SUSTAINED RELEASE EFFERVESCENT FLOATING BILAYER TABLETS A REVIEW OF NOVEL APPROACH

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FLOATING DRUG DELIVERY SYSTEM
Floating drug delivery systems 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 reliably buoyant on the surface of the meal. Many buoyant systems have been developed based on granules, powders, capsules, tablets, laminated films and hollow microspheres. Floatation of drug delivery system in the drug can be achieved by incorporating floating chamber filled with vacuum, air or inert gas 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. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force is also require to keep the dosage form.

Types of Floating Drug Delivery Systems
Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in the development of FDDS.
A. Effervescent system
a. Volatile liquid containing system
b. Gas generating system
B. Non-effervescent system
a) Alginate beads
b) Hollow microspheres
c) Single layer floating tablets
d) Bilayer floating tablets
e) Colloidal gel barrier system
f) Microporous compartment system 

A. Effervescent FDDS  
a) Volatile liquid containing system: The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber, which contains 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 release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems from the stomach11.  
b) Gas-generating Systems: These buoyant delivery systems utilize 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. 

SUSTAINED RELEASE EFFERVESCENT FLOATING BILAYER TABLETS
Sustained release effervescent floating bilayer tablets is composed of two layers. A layer of sustained release polymer and drug (Sustained release layer) and a layer of effervescent floating components (Floating layer). Such a formulation offers more advantages compared to single layer effervescent floating tablets in terms of stability. Since effervescent components are unstable and incompatible with many potential drug candidates for gastric retention such a approach could be highly beneficial.

Advantages of sustained release bilayer floating tablets
1. This system provides sustained delivery of drugs along with enhanced gastric residence time as this system remains in stomach for many hours via floating.
2. This system finds additional advantages over single layer floating drug delivery system in terms of stability of the formulation.
3. Better patient compliance is achieved due to its ease of administration.
4. It maintains constant blood level.
5. Site specific drug delivery is achieved for the drugs such as Furosemide and Riboflavin which are formulated as floating system.
6. Over all other oral routes these are microbiologically and chemically stable.
  7. Due to higher dose precision and lesser content variation they are the most compatible oral dosage form.
8. They offer the most flexible dosage form.
9. Better suited for large scale production.

Methodology used for bilayer floating tablets [Pujar ND et al.,2012]
1. Oros ® Push Pull Technology
2. L-Oros Tm Technology
3. DUROS Technology
4. Elan Drug Technologies’ Dual Release Drug Delivery System
5. EN SO TROL Technology
6. Rotab Bilayer
7. Geminex Technology     

1. Oros ® Push Pull Technology: Two or three layer system a drug layer and push layer. Drug layer contain drug with other agents and due to this drug is less soluble. Sometimes suspending agent and osmotic agent are also added. The tablet core is surrounded by semi permeable membrane.   
2. L-Oros Tm Technology: Alza developed L-OROS system due to solubility problem. The system contain a drug in dissolved state in a lipid soft gel product which is produced first and then barrier membrane, after which osmotic membrane and semi permeable membrane coat is applied and is then drilled out through external orifice.   
3. DUROS Technology: This technology is also known as miniature drug dispensing system which works like a miniature syringe and release small quantity of drug consistently over a period of time .There is an outer cylindrical titanium alloy reservoir which has high impact strength due to which drug molecules inside it are protected from enzymes.  
4. Elan Drug Technologies’ Dual Release Drug Delivery System: The DUREDASTM Technology provides combination release of drugs together and different release pattern of single drug i.e. it provides sustained release as well as immediate release. This technology provides various advantages i.e. two drug components provide tailored release and its another benefit is that it consist of bilayered tablet technology in which it contain modified as well as immediate release pattern in one tablet. In these different controlled release formulations are combined together.  
5. EN SO TROL Technology: An integrated approach is used by Shire laboratory for drug delivery system which focus on identification and incorporation of enhancer which is identified to form optimized dosage form in controlled release system. By this enhancement in solubility is achieved.  
6. RoTab Bilayer: RoTab bilayer when using is switched to production mode. Dose and compression force is automatically regulated by adjusting filling speed and die table. Hardness is also regulated when required.
7. Geminex Technology: In this drug delivery system at different times more than one drug can be delivered. This technology basically increases the therapeutic efficacy of the drug by decreasing its side effects. It is useful both to industry as well as patient as in single tablet it provides delivery of drug at different rates.

Characterization of bilayer floating tablets [Dixit N.2011]
In-vitro evaluation of floating tablets Evaluation was performed to assess the physicochemical properties and release characteristics of the developed formulations.
Pre-compression parameters
Angle of Repose
In powder, frictional forces can be measured with the help of angle of repose. Angle of repose is the maximum angle which is possible between surface of pile of powder and horizontal plane i.e. height.
tanΘ= h/r Θ=tan-1h/r
Where Θ = Angle of repose, h= height of pile, r = radius of pile. 

Compressibility Index
The propensity of the powder to be compressed is measured by compressibility index and it also helps in measurement of settling property and interparticulate interaction.  
Compressibility index (%) = ρt – ρo* 100 / ρt  
Where ρt = Tapped density gram/ml, ρo = Bulk density gram/ml.

Bulk Density
It is denoted by ρb and is defined as mass of powder divided by bulk volume (The United States Pharmacopeial Convention Stage 6 Harmonization Official December 1, 2012, 616.). 

Tapped Density
An increase in bulk density which is attained after mechanical tapping in measuring cylinder is called as tapped density.  
Tapped density= Weight of powder taken/ Tapped Volume

Hausner Ratio
The propensity of the powder to be compressed is measured by Hausner ratio. Interparticulate interaction and settling property can be measured by Hausner ratio.  
Hausner ratio= Tapped density/ Bulk density Hausner ratio= Vo/Vf
Where, Vo= Unsettled apparent volume, Vf= Final tapped volume. 

Particle Size Distribution
Particle size distribution was done by sieving method.  
Post-compression parameters

Tablet Thickness
In this three tablets are randomly taken and then their thickness and diameter are measured by Vernier calliper or by using calibrated screw gauze. 

Weight Variation Test
Twenty tablets are selected and weighed individually. Then the average weight and standard deviation is calculated. Test passes when not more than two tablets deviate from average weight. 

Hardness
Expressed in kg/cm2 and it is checked using Monsanto hardness tester by randomly picking three tablets. Hardness helps in knowing ability of the tablet to withstand mechanical shock during handling of tablets. 

Friability
Ten tablets are selected and weighed and then placed in friabilator apparatus which rotate at 25 rpm speed for 4 minutes. After 4 minutes tablets are weighed again.
% F= [1-(Wt/W)]*100

where
W– Initial weight of tablet, Wt - Weight of tablet after revolution. If % Friability of tablets is less than 1% is considered acceptable.
Tablet Density t is an important parameter in case of floating tablets. If density is less than (1.004) gastric fluid, than only the tablets will float. It is calculated using formula:
V=πr2h, d = m/v,
r = Radius of tablet, h = crown thickness (g/cc), m = Mass of tablet.

Disintegration Time
In this one tablet is placed in disintegration apparatus containing buffer 0.1N Hcl or PBS pH 6.8 and test is carried out at 37oC. The time taken by tablet to Disintegrate is noted as disintegration time.  
In Vitro Dissolution Studies Dissolution study is performed using USP paddle apparatus by maintaining optimum temperature i.e., 370C at 50 rpm rotational speed. At various time interval 5 ml sample is withdrawn and is replaced with same amount of buffer. 

Floating Lag Time
It is the time interval taken by the tablets to start floating. It should be less than one minute. It is measured by dissolution test apparatus containing 0.1 N Hcl (900ml).

Floating Time  
It is the total time taken by which the tablets remain floating in the media.  
Drug Content Uniformity
Ten tablets are taken and powdered equivalent weight of drug dose is taken and is transferred to volumetric flask and then buffer is added and absorbance is determined using U.V spectrophotometer.

Swelling Study
Initially tablet is weighed (W1) and placed in a glass beaker, containing 200 mL of 0.1 N HCl, maintained in a water bath at 37 ± 0.5 _C. At different time intervals, the tablet is removed and the excess of liquid is carefully removed by a filter paper. The swollen tablet is reweighed (W2). The swelling index (SI) is calculated using the formula  
SI= Wt -W0/W0*100
Wt= (Weight of swollen tablet), W0= (Initial weight of tablet).  
In-vivo evaluation

a) Radiology
 X-ray is widely used for examination of internal body systems. Barium Sulphate is widely used Radio Opaque Marker. So, BaSO4 is incorporated inside dosage form and X-ray images are taken at various intervals to view gastric retention.  
b) Scintigraphy
Similar to X-ray, emitting materials are incorporated into dosage form and then images are taken by scintigraphy. Widely used emitting material is 99Tc.
c) Gastroscopy
Gastroscopy is peroral endoscopy used with fiber optics or video systems. Gastroscopy is used o inspect visually the effect of prolongation in stomach. It can also give the detailed evaluation of GRDDS.  
d) Magnetic Marker Monitoring  
In this technique, dosage form is magnetically marked with incorporating iron powder inside, and images can be taken by very sensitive bio-magnetic measurement equipment. Advantage of this method is that it is radiation less and so not hazardous.  
e) Ultrasonography
Used sometimes, not used generally because it is not traceable at intestine.  f) 13C Octanoic Acid Breath Test
13C Octanoic acid is incorporated into GRDDS. In stomach due to chemical reaction, octanoic acid liberates CO2 gas which comes out in breath. The important Carbon atom which will come in CO2 is replaced with 13C isotope. So time up to which 13CO2 gas is observed in breath can be considered as gastric retention time of dosage form. As the dosage form moves to intestine, there is no reaction and no CO2 release. So this method is cheaper than other.

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