INTRODUCTION:

Stomach Specific FDDS have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, 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 fluctuations in plasma drug concentration.

The floating sustained release dosage forms present most of the characteristics of hydrophilic matrices and are known as ‘hydrodynamic ally balanced systems’ (‘HBS’) since they are able to maintain their low apparent density, while the polymer hydrates and builds a gelled barrier at the outer surface. The drug is released progressively from the swollen matrix, as in the case of conventional hydrophilic matrices. These forms are expected to remain buoyant (3- 4 hours) on the gastric contents without affecting the intrinsic rate of emptying because their bulk density is lower than that of the gastric contents. Among the different hydrocolloids recommended for floating formulations, cellulose ether polymers are most popular, especially hydroxypropylmethyl cellulose (HPMC). Fatty material with a bulk density lower than one may be added to the formulation to decrease the water intake rate and increase buoyancy.^[1,2] Gastric emptying of pharmaceuticals is highly variable and is dependent on the dosage form and the fed/fasted state of the stomach. Normal gastric residence times usually range between 5 mints and 2 hrs. In the fasted state the electrical activity in the stomach, the interdigestive myoelectric cycle or migrating myoelectric complex (MMC) governs the activity and, hence, the transit of dosage forms.^{[3, 4]}

Anatomy of Stomach:

The stomach is an organ with a capacity for storage and mixing. Anatomically the stomach is divided into 3 regions, namely, the fundus, the body and the antrum (pylorus). The fundus and the body regions are capable of displaying a large expansion to accommodate food without much increase in the intra-gastric pressure. The stomach line is devoid of villi but consists of a considerable number of gastric pits that contribute to the storage capacity of the stomach.^[5,6] The pylorus region is responsible for the mixing and grinding of gastric contents. Under fasting conditions the stomach is a collapsed bag with a residual volume of 50ml and contains a small amount of gastric fluid of pH 1- 3 and air. The two main secretions, mucus and acid are produced by specialized cells in the stomach lining. Mucus is secreted by goblet cells and gastric acid by oxyntic (parietal) cells. The mucus spreads and covers the mucosal surface of the stomach as well as the rest of the gastrointestinal tract. The thickness of this mucus coating varies from one region of the gastrointestinal tract to another.^[^7] The gastric absorption of most drugs is insignificant under physiological conditions. The limited surface area (0.1 – 0.2 m²) covered by a thick layer of mucus coating, the lack of villi on the mucosal surface and the short residence time of most drugs in the stomach are the physiological conditions responsible for the insignificant absorption of drugs in the stomach.^{[8, 9,10]}

Fig1: Anatomy of stomach

Phases of Gastric Retention:^[^{11, 12]}

There are four phases of gastric retension as following

Phase I: (Basal phase) is a period of no contraction and it lasts from 40 to 60 minutes.

Phase II: (Preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions.

Phase III: (Burst phase) Short period of intense, contraction lasting from 4 to 6 minutes

Phase IV: (Traditional phase) that occurs between phase III and phase I for two consecutive cycles for 0 – 5 minutes.

Drugs Candidates suitable for FDDS^[^13-16]

1)Drugs that have narrow absorption window in GIT (e.g. L-DOPA, paminobenzoic acid, furosemide, riboflavin)

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

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

4) Drugs that disturb normal colonic microbes (e.g. antibiotics used for the eradication of Helicobacter pylori, such as tetracycline, clarithromycin, amoxicillin)

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

Advantages of floating drug delivery system^[^17,
18]

§ Used for local action in the stomach.

§ In the treatment of peptic ulcer disease.

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

§ Reduced dosing frequency.

§ Improved bioavailability of the drug.

§ Used for drugs which are unstable in intestinal fluids

§ Used to sustain the delivery of drug

§ Used for maintaining the systemic drug concentration within the therapeutic window

§ Site specific drug delivery is also possible

Disadvantages of floating drug delivery systems^[¹⁷^]

1) There are certain situations where gastric retention is not desirable. Aspirin and non-steroidal

Anti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in

the stomach is unwanted.

2) Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment

should not be formulated in gastroretentive systems.

3) Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well throughout the GI tract will not benefit from incorporation into a gastric retention system.

Mechanism of Floating System^[^19]

Various attempts are made to obtain retention of dosage form in stomach by increasing RT of stomach. These include introduction of different gastro retentive dosage forms as floating system (gas generating system and swelling and expanding system), mucoadhesive system, high density systems, modified shape systems, gastric-empting delaying devices and co-administration of gastric empting delaying drugs. From this the floating drug delivery system (FDDS) is most commonly used. FDDS have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolong period of time. When the system floats on gastric contents the drug is released slowly at the desire rate from the system. After the drug is released, the residue is emptied from the stomach. This results in increasing the gastric empting time of stomach as well as controlling the fluctuations in PDC.

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

Where,

F= total vertical force,

Df = fluid density

Ds = object density

V= volume

G= acceleration due to gravity

Fig 2: The mechanism of floating systems

Types of floating drug delivery systems (FDDS)

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.

Floating System^[^20]

It is a low density approach which has a bulk density lower than gastric fluids and hence remains buoyant in the stomach, releasing the drug slowly without affecting the gastric emptying rate for a prolonged period of time. After the drug is released from the stomach, the delivery system is expelled. Based on the buoyancy mechanism, floating systems are classified as follows

I. Effervescent systems

II. Non-Effervescent systems

I) Effervescent systems

The main mechanism involved in this system is the production of carbon-dioxide gas due to reaction between sodium bicarbonate, citric acid and tartaric acid. The gas produced results in the reduction of density of the system thereby making it to float on the gastric fluids. These systems are further classified as below.

i.) Volatile liquid containing systems:

These are further categorized as

a. Intragastric floating gastrointestinal drug delivery system:

This system contains afloatation chamber which contains vacuumor an inert, harmless gas and a micro porous compartment enclosing drug reservoir. It is shown in Figure 3.

Fig 3: Showing intragastric floating gastrointestinal drug Delivery system^[^20]

b. Inflatable gastrointestinal delivery system:

These systems possess inflatable chamber containing liquid ether which gasifies at body temperature to inflate the stomach. Inflatable chamber contains bio erodible polymer filament (e.g., copolymer of polyvinyl alcohol and polyethylene) that gradually dissolves in gastric fluid and finally causes inflatable chamber to release gas and collapse. It is shown in Figure 4.

Fig 4: showing inflatable gastrointestinal delivery system^[^20]

c. Intragastric-osmotically controlled drug delivery system:

It is composed of osmotic pressure controlled drug delivery device and an inflatable floating capsule. In the stomach, inflatable capsule disintegrates and releases the osmotically controlled drug delivery system which contains two components; drug reservoir compartment and osmotically active compartment. It is shown in Figure 5.

Matrix tablets

It may be formulated as a single layer matrix tablet by incorporating bicarbonates in matrix forming hydrocolloid gelling agent or a bilayer matrix tablet with gas generating matrix as one layer and drug being the second layer. It can also be formulated as triple layer matrix tablet with gas generating matrix as one layer and 2 drug layers.

Gas generating systems

These systems utilize effervescent compounds like sodium bicarbonate, citric acid and tartaric acid. It is further divided as follows

d).Floating capsules:

These are prepared by formulating mixture of sodium bicarbonate and sodium alginate. On exposure to acidic environment, carbon dioxide gas is generated which is trapped in the hydrating gel network and makes the system to float.

e).Floating pills:

These are a type of sustained release formulations which are basically multiple unit type of dosage forms. The Sustained release pill is surrounded by two layers. Outer layer consists of swellable membrane and the inner layer consists of effervescent agents. The system swells due to swellable membrane and then sinks. Due to presence of effervescent agents, CO2 is released and the system floats.

f).Floating systems with ion exchange resins:

The most common approach for formulating these systems involves resin beads loaded with bicarbonate. This is then coated with ethyl cellulose which is usually insoluble but permeable to water. This causes carbon dioxide to release and the system to float^{[21, 22]}

II) Non- Effervescent systems

These are a type of floating gastroretentive drug delivery systems in which gel forming hydrocolloids, polysaccharides and matrix forming polymers like polycarbonate, polystyrene, polymethacrylate etc. are used. These are further classified as follows

i. Hydrodynamically balanced systems

This system contain drug with gel forming hydrocolloids formulated into a single unit dosage form. Upon contact with gastric fluids, the hydrocolloids swell to form a gel barrier which facilitates the system to remain buoyant in the stomach.

ii. Microballoons / hollow microspheres

These systems contain outer polymer shell loaded with drug. The outer polymer shell is made up of polymers like polycarbonate, cellulose acetate, calcium alginate, agar, etc. Buoyancy lag time and drug release from the system is dependent on the quantity of polymers used in the formulation. These are prepared by emulsion-solvent diffusion method. The steps involved are summarized in Figure 6

i) Alginate beads

Talukdar and Fassihi developed multiple-unit floating system based on cross-linked beads. These are formulated using calcium and low methoxylated pectin or calcium low methoxylated pectin and sodium alginate. In this type, sodium alginate solution is added to aqueous solution of calcium chloride which causes precipitation of calcium alginate (beads). These beads are then separated and dried by air convection and freeze dried. This results in the formation of a porous system which remains buoyant in the stomach.^[^{23,
24, 25]}

ii) Layered tablets

These may be of single layer or double layered.

a. Single layered floating tablets: This type of tablets contain drug mixed with gel forming hydrocolloids and other excipients. Upon contact with gastric fluids, the hydrocolloids swell and maintain bulk density less than one and hence remain buoyant in the stomach.5 It is shown in Figure 7.

b. Double layered floating tablets:

This type of tablets contain two layers, one of which is immediate releasing layer and the other is sustained release layer containing drug and hydrocolloids which remains in the stomach for a prolonged period. It is shown in figure 8.

Evaluation of floating drug delivery

Characterization of Parameter

Size and Shape Evaluation^[^{31, 32]}

The particle size and shape plays a major role in determining solubility rate of the drugs and thus potentially its bioavailability76. The particle size of the formulation was determined using Sieve analysis, Air elutriation (BahcoTM) analysis, Photo analysis, Optical counting method, microscope, Electro resistance counting methods (Coulter counter), Sedimentation techniques, Laser diffraction methods, ultrasound attenuation spectroscopy , Air Pollution Emissions Measurements etc.

Floating Properties^[^33]

Effect of formulation variables on the floating properties of gastric floating drug delivery system was determined by using continuous floating monitoring system and statistical experimental design.

Surface Topology^[^34]

The surface topography and structures were determined using scanning electron microscope (SEM)operated with an acceleration voltage of 10k.v, Contact angle meter, Atomic force microscopy (AFM), Contact profiliometer.

Determination of Moisture Content^[^{35, 36]}

The water content per se is seldom of interest. Rather, it shows whether a product intended for trade and production has standard properties such as

Storability

Agglomeration in the case of powders

Microbiological stability

Flow properties, viscosity

Dry substance content

Concentration or purity

Commercial grade (compliance with quality agreements)

Thus moisture content of the prepared formulations was determined by Karl fisher titration, vacuum drying, Thermo gravimetric methods, Air oven method, Moisture Meters, Freeze drying as well as by physical methods.

Swelling Studies^[^37]

Swelling studies were performed to calculate molecular parameters of swollen polymers. Swelling studies was determined by using Dissolution apparatus, optical microscopy and other sophisticated techniques which include H1NMRimaging, Confocal laser scanning microscopy (CLSM), Cryogenic scanning electron microscopy (Cryo-SEM), Light scattering imaging (LSI) etc. The swelling studies by using Dissolution apparatus was calculated as per the following formula.

Weight of wet formulations

Swelling ratio =___________________________

Weight of formulations

Determination of Drug Content^[^{38, 39]}

Percentage drug content provides how much amount of the drug that was present in the formulation. It should not exceeds the limits acquired by the standard monographs. Drug content was determined by using HPLC,HPTLC methods, Near infrared spectroscopy (NIRS), Micro titrimetric methods, Inductively Coupled Plasma Atomic Emission Spectrometer (ICPAES) and also by using spectroscopy techniques.

Percentage Entrapment efficiency^[^38]

Percentage entrapment efficiency was reliable for quantifying the phase distribution of drug in the prepared formulations. Entrapment efficiency was determined by using three methods such as Micro dialysis method, Ultra centrifugation, and pressure Ultra filtration.

In – Vitro Release studies^[^{40, 41]}

In vitro release studies were performed to provide the amount of the drug that is released at a definite time period. Release studies were performed by using Franz diffusion cell system and synthetic membrane as well as different types of dissolution apparatus.

Fourier Transform Infrared Analysis(FT-IR)^[42]

Fourier transform infrared spectroscopy (FT-IR) is a technique mostly used to identify organic, polymeric, and some inorganic materials as well as for functional group determination. Fourier Transform Infrared Analysis (FT-IR) measurements of pure drug, polymer and drug-loaded polymer formulations were obtained on FT-IR. The pellets were prepared on KBr-press under hydraulic pressure of 150kg/cm2; the spectra were scanned over the wave number range of 3600 to 400 cm-1 at the ambient temperature.

Differential Scanning calorimetry(DSC) ^[43-45]

DSC is used to characterize water of hydration of pharmaceuticals. Thermo grams of formulated preparations were obtained using DSC instrument equipped with an intracooler. Indium/Zinc standards were used to calibrate the DSC temperature and enthalpy scale. The sample preparations were hermitically sealed in an aluminum pan and heated at a constant rate of 10ºC/min; over a temperature range of 25ºC - 65ºC. Inert atmosphere was maintained by purging nitrogen gas at the flow rate of 50ml/min.

CONCLUSION:

Among various types of gastroretentive drug delivery system floating drug delivery system (FDDS) is most promising. 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 drug delivery systems have emerged as an efficient means of enhancing the bioavailability and controlled drug delivery of many drugs. Floating drug delivery system can provide sufficient gastric retention which may help to provide sustained release dosage form with enhanced absorption.

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Received on 04.01.2016 Accepted on 30.01.2016

Asian J. Pharm. Res. 6(1): January -March, 2016; Page 31-38

DOI: 10.5958/2231-5691.2016.00006.X

Sr. no.	Natural Polymer	Uses
1	Alginate	Binder and disintegrant in tablet, Diluent in capsule, thinking and suspending agents in creams and pates and gels
2	Pectin	Adsorbent and bulk forming agents, an emulsion stabilizer,
4	Xanthan gum	To use as suspending agent, too increase bioadhesive strength in vaginal formulations, thinking agent in shampoo in cosmetics
5	Carbomer/ carbopol	Suspending or viscosity increasing agent, emulsifying agent in the preparation of oil- in- water emulsion
6	Citric acid	Used experimentally adjust the pH of tablet matrices, preparation of effervescent granules, sequestering agent and antioxidant synergist,
7	HPMC	Suspending and thickening agent, emulsifier and stabilizing agent in topical gels, adhesive in plastic bandages
8	Corn Oil	Solvent for intramuscular injection, as a oral nutritional supplement, used as edible oil, used in tablets or capsules in oral administration