INTRODUCTION:^1-15

Recent trend in research for oral dosage formulations involves with a primary objective to reduce dosing frequency, avoid the toxic effects and increased bioavailability. Majority of the drugs are absorbed in the GIT and the process of absorption from the GIT is a complex phenomenon. However the gastric emptying has an important role to sustain the efficacy of the dose administered.

A design to extend and control the gastric transit time could serve as a precise tool to retain the dosage form in the stomach for a longer duration and to control the drug release. FDDS has the ability of increasing gastric retention time and thereby increase the drug solubility and subsequently the systemic bioavailability. FDDS is more useful for drugs which are more soluble in gastric pH. FDDS utilizes the one among the following mechanisms, i.e. floating, mucoadhesion, expansion, sedimentation and modified shape.

Fig-1: Drug level verses time profile showing differences between zero order, controlled releases, slow first order sustained release and release from conventional tablet

Physiology of GIT:

Stomach consists of 3 different regions; i.e.: fundus, body and pylorus. Fundus and body reserves the undigested material and pylorus helps in mixing and followed by pumping the materials for gastric emptying. Gastric emptying is observed in both fasting and fed state, but distinct in each case. In fasting state, a series of electrical events take place throughout the digestion phase, which cycle including stomach and intestine every 2 to 3 hours. This is called the Migrating Myoelectric Cycle (MMC). Different phases of migrating myoelectric complex (MMC) has been described as below:

Phase-I: In this phase rare contraction happens, so it is called as no contraction phase and it lasts for 30 – 60 minutes.

Phase-II: In this phase intermittent contraction happens and gradually intensity and frequency increases. This phase lasts for 20 – 40 minutes.

Phase-III: In this phase intensive and regular contraction happens with maximum frequency for a short period and as a result all the contents of the stomach moves towards the small intestine. It is also called as housekeeping waves and lasts for 10-20 minute.

Phase IV: It is a transaction phase between phase III and I and also lasts for 0 – 5 minutes.

Fig-2: Diagram of phases of MMC

The above phase generally observed in fasted state, where as in fed state which comprises the intermittent or continuous contraction as in phase II of fasted state.

Advantages of FDDS¹⁶:

· Localized action of drugs in the stomach.

· Controlled release of drugs there by reducing the mucosal irritation.

· Drugs with higher solubility in acidic pH gets more improved absorption due to more retention time in the acidic pH.

· Treatment of Gastro Intestinal Tract disorders.

· Ease of administration and better patient compliance.

· Stomach targeted drug delivery system.

· Better system for drugs having narrow absorption window, poorly soluble in the alkaline pH and degrade in the colon.

Limitations of FDDS¹⁶:

· Floating of the system cannot be predicted as the floating is affected by several factors like pH, presence of food, nature of food and gastric mobility.

· Drugs which have irritation properties.

· Floating shall vary with the posture, i.e. supine or upright.

· Floating also affected by density of the dosage form.

Ideal Properties of Drug substance Suitable for FDDS:

· Highly soluble in the gastric pH region.

· Should be stable in the gastric pH region.

· Low half life

· Low molecular weight

· Multiple dosing frequency

Drugs used for Floating Drug delivery systems for Research:

Drugs	Category	Dosage form
Aspirin	NSAID	Floating Microsphere
Griseofulvin	Anti-Fungal
Ibuprofen/Ketoprofen	NSAID
Piroxicam	NSAID
Verapamil Hydrochloride	Anti Anginal
Cholestaryamine	Bile Acid Sequesterant
Theophylline	Anti Asthma
Nifedipine	Anti Hypertensive
Nicardipine	Anti Hypertensive
Dipyridamole	Anti Coagulant
Tranilast	Anti Allergic
Terfinadine	Anti Histaminic
Diclofenac Sodium	NSAID	Floating Granules
Indomethacin	NSAID
Prednisone	Corticosteroid
Cinarizine	Anti Histaminic	Floating Films
Albendazole	Antihelminthic	Floating Films
Isosorbidemononitrate	Anti Anginal	Floating Tablets
Diltiazem	Anti Hypertensive
Acetyl Salicylic Acid	NSAID
Sotalol	Antiarrhythmic
Carbamazepine	Anti convulsant
Furosemide	Diuretics
Diazepam	Anti Anxiety	Floating Capsules
Ursodeoxychloic Acid	Bile and liver Therapy
Pentoxyphylline	Hemorrheologic agents
Captopril	Anti Hypertensive
Nimodipine	Anti Hypertensive
Verapamil Hydrochloride	Anti Anginal
Nicadipine	Anti Hypertensive
Furosemide	Diuretics
Acetaminophen	Analgesic
Amoxicillin	Antibiotic
Diazepam	Anti Anxiety

PATENTS ON FDDS^17-23:

S.No.	Patent Number	Year	Summary
1.	4167558	1979	An unique sustained release formulation which describes the preparation of tablets for oral administration is disclosed. The formulation is hydro-dynamically balanced to be floated in gastric environment thereby remaining in the stomach for a longer duration of time.
2.	4140755	1979
3.	20100015224	2010	A system for spatially and temporally programmable delivery of an active agent. After oral administration, the System can be retained in the gastric region for an extended period of time.
4.	20100286660	2010	This invention describes a swallow able medical treatment device, which is designed to initially assume a contracted state having a volume of less than 4 cm³.
5.	20090324694	2009	The product is manufactured by extrusion and it helps to take many useful dosage forms. The product may comprise a sheet of hydratable polymer, the product being of a size which will not pass out of the stomach, for example a shaped sheet or a roll.
6.	20060013876	2006	Present invention describes a novel pharmaceutical composition containing an active ingredient(s) which is retained in the stomach or upper part of gastrointestinal tract for controlled release of medicament for enhanced local treatment, and/or better absorption from upper parts of gastrointestinal tract for better therapeutic effects.

COMMERCIALLY AVAILABLE FORMULATIONS^24-27:

Brand Name	Drug	Dosage Form	Manufacturer
Modapar	Levodopa, benserazide	Floating capsule	Roche, USA
Valrelease	Diazepam	Floating capsule	Hoffmann-LaRoche, USA
Topalkan	Aluminium and magnesium mixture	Floating antacid	Pierre Fabre Drug, France
Conviron	Ferrous sulphate	Colloidal gel forming FDDS	Ranbaxy, India
Cifran OD	Ciprofloxacin	Floating Tablet	Ranbaxy, India
Cytotec	Misoprostol	Floating Capsule	Pharmacia, USA
Liquid Gaviscone	Alginic Acid and Sodium Bicarbonate	-	Glaxo Smith Kline, India
FlatCoat	Aluminium-magnesium antacid	Floating antacid	-
Oflin OD	Ofloxacin	Floating Tablet	Ranbaxy, India
Glumetza GRTM	Metformin Hydrochloride	Floating Tablet	Biovail and Depomed

Polymers for FDDS²⁸

Cellulosic Hydrocolloids

Gel forming and Matrix forming polymers

Natural polymers

· Hydroxy Propyl Methyl Cellulose

· Hydroxy Ethyl Cellulose

· Hydroxy Propyl Cellulose

· Methyl Cellulose

· Sodium Carboxy Methyl Cellulose

· Ethyl Cellulose

· Carragennan

· Carbopol

· Polyethylene Oxide

· Polyacrylate

· Polyvinyl Acetate

· Chitosan, Gelatin

· Guar gum

· Pectin

· Chitosan

· Xanthan Gum

· Psyllium Husk Starch

· Gellan Gum, Alginates

FACTOR AFFECTING FLOATING LAG TIME AND FLOATING TIME:

· Density

· Dosage Design (size and shape)

· Nature of meal, calorie content, volume of meal and viscosity of the meal

· Age

· Posture

· Gender

· Fasting or Fed state

· Concomitant drug administration

DIFFERENT DESIGNS OF FDDS^29-46:

The first glance of the concept for Floating Drug Delivery System, came in to light early in 1968. White Davis discloses a method to overcome the difficulty experienced after swallowing of the pill. Then he suggested this difficulty shall be overcome by providing pill with density less than 1.0g/cm³ and it will float on the surface, then several approaches used. The main approaches includes as given below:

A. Single Unit Floating Dosage Systems: In these forms a low density approach is required in which the globular shells apparently having lower density than that of gastric fluid can be used as a carrier for drug to control the release. Buoyant dosage forms can also be prepared by use of liquids that remains float in the stomach.

a) Non-effervescent Systems: Such systems starts swelling when comes in contact with the gastric fluid. The air entraps in to the swollen matrix and allows the system to float. Also another mechanism involves the unrestrained swelling of the system up on contact with the gastric fluid to such an extent that prevents the system to exit from the stomach. Commonly used excipients are hypromellose, polyacrylate polymers, polyvinyl acetate, carbopol, sodium alginate, polyethylene oxide and polycarbonates.

1. Hydrodynamic balanced system (HBS): These are single-unit dosage forms, containing hydrophilic swell able polymers along with drug and usually administered in a gelatin capsule. The capsule rapidly dissolves in the gastric fluid, and hydration and swelling of the surface polymers produces a floating mass.

2. Floating chamber: Fluid –filled floating chamber which includes incorporation of a gas- filled flotation chamber into a micro porous component that houses a drug reservoir. Apertures or openings are present along the top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug.

3. Multilayer flexible film: This device is multilayered, flexible sheet like medicament device that was buoyant in the gastric juice of the stomach and had sustained released characteristics. The device consisted of self-supporting carrier films made up water insoluble polymer matrix with the drug dispersed there in, and a barrier film overlaying the carrier film. The barrier film consisted of the water insoluble and water and a drug permeable polymer or copolymer. Both films were sealed together along their periphery, in such a way as to entrap a plurality of small air pockets, which imparted the laminated films their buoyancy and the rate of drug release can be modulated by the appropriated selection of the polymer matrix.

Examples of research work for some of the Non-effervescent Systems are as given below:

1. Kaza et al prepared sustained release floating tablets of Ranitidine Hydrochloride by using polymers like HPMC K 100M and HPMC K 15M. The tablets were found buoyant for around 24 hrs.

2. Nur and Zhang developed floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after immersion into the gastric media floated immediately and tablets with hardness 4 kg/cm2 sank for 3 to 4 minutes and then came to the surface. Tablets in both cases of hardness remained floating for 24 hours.

b) Effervescent Systems (Gas-generating Systems): These systems are matrix based systems which comprises swellable polymers and effervescent compounds. Also called as buoyant systems and it has been fabricated in such a way that it liberates CO₂ up on immediate contact with the acidic environment of stomach. Effervescent system include used of gas generating agents, carbonates (e.g. Sodium bicarbonates) 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 the system and making it float on the gastric fluid.

1. Floating systems containing effervescent components: These are the matrix type of systems prepared with the help of swell able polymers, formulated in such a way that when in contact with the acidic gastric contents, CO₂ is liberated and gets entrapped in swollen hydrocolloids, which provide buoyancy to the dosage forms.

2. Floating system based on ion exchange resin: The resin beads were loaded with bicarbonate and drug which were bound to the resin. The loaded resin beads were coated with a semi permeable membrane to overcome rapid loss of CO₂. After exposure to gastric media, exchange of bicarbonate and chloride ions took place and leads to the formation of CO₂, which was trapped within the membrane, causing the particles to float.

3. Floating system with inflatable chamber: An alternative mechanism of the gas generation can be developed as an osmotically controlled floating device, where gases with a boiling point < 37^oC (e.g. cyclopentane, diethyl ether) can be incorporated in solidified or liquefiedform into the systems. At physiological temperatures, the gases evaporate enabling the drug containing device to float.

4. Programmable drug delivery: Programmable, controlled released drug delivery system was developed in the form of a non-digestible oral capsule (containing drug in slowly eroding matrix for controlled release). These systems were designated to utilize an automatically operated geometric obstruction that keeps the device floating in the stomach and prevents it from passing through the reminder of the GIT.

Examples of research work for some of the Effervescent Systems are as given below:

1. Sriamornsak et al prepared calcium pectinate beads containing carbonate salt as a gas forming agent. The manufacturing procedure includes dispersing carbonate salt in pectin solution and then extruding into neutral or acidified solution of calcium chloride. By inclusion of carbonate salt it results in formation of porous beads which upon reaction with acid caused release of carbon dioxide providing floating to beads.

2. Sonar et al prepared bilayered, floating bioadhesive tablets of Rosiglitazone maleate bilayer tablets contained two layers, a floating layer and a sustained release (SR) layer. The sustained release layer was compressed and granules of the floating layer were added to it then both layers were compressed. HPMC and Sodium bicarbonate were added in the floating layer and when immersed in 0.1 N HCl the tablets expanded and rise to the surface.

Fig-3: Diagram for working principle of effervescent floating drug delivery system

Multiple Unit Floating Dosage Systems: The purpose of designing multiple unit dosage forms is to develop a dosage form that has all the advantages as that of a single unit dosage form. In pursuit of this endeavor many multiple unit floatable dosage forms have been designed. Microspheres have high loading capacity and many polymers have been used such as albumin, gelatin, starch, polymethacrylate, polyacrylamine etc.

a) Non-effervescent Systems Alginate beads: Multiple unit floating dosage forms has been developed from freeze dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium alginate. The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -40^o for 24 hours, leading to the formation of porous system, which can maintain a floating force over 12 hours.

b) Effervescent Systems (Gas-generating Systems): Multiple type of floating dosage system composed of effervescent layers and Swell able membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sub layers to avoid direct contact between polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37⁰C, it produces swollen pills (like balloons) with a density less than 1.0g/ml due to incorporation of CO₂

c) Hollow Microspheres: Hollow microspheres are considered as one of the most promising buoyancy systems, as they possess the unique advantages of multiple unit systems as well as the better floating properties, because of the central hollow space inside the microspheres.

d) Raft Forming Systems: Here, a gel-forming solution (e.g. sodium alginate solution containing carbonates or bicarbonates) swells and forms a viscous cohesive gel containing entrapped CO₂ bubbles on contact with gastric fluid.

Examples of research work for some of the Multiple unit floating dosageforms are as given below:

1. Sato et al, prepared micro ballons with floating properties by emulsion solvent diffusion method utilizing enteric acrylic polymer codissolved with drug in a mixture of dichloromethane and ethanol. The release properties of five different drugs (Aspirin, Salicylic Acid, Ethoxybenzamide, Indomethacin and Riboflavin) exhibiting distinct aqueous solubilities entrapped within micro ballons were investigated.

2. Ichikawa et al, developed a new type of floating dosage system composed of both effervescent layers and swellable membrane layers which is coated on sustained release pills. Further, the inner layer of of the dosage form contains sodium bicarbonate and tartaric acid as effervescent agent and was divided into 2 sub layers to avoid direct contact between the 2 agents. These sublayers were again surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac.

3. Kawashima et al prepared multiple-unit hollow microspheres by emulsion solvent diffusion technique. Drug and acrylic polymer were dissolved in an ethanol-dichloromethane mixture, and poured into an aqueous solution of PVA with stirring to form emulsion droplets.

Fig-4: Diagram of Multiple-unit oral floating drug delivery system

EVALUATION OF FDDS^47-61:

Important parameters need to be evaluated for FDDS are mainly divided in to two parts:

(a) In-vitro evaluation

· Floating lag time and Floating time: Time taken by the dosage form to start floating is known as floating lag time. The total time taken by the dosage form to be remain in floating state is known as floating time. Both floating lag time and floating time studies performed in 0.1(N) HCl, 900ml maintained at 37°C.

Li et al, disclosed an online continuous floating monitoring system that was a modification of the system described by Timmermans and Andre. It was used to provide quantitative measurement of resultant floating force.

· Dissolution profile: Dissolution studies are carried out in simulated gastric fluid by selecting USP dissolution apparatus or any modified apparatus. At a predefined intervals a defined amount of samples are collected from the medium and the same volume is replenished. The collected sample then further analyzed to obtain the %drug release.

Goheletal, proposed a more relevant in-vitro dissolution method to evaluate Floating Drug Delivery System (for tablet dosage forms). A 100ml glass beaker was modified by adding a side arm at the bottom of the beaker, so that the beaker can hold the dissolution medium and allow collection of samples. A burette was mounted above the beaker to deliver the dissolution medium with a defined flow rate. The tablet does not stick to the agitating device in the proposed dissolution method.

· Resultant weight test: To measure floating capabilities of FDDS an in-vitro measuring apparatus has been developed

· Differential scanning colorimetry

· Particle Size Distribution

· Surface morphology

· Mechanical properties

(b) In-vivo evaluation

· X-Ray method / Gamma scintigraphy: X-Ray or gamma scintigraphy is a very widely accepted evaluation parameter for FDDS. It locates the dosage form in the GIT and clearly predicts the gastric emptying time passage of the dosage form in the GIT. For X-ray radio opaque material is included in the dosage form and for gamma scintigraphy a stable isotope.

· Gastroscopy / Ultrasonography: Gastroscopy includes per oral endoscopy with a fiber optic and video system which inspect visually the effect of prolonged stay of dosage form in the stomach. Ultrasonic waves reflected substantially different acoustic impedance across interface enables imaging of abdominal region.

· Pharmacokinetic study: Pharmacokinetic assessments are an integral part of in-vivo evaluation. In this evluation pharmacokinetic parameters like AUC, Cmax and Tmax are evaluated. Cmax provides information about rate of absorption, Tmax represents the time taken to reach the maximum concentration and AUC represents the extent of absorption.

Miyazaki et al, conducted pharmacokinetic studies on floating granules of indomethacin prepared with chitosan and compared the peak plasma concentration and AUC with the conventional commercially available capsules. It was concluded that the floating granules prepared with chitosan were superior in terms of decrease in peak plasma concentration and maintenance of drug in plasma.

Ichikawa et al, developed a multiparticulate system that consisted of floating pills of a drug (p- amino benzoic acid) having a limited absorption site in the gastrointestinal tract. It was found to have 1.61 times greater AUC than the control pills.

APPLICATION OF FDDS:

Applications of FDDS has been achieved by one of the following methods:

(a) Modified drug delivery : In this study floating system remain in the stomach for a long period of time and hence releases the drug for long duration.

(b) Targeting drug delivery: Suitable for drugs having better absorption in the stomach

CONCLUSION:

Floating Drug Delivery System provides a better scope for new therapeutic approach and provides more potential approach for gastric retention. The process of absorption of drugs in the Gastro Intestinal Tract is considered as a highly variable process and due to long gastric retention of the dosage forms, it enhances the drug absorption process. Despite of more number of difficulties to be addressed to achieve prolonged gastro retention, still a more number of organizations are driving towards commercialization of this technique. On the way forward Floating Drug Delivery System promises for a bright future.

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Received on 24.08.2020 Modified on 23.03.2021

Research J. Pharm. and Tech 2022; 15(1):429-435.

DOI: 10.52711/0974-360X.2022.00071