco adhesive systems - these systems permit a given delivery system (DDS) to be incorporated with bio/muco adhesive agents, enabling the device to adhere to the stomach (or other GI) walls, thus resisting gastric emptying. However, the mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence. The stomach is a size-filtering system and so it would seem ideally suited to retaining a DDS is not small enough to be taken orally if sizes larger than the pylorus are required. Several systems have been investigated to encourage gastric retention using increasing size of DDS. Systems have been based on expansion due to gases and swelling due to intake of external liquids.

TYPES OF GASTRORETENTIVE DOSAGE FORMS 2, 4, 6

A. Floating drug delivery systems

Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, 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. FDDS can be divided into non-effervescent and gas-generating system.

(a) Non-effervescent systems

This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach. One of the formulation methods of such dosage forms involves the mixing of the drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier18. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Excipients used most commonly in these systems include hydroxypropyl methyl cellulose (HPMC), polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.

This system can be further divided into four

sub-types:

(i) Colloidal gel barrier system

Sheth and Tossounian first designated this 'hydrodynamically balanced system'19. Such a system contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. This prolongs GRT and maximizes the amount of drug that reaches its absorbtion sites in the solution form for ready absorption. This system incorporates a high

level of one or more gel-forming highly soluble cellulose type hydrocolloid, e.g., hydroxypropyl cellulose, hydoxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), polysacharides and matrix-forming polymer such as polycarbophil, polyacrylate and polystyrene. On coming in contact with gastric fluid, the htdrocolloid in the system hydrates and forms a colloid gel barrier around its surface.

Fig.2. Intragastric floating tablet.

(ii) Microporous compartment system

This technology is based on the encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls20. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric

surface with the undissolved drug. In the stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric content. Gastric fluid enters through the aperture, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption.

(iii) Alginate beads

Multi-unit floating dosage forms have been developed from freeze-dried calcium alginate21. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate. The beads are then separated, snap-frozen in liquid nitrogen, and freeze-dried at -40°C for 24 hours, leading to the formation of a porous system, which can maintain a floating force for over 12 hours. These floating beads gave a prolonged residence time of more than 5.5 hours.

(iv) Hollow microspheres / Microballons

Hollow microspheres loaded with drug in their outer polymer shelf were prepared by a novel emulsion solvent diffusion method22. The ethanol/dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated solution of Poly Vinyl Alcohol (PVA) that was thermally controlled at 40°C. The gas phase is generated in the dispersed polymer droplet by the evaporation of dichloromethane formed and internal cavity in the microsphere of the polymer with drug. The microballoon floated continuously over the surface of an acidic dissolution media containing surfactant for more than 12 h.

(b) Gas-generating (Effervescent) systems

These buoyant systems utilize matrices prepared with swellable polymers such as methocel, polysaccharides (e.g., chitosan), effervescent components (e.g., sodium bicarbonate, citric acid or tartaric acid)23. 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 bicarbonate24, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology, etc.

Fig.4. (a) A multiple-unit oral floating dosage system. Reproduced with permission from Ichikawa et al. [82]. (b) Stages of floating mechanism: (A) penetration of water; (B) generation of CO and floating; (C) dissolution of drug. Key: (a) conventional SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker (378C).

Fig.5 Pictorial presentation of working of effervescent floating drug delivery system based on ion exchange resin.

B. Expandable systems

Expandable gastroretentive dosage forms (GRDFs) have been designed over the past 3 decades. They were originally created for possible veterinary use but later the design was modified for enhanced drug therapy in humans. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their GRT. After drug release, their dimensions are minimized with subsequent evacuation from the stomach25. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating the GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption

properties.

C. Bio/Muco-adhesive systems

Bioadhesive drug delivery systems (BDDS) are used as a delivery device within the lumen to enhance drug absorption in a site specific manner. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach26. Gastric mucoadhesion does not tend to be strong enough to impart to dosage forms the ability to resist the strong propulsion forces of the stomach wall. The continuous production of mucous by the gastric mucosa to replace the mucous that is lost through peristaltic contractions and the dilution of the stomach content also seem to limit the potential of mucoadhesion as a gastroretentive force. Some of the most promising excipients that have been used commonly in these systems include polycarbophil, carbopol, lectins, chitosan and gliadin, etc.

D. High-density systems

Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm-3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8-25 hours, depending more on density than on the diameter of the pellets27. Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase density by up to 1.5-2.4g/cm-3.

Tablets

Cholrpheniramine maleate, Theophylline, Furosemide, Ciprofloxacin, Captopril, Acetylsalicylic acid,

Nimodipine, Amoxycillin trihydrate, Verapamil HCI, Isosorbide di nitrate, Sotalol, Isosorbide

mononitrate, Aceraminophen, Ampicillin, Cinnarazine, Dilitiazem, Florouracil, Piretanide, Prednisolone,Riboflavin- 5`Phosphate.

Capsules

Nicardipine, L-Dopa and benserazide, chlordizepoxide HCI, Furosemide, Misoprostal, Diazepam, Propranlol, Urodeoxycholic acid.

Microspheres

Verapamil, Aspirin, Griseofulvin, and p-nitroanilline, Ketoprofen, Tranilast, Iboprufen, Terfenadine.

Granules

Indomethacin, Diclofenac sodium, Prednisolone.

Films

Drug delivery device. Cinnarizine

Powders

Several basic drugs.

Table 1: List of Drugs Formulated as Single and Multiple Unit Forms of Floating Drug Delivery Systems

Brand name

Drug (dose)

Madopar

Levodopa (100 mg)

Benserazide (25 mg)

Valrelease

Diazepam (15 mg)

Liquid Gaviscon

Al-hydroxide (95 mg)

Mg carbonate (385 mg)

Topalkin

Al-Mg antacid

Algamate Flatcoat

Al-Mg antacid

Conviron

Ferrous sulfate

Cifran OD

Ciprofloxacin (1 g)

Cytotec

Misoprostal

(100 mcg/200 mcg)

Table.2. Marketed products of FDDS

Advantages of Floating drug delivery system

1. The gastroretensive systems are advantageous for drugs absorbed through the stomach. E.g. Ferrous salts, antacids.

2. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs.

3. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is

therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine.

4. The gastroretensive systems are advantageous for drugs meant for local action in the stomach. e.g. antacids.

5. When there is a vigorous intestinal movement and a short transit time as might occur in certain type of diarrhea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.

Disadvantages of floating drug delivery system:

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

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

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

4. Some drugs present in the floating system causes irritation to gastric mucosa.

APPLICATIONS OF FLOATING DRUG DELIVERY SYSTEMS

Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.

Sustained Drug Delivery

HBS systems 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 CR formulation hence can be overcome with these systems. These systems have a bulk density of <1 as a result of which they can float on the gastric contents. These systems are relatively large in size and passing from the pyloric opening is prohibited.

Recently sustained release floating capsules of nicardipine hydrochloride were developed and were evaluated in vivo. The formulation compared with commercially available MICARD capsules using rabbits. 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 and it was shown that the drug was released up to 8 hours in vitro in the former case and the release was essentially complete in less than 30 minutes in the latter case.

Site-Specific Drug Delivery

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, eg, riboflavin and furosemide.

Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets.

A bilayer-floating capsule was developed for local delivery of misoprostol, which is a synthetic analog of prostaglandin E1 used as a protectant of gastric ulcers caused by administration of NSAIDs. By targeting slow delivery of misoprostol to the stomach, desired therapeutic levels could be achieved and drug waste could be reduced.

Absorption Enhancement

Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.

A significant increase in the bioavailability of floating dosage forms (42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric-coated LASIX-long product (29.5%).

Evaluation of FDDS

The test for buoyancy and in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 37 C. in practice, floating time is determined by using the USP disintegration apparatus containing 900 ml of 0.1 N HCL as a testing medium maintained at 37 C. The time required to float the DF is noted as floatation time. Burns et al developed and validated an in vitro dissolution method for a floating dosage form, which had both rapid release and S R properties. The method, although based on the standard BP (1993)/ USP (1990) apparatus 2 methods, was modified such that paddle blades were positioned at the surface of the dissolution medium. The results obtained with this modified paddle method showed reproducible biphasic release dissolution profiles when paddle speeds were increased form 70 to 100 rpm and the dissolution medium pH was varied (6.0-8.0). The dissolution profile was also unaltered when the bile acid concentration in the dissolution medium was increased form 7 to 14 m M. The specific gravity of FDDS can be determined by the displacement method using analytical grade benzene as a displacing medium.

The system to check continuous floating behavior contains a stainless steel basket connected to a metal string and suspended from asartorius electronic balance. The floating object is immersed at affixed depth into a water bath, which is covered to prevent water evaporation. The upward floating force could be measured by the balance and the data transmitted to an online PC through RS232C interphase using a sarto wedge program. A lotusspread sheet could automatically pick up the reading on the balances. Test medium used in floating kinetics measurements was 900 ml simulated gastric fluid (pH 1.2) maintained at 37 C, data was collected at 30 sec interval; baseline was recorded and subtracted form each measurement. Dissolution basket had a holder at the bottom to measure the downward force.

γ-Scintigraphy

γ-Emitting radioisotopes compounded into CR-DFs has become the state-of-art for evaluation of gastroretentive formulation in healthy volunteers. A small amount of a stable isotope e.g. Sm, is compounded into DF during its preparation. The main drawbacks of γ-Scintigraphy are the associated ionizing radiation for the patient, the limited topographic information, low resolution inherent to the technique dn the complicated and expensive preparation of radiopharmaceuticals.

Radiology

This method if the state of art in preclinical evaluation of gastroretentivity. Its major advantages as compared to γ-Scintigraphy are simplicity and cost. However, use of X-ray is declined due to strict limitations, regarding the amount of exposure and its often requirement in high quantity. A commonly used contrast agent is barium sulphate.

Gastroscopy

It comprises of perusal endoscopy, used with a fibreoptic and video systems. It is suggested that gastroscopy may be used to inspect visually the effect of prolonged stay in stomach milieu on the FDDS. Alternatively, FDDS may be drawn out of the stomach for more detailed evaluation.

Ultrasonography

Ultrasonic waves reflected substantially different acoustic impedances across interface enable the imaging of some abdominal organs. Most DFs do not sharp acoustic mismatches across their interface with the physiological milieu. Therefore, ultrasonography is not routinely used for the evaluation of FDDS. The characterization included assessment of intragastric location of the hydrogels, solvent penetration into the gel and interactions between gastric wall and FDDS during peristalsis.

Magnetic resonance imaging (MRI)

In the last couple of years, MRI was shown to be valuable tool in gastrointestinal research for the analysis of gastric emptying, motility and intragastric distribution of macronutrients and drug models. The advantages of MRI include high soft tissue contrast, high temporal and spatial resolution, as well as the lack of ionizing irradiation. Also, harmless paramagnetic and supra magnetic MR imaging contrast agents can be applied to specifically enhance or suppress signal of fluids and tissues of interest and thus permit better delineation and study of organs.

FUTURE POTENTIAL

Floating dosage forms offer various future potential as evident form several recent publications. The reduced fluctuations in the plasma level of drug results from delayed gastric emptying. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavailability. Buoyant delivery system considered as a beneficial strategy for the treatment of gastric and duodenal cancers.

The floating concept can also be utilized in the development of various anti-reflux formulations. Developing the control release system for drugs, which are potential to treat the Parkinson's disease. To explore the eradication of helicobacter pylori by using the narrow spectrum antibiotics.