INTRODUCTION:

Despite tremendous advancement in drug delivery oral route of administration is increasingly being used for the delivery of the therapeutic agents because the low cost of therapy and the ease of administration ^[1].FDDS is a class of gastro retentive drug delivery system. It has the low density systems that have sufficient buoyancy to float over the gastric content and remain in the stomach for a prolong period ^[2]. In these review article,the various aspects of pharmaceutical floating drug delivery system(FDDS) were complied together and the target ordinance are specifically the M.Pharm and B Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

CLASSIFICATION OF FDDS

Based on mechanism of buoyancy FDDS can be classified into ^[3]

(A) Single unit floating dosage systems:

a) Non-effervescent system

b) Effervescent system (gas-generating system)

(B) Multiple unit floating dosage systems:

a) Non-effervescent system

b) Effervescent system

c) Raft forming system

d) Hallow microsphere

e) Magnetic system

BASIC GASTRO INTESTINAL TRACT PHYSIOLOGY

Anatomically the stomach is divided into three regions. 1. The proximal part fundus which acts as a reservoir for undigested material. 2. Antrum is the main site for mixing motions and it act as a pump for gastric emptying by propelling action^[4]. Fig.1 below shows anatomy of a stomach..

Figure 1: Anatomy of stomach (Adopted from Shah SH, Patel JK, Patel NV, “Stomach specific Floating drug delivery system: A Review”, Int. J. Pharm. Res., 2009)

Gastric emptying occur during fasting as well as fed states the pattern of motility is distinct in the two states.During the fasting state an interdigestives series of electrical events taken place, which cycle both through stomach and intestine every two to three hours ^[5].This is called inter digestive myloelectric cycle or migrating myloelectric cycle (MMC) which is divided in 4 phases Fig.2 shows phases of gastric emptyting ^[6].

Figure 2 :Phases of gastric emptying (Adopted from Groning R, Heun G. Dosage forms with controlled gastrointestinal transit. Drug Dev Ind Pharm 1984; 10:527‐GroningR, Heun G. Dosage forms with controlled gastrointestinal transit. Drug Dev Ind Pharm 1984)

MECHANISM OF FLOATING TABLETS

Figure 3 (a) Drug release mechanism (b) Floating drug delivery system (Adopted from Ponchel G, Irache JM. Specific and non-specific bioadhesive particulate system for oral delivery to the gastrointestinal tract. Adv Drug Del Rev. 1998).

FDDS has 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. F= Fbuoyant-Fgravity=(DF-Ds) gV. Where, F=total vertical force, DF=object density, V = volume G=acceleration due to gravity^[7]Fig. 3 and Fig .4 shows Drug release mechanism and mechanism of floating drug delivery system^[8].

Figure 4 Mechanism of floating system (Adopted from Rouge N, Buri P, Doelker E. Drug absorption sites in the gastrointestinal tract and dosage forms for site specific delivery. Int J Pharm 1996 )

Approaches to Gastro Retention

Several techniques are reported in the literature to increase the gastric retention of drugs.

High Density Systems

These systems, which have a density of~3g/cm3, are retained in the rogue of stomach and capable of withstanding its peristaltic movements. The only major drawback with these systems is that it is technically difficult to manufacture them with a largeFig.5: Swellable Tablet in Stomach amount of drug (>50%) and achieve required density of 2.4-2.8g/cm3. Diluents such as barium sulphate (density= 4.9), zinc oxide, titanium oxide, and iron powder must be used to manufacture such high density formulation ^[9]

Figure 5 Swellable Tablet in Stomach amount of drug (>50%) and achieve required density (Adopted from arora s.an updated review on floating drug delivery system (2005) ;6(3): e372-e390)

Swelling and Expanding Systems

These systems are also called as “Plug type system”, since they exhibit tendency to remain logged in the pyloric sphincters. These polymeric matrices remain in the gastric cavity for several hours even in fed state.

Figure 6: Swellable Tablet in Stomach.(Adopted from Wilson cg, Washington n. the stomach: its role in oral drug delivery. in: rubinstein, mh., (ed.). physiological pharmaceutics: biological barriers to drug absorption. Ellis Harwood, Chechester, 1989: 47‐70.)

Fig.6: Swellable Tablet in Stomach. By selection of polymer with the proper molecular weight and swelling properties controlled and sustained drug release can be achieved. Upon coming in contact with gastric fluid, the polymer imbibes water and swells. The extensive swelling of these polymers is salt of the presence of physical and chemical cross links in the hydrophilic polymer network. These cross link prevents the dissolution of polymer dosage form^[10]. A high degree of cross linking retards the swelling ability of the system and maintains its physical integrity for prolonged period. On the other hand, a low degree of cross linking results in extensive swelling followed by the rapid dissolution of polymers.

Incorporating Delaying Excipients

Another delayed gastric emptying approach of interest include feeding of digestible polymers or fatty acid salts that charges the motility pattern, of the stomach to a fed stage thereby decreasing the gastric emptying rate and permitting considerable prolongation of the drug release. Prolongation of GRT of drug delivery system consists of incorporating delaying excipients like tri ethanolamine myristate in a Delivery system.

Modified Systems

Systems with non-disintegrating geometric shape moulded from silastic elastomers or extruded from polyethylene blends, which extend the GRT depending on size, shape and flexural modules of drug delivery device.

Mucoadhesive andBioadhesive Systems

Bioadhesive drug delivery systems are used to localize a delivery device within the lumen to enhance the drug absorption in a site specific manner ^[11]. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach. Some of the almost promising excipients that have been used commonly in these systems include polycarbophil, carbopol, lectins, chitosan, CMC and gliadin, etc.

FACTORS AFFECTING GASTRIC RESIDENCE TIME OF FDDS

a) Formulation factors

Size of tablets ^[12]

Retention of floating dosage forms in stomach depends on the size of tablets. Small tablets are emptied from the stomach during the digestive phase, but large ones are expelled during the house keeping waves. Floating and nonfloating capsules of 3 different sizes having a diameter of 4.8 mm (small units), 7.5 mm (medium units), and 9.9mm (large units), were formulated and analyzed for their different properties. It was found that floating dosage units remained buoyant regardless of their sizes on the gastric contents throughout their residence in the gastrointestinal tract, while the nonfloating 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 nonfloating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase.

Density of tablets

Density is the main factor affecting the gastric residence time of dosage form. A buoyant dosage form having a density 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. A density of less than 1.0g/ml i.e. less than that of gastric contents has been reported. However, the floating force kinetics of such dosage form has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyancy capabilities.

Shape of tablets

The shape of dosage form is one of the factors that affect its gastric residence time. Six shapes (ring tetrahedron, cloverleaf, string, pellet, and disk) were screened in vivo for their gastric retention potential. The tetrahedron (each leg 2cm long) rings (3.6 cm in diameter) exhibited nearly 100% retention at 24 hr.

Viscosity grade of polymer

Drug release and floating properties of FDDS are greatly affected by viscosity of polymers and their interaction. Low viscosity polymers (e.g., HPMC K100 LV) were found to be more beneficial than high viscosity polymers (e.g., HPMC K4M) in improving floating properties. In addition, a decrease in the release rate was observed with an increase in polymer viscosity.

b) Idiosyncratic factors

Gender

Women have slower gastric emptying time than do men. Meanambulatory GRT in meals (3.4±0.4 hours) is less compared with their age and race‐matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface4.

Age

Low gastric emptying time is observed in elderly than do in younger subjects.Intrasubject and intersubject variations also are observedin gastric and intestinal transit time. Elderly people,nb nn nn especially those over 70 years have a significantly longer GRT.

ADVANTAGES OF FDDS ^[13]

· Enhance the bioavailability.

· Sustained drug delivery/reduced frequency of dosing.

· Targeted therapy for local aliments in the upper GIT.

· Reduced fluctuations of drug concentrations.

· Improve selectively in receptor activation.

· Reduced counter-activity of the body.

· Extend effective concentration.

· Minimized adverse activity at the colon.

DISADVANTAGES OF FDDS

· The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the system ^[14].

· These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently.

· Not suitable for drugs that have solubility for stability problem in GIT ^[15].

Polymers used in formulation of FDDS ^[16]

· Hydrochlorides: - HPMC 1000, HPMC 4000, sodium alginate, HPC-1, HPMC, PVP, HPC-H, HPC-M, carbopol .

· Inert fatty material:- Beeswax, long chain fatty alcohol.

· Effervescent agents:- sodium bicarbonate, citric acid, tartaric acid.

· Release rate accelerates:-Eg. lactose, mannitol.

· Release rate retardants:-talc, dicalcium phosphate

· Buoyancy increasing agents. Eg. Ethyl cellulose.

· Low density material:- polypropylene foam powder

METHODOLOGY ^[17]

1. Direct compression technique.

2. Melt granulation technique.

3. Melt solidification technique.

4. Spray drying technique.

5. Wet granulation technique.

WIDELY USED DRUGS AND DOSAGE FORM ^[18]

Table 1. WIDELY USED DRUGS AND DOSAGE FORM

S.NO	DOSAGE FORMS	DRUGS
1	MICRO SPHERE	Aspirin, griseofulvin, ibuprofen
2	GRANULES	Diclofenac sodium, indomethacine
3	CAPSULE	Diazepam, L-dopa, furosemide
4	FILMS	Cinnarizine
5	TABLET and PILLS	Quinidine gluconate, sotalol, atenolol

EVALUATION PARAMETERS OF FDDS ^[19]

Different studies reported in the literature indicate that pharmaceutical dosage forms exhibiting gastric residence in vitro floating behavior show prolonged gastric residence in vivo .Although, 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 introduction of the tablet into the medium and its rise 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 or flotation time. These tests are usually performed in simulated gastric fluid or 0.1 mole Lit^‐1 HCl maintained at 37⁰C, by using USP dissolution apparatus containing 900 ml of 0.1molar HCl as the dissolution medium.

3) Drug release

The test for in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 37⁰C. Dissolution tests are performed using the USP dissolution apparatus. Samples are withdrawn periodically from the dissolution medium, replaced with the same volume of fresh medium each time, and then analyzed for their drug contents after an appropriate dilution. Recent methodology as described in USP XXIII states that the dosage unit is allowed to sink

to the bottom of the vessel before rotation of blade is started. A small, loose piece of non-reactive material such as not more than a few turns of wire helix may be attached to the dosage units that would otherwise float. However, standard dissolution methods based on the USP or British Pharmacopoeia (BP) have been shown to be poor predictors of in vitro performance for floating dosage forms.

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

Drug loading is assessed 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 spectrophotometry. 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 an cross‐sectional morphology (surface characterization) is done by scanning electron microscope. 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.

5) Resultant weight determination

Bulk density and floating duration have been the main parameters to describe the adequacy of a dosage form’s buoyancy Although single density determination does not predict the floating force evolution of the dosage form because the dry material of it is made progressively reacts or interacts with in the gastric fluid to release its drug contents. So to calculate real floating capabilities of dosage form as a function of time a novel method has been conceived. It operates by force equivalent to the force F required to keep the object totally submerged in the fluid. This force determines the resultant weight of the object when immersed and may be used to quantify its floating or non floating capabilities. The magnitude and direction of the force and the resultant weight corresponds to the Victoria sum of buoyancy (Fbuoy) and gravity (Fgrav) forces acting on the objects as shown in the equal

F = Fbuoy – Fgrav

F = dfgV – dsgV = (df‐ds) gV

F = (df – M/V) gV

In which the F is total vertical force (resultant weight of the object), g is the acceleration due to gravity, df if the fluid density, ds is the object density is the object mass and V is the volume of the object.

6) Weight gain and water uptake (WU)

Weight gain or water uptake can be studied 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 = (Wt – Wo) X 100 / Wo In which Wt and Wo are the weights of the dosage form at time t and initially, respectively^[20].

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 are allowed to fast overnight with free access to water, and a radiograph is 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 is administered by natural swallowing followed by 50 mL of water. The radiographic imaging is taken from each animal in a standing position, and the distance between the source of X‐rays and the animal should kept constant for all imaging, so that the tablet movement could be easily noticed^[21].Gastric radiography was done at 30‐min time intervals for a period of 5 h using an X‐ray machine. Gamma scintigraphy is a technique whereby the transit of a dosage form through its intended site of delivery can be non‐invasively imaged in vivo via the judicious introduction of an appropriate short lived gamma emitting radioisotope. The inclusion of a γ‐emitting radionucleide in a formulation allows indirect external observation using a γ‐camera or scintiscanner. But the main drawback of γ‐scintigraphy are the associated ionizing radiation for the patient, the limited topographic information, low resolution inherent to the technique and the complicated and expensive preparation of radiopharmaceutical.

8) Pharmacokinetic studies

Pharmacokinetic studies include AUC(Area under Curve),C max ,and time to reach maximum plasma concentration were estimated using computer. Statistical analyses were performed using a Student test with p, 0.05 as the minimal level of significance.^[22]

9) Specific Gravity

Displacement method is used to determine the specific gravity of floating system using benzene as a displacing medium.^[23]

CONCLUSION

Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extend the time for drug absorption. FDDS promises to be a potential approach for gastric retention. Floating tablets 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^. Although there are number of difficulties to be worked out to achieved prolonged gastric retention, a large number of companies are focusing toward commercializing this technique. With this complication we ensure that the content of the article would be a useful tool to understand the in-depth knowledge of the subject concerned.

ACKNOWLEDGEMENT

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors are also grateful to the e-library of Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, 490001 for providing UGC-INFLIBNET facility. The authors acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015

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Received on 20.02.2017 Modified on 11.03.2017

Research J. Pharm. and Tech. 2017; 10(4): 1209-1214.

DOI: 10.5958/0974-360X.2017.00217.7