INTRODUCTION:

Floating drug delivery systems (FDDS) or hydrodynamic ally balanced systems (HBS) are low density systems that have sufficient buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on gastric contents, the drug is released slowly at the desired rate from the system. After released of drug, the residual system is emptied from the stomach.

This result in an increased gastric retention time (GRT) and a better control of the fluctuation in plasma drug concentration However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. Drug dissolution and release from the dosage form retained in the stomach fluids occur at the pH of the stomach under fairly controlled conditions. Many floating systems have been based on granules, powders, capsules, tablets, hollow microspheres and laminated films. Gastric emptying of pharmaceuticals is highly variable and is dependent on the dosage form and the fed or fasted state of the stomach. The normal gastric residence times usually range between 5mints and 2 hrs. In the fasted state the electrical activity in the stomach, the interdigestive my electric cycle or migrating my electric complex (MMC) governs the activity and hence, the transit of dosage forms. It is characterized by four phases:

Phase I:

Period of no contractions (40-60 mints),

Phase II:

Period of intermittent contractions (20-40 mints),

Phase III:

Period of regular contractions at the maximal frequency that travel distally also known as house keeper wave (10-20 mints),

Phase IV:

Period of transition between phase III and phase I (0-5mints) .

Advantages:^[^14,15]

1. Used for drugs which are unstable in intestinal fluids.

2. Used to sustain the delivery of drug.

3. Used for maintaining the systemic drug concentration within the therapeutic window.

4. Reduced dosing frequency.

5. Improved bioavailability of the drug.

6. Used for the delivery of drugs with narrow absorption window in the small l intestine.

7. In the treatment of peptic ulcer disease.

8. Used for local action in the stomach.

9. Site specific drug delivery is possible.

Disadvantages:^[^15]

1. Not suitable for drugs with stability or solubility problem in stomach.

2. Drugs which undergo extensive first pass metabolism are not suitable candidates.

3. They require sufficiently high levels of stomach fluids for the system to float and to work efficiently.

4. Drugs with irritant effect also limit the applicability

Mechanism of floating systems:^[^16]

When the system is floating on the gastric contents, the drug is released slowly at desired rate from the system. After these the residual system is emptied from the stomach and minimum gastric content needed to allow proper achievement of the buoyancy retention principle. A minimum level of floating force (F) is required to keep the dosage form reliably buoyant on surface of the meal. The apparatus which operates by measuring the floating force kinetics continuously the force is equivalent to F that is required to maintain the submerged object. The object floats better if F is on the higher positive side is shown in Fig.1(b). This apparatus helps in optimizing Floating Drug Delivery System with respect to stability and durability of floating forces which prevent the intragastric buoyancy capability variations.

F = F buoyancy – F gravity

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

Where, F = Total vertical force , Df = Fluid density , Ds = Object density , v = Volume and g = Acceleration due to gravity .

Fig.1 Mechanism of Floating Systems

Approaches for gastric

retention^[^14-25]

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

a) Floating Systems:

Floating Drug Delivery Systems (FDDS) or Hydrodynamic ally Balanced Systems (HBS) have a bulk density lower than gastric fluids and hence remain floating in the stomach for a prolonged period of time. The drug is slowly released from the floating system at a desired rate without fluctuations in plasma drug concentration which increase in gastric residence time (GRT). After complete release of drug from the delivery, the residual is expelled from the stomach.

b) Bioadhesive Systems :

To localize delivery device within a cavity of body, bioadhesive systems are usually formulated. In these system, bioadhesion is achieved by using bioadhesive polymers which adhere to the epithelial surface of gastrointestinal tract. The formation of hydrogen and electrostatic bonding at the mucus polymer interface leads to bioadhesion.

c) Swellable/Expandable Systems :

Swellable systems are a type of gastro-retentive dosage forms which swell in the stomach to an extent that prevents its exit through the pyloric sphincter resulting in the retention of swellable system in the stomach for a prolonged period of time.

d) High Density Systems :

Altered density gastro-retentive dosage forms includes system that have density either greater or lower than the stomach contents leading to an increase in GRT and hence, drug release for a prolonged time period .

Fig. 2 Approaches for gastric retention

Drug candidate suitable for gastroretentive drug delivery system^[26-30]

1) Drugs those are unstable in the intestinal or colonic environment e.g. metronidazole, ranitidine , captopril .

2) Drugs that have narrow absorption window in gastrointestinal tract (GIT) e.g. furosemide, paraaminobenzoic acid (PABA) riboflavin, L-DOPA .

3) Drugs that disturb normal colonic microbes e.g. antibiotics against Helicobacter pylori.

4) Drugs those are locally active in the stomach e.g. antacids, misoprostol.

5) Drugs that exhibit low solubility at high pH values e.g. verapamil hydrochloride, diazepam, chlordiazepoxide.

Drug candidate unsuitable for gastroretentive drug delivery systems^[^26-30]

1) Drugs that suffer instability in the gastric environment e.g. erythromycin etc.

2) Drugs that have very limited acid solubility e.g. phenytoin etc .

3) Drugs intended for selective release in the colon e.g. corticosteroids and 5 – amino salicylic acid etc .

Types of gastroretentive floating drug delivery systems^[^14-25]

Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in development of FDDS which are:

A. Effervescent System, and

B. Non-Effervescent System.

A. Effervescent System:

Effervescent systems include use of gas generating agents, carbonates (e.g. Sodium bicarbonate) and other organic acid(e.g. citric acid and tartaric acid) present in the formulation to produce carbon dioxide(CO₂) gas, thus reducing the density of system and making it float on the gastric fluid. An alternative is the incorporation of matrix containing portion of liquid, which produce gas that evaporate at body temperature. The effervescent systems can be further classified into two types:

1) Gas Generating systems

2) Volatile Liquid/Vacuum Systems

1. Gas-generating Systems:

a) Intra Gastric Single Layer Floating Tablets or Hydrodynamically Balanced System (HBS) :

These are as shown in Fig.3 and formulated by intimately mixing the CO₂generating agents and the drug within the matrix tablet. These have a bulk density lower than gastric fluids and therefore remain floating in the stomach unflattering the gastric emptying rate for a prolonged period. The drug is slowly released at a desired rate for a prolonged period.

Fig.3. Intra Gastric Single Layer Floating Tablet

The drug is slowly released at a desired rate from the system and is expelled from the stomach. This leads to an increase in the gastro retentive time and a better control over fluctuation in plasma drug concentration.

b) Intra Gastric Bilayer Floating Tablets:

These are also compressed tablet as shown in Fig. 4 and containing two layer i.e.,

i. Immediate release layer and

ii. Sustained release layer.

Fig.4. Intra Gastric Bilayer Floating Tablet

c) Multiple Unit type floating pills:

These system consist of sustained release pills as ‘seeds’ surrounded by double layers. The inner layer consist of effervescent agents while the outer layer is of swell able membrane layer. When the system is immersed in dissolution medium at body temp, it sinks at once and then forms swollen pills like balloons, which float as they have lower density. This lower density is due to generation and entrapment of CO₂ within the system.

Fig. 5 : (a) A multi-unit oral floating dosage system. (b) Stages of floating mechanism: (A) penetration of water; (B) generation of CO2 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 (37⁰C) .

Fig. 6 Intra Gastric Floating Gastrointestinal Drug Delivery Device

2. Volatile Liquid / Vacuum Containing Systems:

a) Intragastric Floating Gastrointestinal Drug Delivery System:

These system can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a microporous compartment , as shown in Fig.6.

b) Inflatable Gastrointestinal Delivery Systems:

In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach. These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug impregnated polymeric matrix, then encapsulated in a gelatin capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir compartment in the stomach. The drug continuously released from the reservoir into the gastric fluid. This system is shown in Fig. 7 .

Fig. 7 Inflatable Gastrointestinal Delivery System

c) Intragastric Osmotically Controlled Drug Delivery Systems :

It is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule. In the stomach, the capsule quickly disintegrates to release the intragastric osmotic ally controlled drug delivery device.

Fig. 8 Intragastric Osmotically Controlled Drug delivery System

The inflatable support inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body temperature to inflate the bag. The osmotic pressure controlled drug delivery device consists of two components: drug reservoir compartment and an osmotic ally active compartment. The drug reservoir compartment is enclosed by a pressure responsive collapsible bag, which is impermeable to vapor and liquid and has a drug delivery orifice. The osmotic ally active compartment contains an osmotic ally active salt and is enclosed within a semi permeable housing. In the stomach, the water in the GI fluid is continuously absorbed through the semi permeable membrane into osmotic ally active compartment to dissolve the osmotic ally active salt. An osmotic pressure is then created which acts on the collapsible bag and in turn forces the bag reservoir compartment to reduce its volume and activate the drug release of a drug solution formulation through the delivery orifice. The floating support is also made to contain a bioerodible plug that erodes after a predetermined time to deflate the support. The deflated drug delivery system is then emptied from the stomach. This system is shown in Fig. 8 .

B. Non effervescent systems:

The Non-effervescent FDDS based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GIT. The most commonly used excipients in non-effervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bioadhesive polymer such as chitosan and carbopol . The various types of this system are as :

1. Single Layer Floating Tablets:

They are formulated by intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms .

Table . 1Floating beads

Researcher	Drug used	Method used	Polymer used	Achievements
Jaiswal etal.	Ranitidine Hydrochloride	Emulsion Gelation	Sodium alginate, pectin	Beads entrapped even a water soluble drug as ranitidine HCL in sufficient amount and also can successfullydeliver the drug in stomach for a prolong duration of time.
Mishara etal.	Loratidine	Emulsion Gelation	Sodium alginate, pectin, ethyl cellulose	Controlled release formulation of loratidine provided zero-order release for 8 h.
Tripathi etal.	Clarithromycin	Ionic gelation	Pectin, ethyl cellulose	The formulation exhibited sustained release profile and was best fitted to the Peppas model with n < 0.45.
Vidyasagar et al.	Clarithromycin	Emulsion Gelation	Sodium alginate, hydroxy propyl methyl cellulose (HPMC)	In-vitro dissolution studies reveals that this formulation gave sustained release pattern of clarithromycin up to 12 hr.
Mandal et al.	Furosemide	Emulsion gelation	Sodium alginate	A higher level of oil increased drug entrapment efficiency but retarded drug release rate as compared to a lower level of oil containing beads.
Vedha et al.	Nevirapine	Ionic gelation	Sodium alginate, hydroxypropyl methylcellulose	The beads containing higher amounts of calcium carbonate demonstrated an instantaneous, complete, and excellent floating ability over a period of 24 hr.
Mishra et al.	Acetohydroxamic acid (AHA)	Ionotropic gelation	Gellan gum	Oral dosage form of floating gellan beads containing AHA may form a useful stomach site specific drug delivery system for the treatment of H. pylori infection.
Shishu et al.	5-flurouracil (5- FU)	Ionic gelation	Sodium alginate and hydroxypropyl methylcellulose	The beads containing higher amounts of calcium carbonate demonstrated instantaneous, complete, and excellent floating ability over a period of 24hr.
Verma et al.	Rifabutin	Ionotropic	Gellan gum	The beads exhibited excellent buoyancy in simulated gastric fluid (SGF) and remained buoyant for 18 hr.
Kouchaka etal.	Diclofenac	Ion exchange	Ethyl cellulose, Eudragit RS-100	Ethyl cellulose-coated beads have a desirable floating capability in comparison with the Eudragit RS-100 coated beads.
Raja et al.	Acyclovir	Ionic gelation	Sodium alginate, HPMC, guar gum	Floating alginate beads may act as a promising carrier for acyclovir to improve its oral bioavailability.
Vani et al.	Ranitidine hydrochloride	Extrusion congealing	HPMC, sodium alginate	Study revealed that the gastro retentive drug delivery system designed as floating beads could be suitable drug delivery system for ranitidine hydrochloride.
Somani et al.	Aceclofenac	Ionotropic crosslinking	Pectin	Calcium pectinate microparticles as a promising floating pulsatile drug delivery for site and time specific release of drug acting as per the chronotherapy of disease.
Sriamornsak et al.	Metronidazole	Modified emulsion gelation	Pectin	The study revealed that as the amount of incorporated wax increased in the formulation significantly sustained the drug release while beads remaining floating.

Fig. 9 Flowchart showing different approaches of gastroretentive floating drug delivery systems

Formulation of floating dosage form^[^31]

Table . 2 Formulation of floating dosage form

Sr. No.	Ingredients	Role	Examples
1.	Hydrocolloids	Hydrate acidic medium .	Pectin , alginates , chitosan, acacia , gelatine, HPMC(K4M,K100M,K15M) , Na CMC , HEC , MC , bentonite , agar .
2.	Inert fatty materials	Decreases hydrophilic property and increases buoyancy of formulation .	Fatty acids , edible oil , long chain alcohol , mineral oils , glycerides .
3.	Release rate accelerant	Modify release rate of the medicament from formulation .	Lactose , mannitol .
4.	Release rate retardant	Decreasesd solubility and retard the release of medicaments .	Dicalcium phosphate , talc , magnesium stearate .
5.	Buoyancy increasing agents	Enhancing the buoyancy of the formulation .	Ethyl cellulose , methyl cellulose .
6.	Effervescent agents	Decreasesd density of particle	Sodium bicarbonate , citric acid , tartaric acid , Di-Sodium Glycine Carbonate , citroglycine .

Factors controlling gastric retention time:^[^32-37]

The gastric retention time (GRT) of dosage forms is controlled by several factors such as density and size of the dosage form , food intake , nature of the food , posture , age , sex , sleep and disease state of the individual (eg. Gastrointestinal diseases and diabetes) and administration of drugs such as prokinetic agents (cisapride and metoclopramide)

1) Density:

Gastric Retention Time (GRT) is a function of dosage form buoyancy that is independent on the density.

2) Size

Dosage form units with diameter of >7.5 mm are reported to have an increased GRT compared with those with diameter of 9.9 mm .

3) Shape:

Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% 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 coadministration 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, the GI motility is characterized by periods of strong motor activity or the migrating my electric 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 four 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; can affect floating time .

13) Biological factors:

Diabetes and Crohn’s disease, etc .

Evaluation gastro retentive floating drug delivery systems^[^38-42]

1) Percentage yield:

This is calculated from ,

Weight of dry material obtained

× 100

Total weight of raw material

2) Swelling index

This is calculated from ,

Weight of wet material – Weight of dry material

× 100

Weight of wet material

3) Drug entrapment efficiency:

The capture efficiency of the multiparticulate or the percent entrapment can be determined by allowing washed multiparticulate to lyse. The lysate is then subjected to the determination of active constituents as per monograph requirement. The percent encapsulation efficiency is calculated using equation :

Total drug – Drug in solution

DEE% = × 100

Total drug

4) Particle size analysis:

The particle size and the size distribution of beads or microspheres is determined in the dry state using the optical microscopy method .

5) Surface characterization:

The external and cross-sectional morphology (surface characterization) is done by scanning electron microscope (SEM) .

6) Floating lag time:

It is the time taken by the tablet to emerge onto the surface of dissolution medium and is expressed in seconds or minutes .

7) Buoyancy time:

Appropriate quantity of the floating micro particulate is placed in 100 ml of the simulated gastric fluid (SGF, pH 2.0), the mixture is stirred with a magnetic stirrer . The layer of buoyant micro particulate is pipette and separated by filtration. Particles in the sinking particulate layer are separated by filtration . Particles of both types are dried in a desiccators until constant weight is achieved . Both the fractions of microspheres are weighed and buoyancy is determined by the weight ratio of floating particles to the sum of floating and sinking particles .

Buoyancy time(%) = Wf / Wf + Ws × 100

Where , Wf = Weight of floating

Ws = Weight of settled

8) Drug – Excipient interactions:

This is done using FTIR. Appearance of a new peak, and/or disappearance of original drug or excipient peak indicates the DE interaction .

9) In Vitro drug release:

This is determined by using USP II apparatus (paddle) stirring at a speed of 50 or 100 rpm at 37 ± 0.2 °c in simulated gastric fluid (pH 1.2 without pepsin). Aliquots of the samples are collected and analysed for the drug content. The time (hrs) for which the tablets remain buoyant on the surface of the dissolution medium is the duration of floating and is visually observed.

10) In Vivo evaluation:

This is carried out by means of X-ray or Gamma scintigraphic monitoring of the dosage form transition in the GIT . The tablets are also evaluated for hardness , weight variation , etc.

Application of gastroretentive floating drug delivery systems^[^43-46]

1) 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, e.g., Riboflavin, furosemide. 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.

2) 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.

3) Sustained drug delivery:

Hollow microspheres of non-steroidal anti inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of indomethacin are quiet beneficial for rheumatic patients .

4) Floating system are particularly useful for acid stable drugs, drugs which are poorly soluble or unstable in intestinal fluids and for those which undergo abrupt changes in their pH-dependent solubility due to food, age and pathophysiological conditions of GIT. e.g. floating system for furosemide lead to potential treatment of Parkinson’s disease .

5) FDDS served as an excellent drug delivery system for the eradication of Helicobacter pylori, which is now believed to be causative bacterium for chronic gastritis and peptic ulcers. The patients require high concentration to be maintained at the site of infection that is within the gastric mucosa. The floating dosage form by virtue of its floating ability was retained in stomach and maintained high concentration of drug in the stomach .

6) There are some cases in which the relative bioavailability of floating dosage form is reduced as compared to conventional dosage form e.g. floating tablets of amoxicillin trihydrate has bioavailability reduced to 80.5% when compared with conventional capsules. In such cases, the reduction in bioavailability is compensated by the advantages offered by FDDS e.g. patients with advanced Parkinson’s disease, experienced pronounced fluctuations in symptoms while treatment with standard L-dopa. A HBS dosage form provided a better control of motor fluctuations although its bioavailability was reduced by 50-60% of the standard formulation .

Table . 3 Marketed products of GFDDS

Sr. No.	Brand name	Drug (Dose)	Company , Country	Remarks
1.	Modopar®	Levodopa (100 mg ) Benserazide (25 mg )	Roche Product USA	Floating CR capsule
2.	Valrelease®	Diazepam (15 mg )	Hoffmann – LaRoche USA	Floating capsule
3.	Topalkan®	Al-Mg antacid	Pierre Fabre Drug France	Floating liquid alginate preparation
4.	Conviron®	Ferrous sulphate	Ranbaxy India	Colloidal gel forming FDDS
5.	Cifran OD®	Ciprofloxacin (1 gm )	Ranbaxy India	Gas generating floating tablet
6.	Cytotec®	Misoprostal (100 mcg/200 mcg )	Pharmacia USA	Bilayer floating capsule
7.	Oflin OD®	Ofloxacin (400 mg )	Ranbaxy India	Gas generating floating tablet
8.	Liquid Gavison®	Al hydroxide (95 mg ) Mg carbonate (358 mg )	Glaxo Smith Kine India	Effervescent floating liquid alginate preparation

CONCLUSION:

This article provides information regarding the gastroretentive floating drug delivery system and its evaluation process . Gastroretntive floating drug delivery offers various potential advantages for drug with poor bioavailability due their absorption is restricted to the upper gastrointestinal tract (GIT) and they can be delivered efficiently thereby maximizing their absorption and enhancing absolute bioavailability . A novel floating controlled – release drug delivery system was formulated in an effort increase the gastric retention time of the dosage form and to control drug release . Floating alginate beads are designed to prolong the gastric residence time after oral administration , at a particular site and controlling the release of drug especially useful for achieving controlled plasma level as well as improving bioavailability . Buoyant delivery system is also considered as a beneficial strategy for the treatment of gastric and duodenal cancers . The floating concept can be utilized in the development of various anti-reflux formulations .

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Received on 27.11.2015 Accepted on 21.12.2015

Asian J. Pharm. Res. 5(4): October- December., 2015; Page 211-220

DOI: 10.5958/2231-5691.2015.00033.7