INTRODUCTION:

Oral delivery of drug is considerably the most preferable route of drug delivery due to ease of administration, patient compliance and flexibility in formulation. Floating drug delivery system (FDDS) or hydrodynamically controlled system is low density system that has sufficient buoyancy to float over the gastric contents without affecting the gastric emptying rate for an extended period of time. The gastric retention is a better approach for the drug delivery in which desirable for optimizing the therapeutic benefit of drug. While the system is floating on the gastric contents, the drug slowly released at the preferred rate from the system which results in an increased GRT and a better control of the fluctuations in plasma drug concentration. ^1-3

Received on 02.01.2015 Modified on 09.01.2015

Research J. Pharm. and Tech. 8(4): April, 2015; Page 490-495

DOI: 10.5958/0974-360X.2015.00082.7

PHYSIOLOGICAL FACTORS AFFECTING GASTRIC RETENTION

Density:

The buoyancy property depends on the density of a dosage form which affects the gastric emptying rate. A buoyant dosage form is supposed to have a density of less than that of the gastric fluids floats.

Size:

Dosage form having a diameter of more than 7.5 mm are reported to have an increased gastric residence time compared with those having a diameter of 9.9 mm. Gastric retention time of an dosage form in the fed state can also be influenced by its size.

Shape of dosage form:

The six different shapes tested, i.e., ring, tetrahedron, cloverleaf, disk, string and pellet displayed different gastric retention times, due to their size and geometry of the systems. The tetrahedron resides in the stomach for longer period of time.⁴

Effect of Buoyancy:

It was found that floating dosage units remain buoyant in spite of their sizes on the gastric contents throughout their residence in the gastrointestinal tract, while the non floating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastro‐duodenal junction were protected from the peristaltic waves during digestive phase while the non-floating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase.⁵

Nature of Meal:

The feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus falling the gastric emptying rate and prolong the release of drug.

Caloric Content:

Gastric residence time (GRT) can be increased by 4 to 10 hours with a meal that is high in proteins and fats.

Frequency of Feed:

The GRT can increase by over 400 minutes when successive meals are given compared with a single meal.

Gender:

Mean ambulatory GRT in males (3.4±0.6hours) is less compared with the age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface.

Age:

Elderly people (especially those over 70) have a significantly longer GRT.

Posture:

GRT can differ between supine and upright ambulatory states of the patient. In case of 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.⁶

Table 1: List of natural polymers used in floating drug delivery system

S. No	Polymer Name	Basic chain	Source	Advantages in Floating Drug delivery
1	Chitosan	Deacetylated P-1, 4-N-acetyl-1- D-glucosamine	Shell of marine invertebrates	Chitosan granules and chitosan-laminated preparations might be helpful in developing drug delivery systems that will reduce the effect of gastrointestinal transit time.^10,11
2	Xanthan gum	λ-(1,4)-linked D-glucose	Fermentation of glucose by Xanthomonas campestris	Used as a tablet excipient to increase or decrease the drug release rate but not much has been reported regarding its use for sustained drug release. It has the potential advantage of drug release with zero order release kinetics.¹²
3	Alginates	1-4' linked-ß-D-mannuronic acid and β-L-glucuronic acid	Laminaria hyperborea,Ascophyllum nodosum, Macrocystis pyrifera etc.	It is practically insoluble in ethanol (95%), ether, chloroform and slowly soluble in water, forming viscous colloidal solution. Good properties of alginates have attracted a lot of concern towards the development of different floating dosage forms.¹³
4	Guar gum	λ-D-mannopyranose	Endosperm of the seeds of Cyamopsis tetragonolobus	Srivastava et al developed floating matrix tablets of atenolol using polymers such as hydroxypropyl methylcellulose (K4M, K15M), guar gum and sodiumcarboxy methylcellulose to prolong gastric residence time and increase in drug bioavailability.^14,15
5	Gellan gum	D-glucose, D-glucuronic acid and rhamnose in ß-1, 4 linkage	Pseudomonas elodea	Gellan gum has an wonderful flavor release, high gel strength, an excellent stability, process flexibility, high clarity, good film former and thermally reversible gel characteristics and has been considered as a potential carrier for different floating dosage forms by various investigators.¹⁶
6	Starch	α-(1,4)-linked D-glucose and α-(1,6)-linked D-glucose	Storage polysaccharide in plants	Starch has enormous applications in the fabrication of different floating dosage forms.¹⁷
7	Pectin	λ-(1,4)- linked D-galacturonic acid	Citrus peel, apple pomace, sugar beet pulp etc.	The Pectin floating beads obtained were porous and hollow in nature with bulk density less than 1. In-vivo studies by gamma scintigraphy determined on rabbits showed gastroretention of beads upto 5 hrs. ^{18, 19}

TYPES OF FLOATING DRUG DELIVERY SYSTEM:

There are two types of floating drug delivery systems based on the mechanism of buoyancy:

1. Effervescent System

2. Non- Effervescent System

Effervescent System:

Volatile liquid containing system:

The Gastric residence time of a drug delivery system can be sustained by incorporating an inflatable chamber containing a liquid, e.g., ether, cyclopentane, that gasifies at body temperature to cause the inflatation of the chamber in the stomach. The device may also consist of a bioerodible plug made up of Polyvinyl alcohol, Polyethylene etc. that gradually dissolves causing the inflatable chamber to discharge gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems from the stomach.²⁰

Gas-generating Systems:

These systems use effervescent reactions between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO₂, which gets entrapped in the jellified hydrocolloid layer of the systems thus decreasing its specific gravity and making it to float over gastric content.²¹

Non-Effervescent System:

The Non-effervescent systems are based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GIT. The most widely used excipients in non effervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, hydrophilic gums, polysaccharides and matrix forming materials such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bioadhesive polymers such as Chitosan and carbopol.

The various types of this system are as:

Single Layer Floating Tablets:

These types of tablets are developed by intimate mixing of drug with a gel forming hydrocolloid, which swells in contact with gastric fluid having bulk density of less than unity. They are formulated by intimate mixing of drug with low-density enteric materials such as HPMC.

Bi-layer Floating Tablets:

A bi-layer tablet is consist of two layers one immediate release layer which releases initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it floats in the stomach

Alginate Beads:

Multi-unit floating dosage forms were developed from freeze dried calcium alginate. Spherical beads of approximately 2.5 mm diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing precipitation of calcium alginate leading to formation of porous system, which can maintain a floating force for over 12 hours. When compared with solid beads, which gave a short residence time of 1 hour, and these floating beads gave a prolonged residence time of more than 5.5 hours.

Hollow Microspheres:

Hollow microspheres (micro balloons), loaded with drug in their outer polymer shells are prepared by a novel emulsion solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer is poured into an agitated aqueous solution of PVA that is thermally controlled at 40°C. The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane forms an internal cavity in microsphere of polymer with drug. The micro balloons float continuously over the surface of acidic dissolution media containing surfactant for more than 12 hours.^{22, 23}

Advantages and Disadvantages of Floating drug delivery system ²⁴

S.No	Advantages	Disadvantages
1	These systems are mostly useful for drugs that are exclusively absorbed from stomach or the proximal part of the small intestine, e.g., riboflavin and furosemide.	A high level of fluid in the stomach is required for drug delivery to float and work powerfully
2	The fluctuations in plasma drug concentration 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.	Drugs having stability and solubility problems in GIT are not suitable for these types of systems.
3	The effectiveness of the drugs administered utilizing the sustained release principle of floating formulation has been found to be independent of the site of particular drugs.	Drugs such as nifedipine, which under goes first pass metabolism may not be advantageous for the preparation of these types of systems.
4	Complete absorption of the drug from the floating dosage form is expected even at the alkaline pH of the intestine. The dissolution of the drug in gastric fluid occurs and then the dissolved drug is available for absorption in the small intestine after emptying of the stomach contents.	Drugs which are irritant to Gastric mucosa are also not desirable
5	Reduced absorption is predictable when there is forceful intestinal movement and a shorted transit time as might occur in certain type of diarrhea. Under such conditions it may be helpful to keep the drug in floating condition in stomach to obtain a comparatively better response.	Drugs that are unstable in the acidic environment of the stomach are not suitable in this type of systems
6	The drugs that having bioavailability due to site‐specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thus maximize their absorption. A considerable 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%).

IN VITRO AND IN VIVO EVALUATION PARAMETERS FOR FDDS:

Different studies reported in the literature shows that pharmaceutical dosage forms exhibiting gastric residence in vitro floating behavior show extended gastric residence in vivo while in vitro floating behavior alone is not sufficient proof for efficient gastric retention so in vivo studies can provide definite proof that prolonged gastric residence is obtained.

1) Hardness, friability, assay, content uniformity (Tablets):

These tests are performed as per described in specified monographs.

2) Floating lag time and total floating time determination:

The time between the beginning of the dosage form into the medium and its go up to upper one third of the dissolution vessel is termed as floating lag time and the time for which the dosage form floats is termed as the floating time. These tests are usually performed in simulated gastric fluid or 0.1 mole/liter HCl maintained at 37^oC in USP dissolution apparatus containing 900 ml of 0.1 molar HCl as the dissolution medium.²⁵

3) Drug Release:

The in vitro Dissolution tests are performed using the USP dissolution apparatus and are usually carried out in simulated gastric and intestinal fluids maintained at 37⁰ C. The samples are withdrawn periodically from the dissolution medium and replaced with the same volume of fresh medium each time, and then analyzed for their drug contents by standard method after an appropriate dilution.

4) Drug loading, drug entrapment efficiency, particle size analysis, surface characterization, micromeritics studies and percentage yield (for floating microspheres and beads):

Drug loading is determined by crushing accurately weighed sample of beads or microspheres in a mortar and added to the appropriate dissolution medium which is then centrifuged, filtered and analyzed by various analytical methods, like spectrophotometric. The percentage drug loading is calculated by dividing the amount of drug in the sample by the weight of total beads or microspheres. The particle size and the size distribution of beads or microspheres are determined in the dry state using the optical microscopy method. The external and cross‐sectional morphology (surface characterization) is done by scanning electron microscope (SEM). The measured weight of prepared microspheres was divided by total amount of all non‐volatile components used for the preparation of microspheres, which will give the total percentage yield of floating microspheres.^{26, 27}

6) Weight Gain and water Uptake (WU):

Weight gain or water uptake can be calculated by considering the swelling behavior of Floating dosage form. The study is done by immersing the dosage form in simulated gastric fluid at 37^oC and determining the dimensional changes like tablet diameter and/ or thickness at regular 1‐h time intervals until 24 h, the tablets were removed from beaker, and the excess surface liquid was removed carefully using the paper. The swollen tablets were then reweighed and WU is measured in the terms of percent weight gain, as given by equation

WU = (W_t – W_o) X 100 / W_o

Where, W_tand W_o are the weights of the dosage form at time t and initially, respectively.²⁸

7) X-Ray/ Gamma Scintigraphy

For in vivo studies, X‐Ray/Gamma Scintigraphy is the main evaluation parameter for floating dosage form. In each experiment, the animals were allowed to fast overnight with free access to water, and a radiograph was made just before the administration of the floating tablet to ensure the absence of radio‐opaque material. Visualization of dosage form by X‐ray is due to the inclusion of a radio‐opaque material. The formulation was administered by natural swallowing followed by 50 ml of water. The radiographic imaging was taken from each animal in a standing position, and the distance between the source of X‐rays and the animal should be kept constant for all imaging, so that the tablet movement could be easily noticed. Gastric radiography was done at 30‐min time intervals for a period of 5 h using an X‐ray machine.^{29, 30}

8) Pharmacokinetic Studies

Pharmacokinetic studies include AUC (Area under Curve), C_max, and time to reach maximum plasma concentration (T_max) were estimated using a computer. Statistical analyses were performed using a Student t test with p, 0.05 as the minimal level of significance.

9) Specific Gravity

The specific gravity of floating system is determined by displacement method by using benzene as a displacing medium.³¹

CONCLUSION:

In this review, all the major aspects of FDDS were studied. The various types of physiological factors affecting on gastric retention, like density, size and effect of buoyancy etc are discussed in this review and it was found that floating dosage units remain buoyant on the gastric contents throughout their residence in the gastrointestinal tract. In this study, the various drugs explored for various floating dosage forms (tablets, granules and microspheres etc) till now are also discussed and it is concluded that out of various type of dosage forms, the floating tablets, microspheres and granules are widely explored. The various types of natural polymers (as shown in table-1) are also discussed, and it is seen that all these polymers have great importance in FDDS. The two types of FDDS (Effervescent and Non- Effervescent) are also discussed in this study and it is observed that now a day’s both types are currently used. In this study, all the in-vitro and in-vivo evaluation parameters for different types of FDDS are also discussed. The FDDS gives a stable and sustained release dosage form and promises to be a potential approach for gastric retention. Although there are number of difficulties to be worked out in order to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique.

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S. No	Type of dosage form	Drugs used
1	Microspheres Tablets/Pills	Chlorpheniramine maleate, Aspirin, griseofulvin, Acetaminophen, p-nitroaniline, Acetylsalicylic acid, Ibuprofen, Amoxicillin trihydrate, Terfenadine, Ampicillin, Trani-last,Atenolol, Theophylline, Captopril, Isosorbide di nitrate, Sotalol, Isosorbide Mononitrate
2	Films	P-Aminobenzoic acid, Cinnarizine, Pireta-nide, Prednisolone, Quinidine gluconate.
3	Granules	Cinnarizine, Diclofenac sodium , Diltiazem, Indomethacin ,Fluorouracil, Prednisolone Isosorbide mononitrate, Isosorbide dinitrate.
4	Powders	Riboflavin, phosphate, Sotalol, Theophylline.
5	Capsules	Verapamil HCl, Chlordiazepoxide HCl, Diazepam, Furosemide, L-Dopa and benserazide Misoprostol, Propranolol HCl, Ursodeoxycholic acid, Nicardipine