Certain factors should be considered during development of gastroretentive dosage form. They include retention in the stomach according to the clinical demand, convenient intake, and ability to load substantial amounts of drugs with different physicochemical properties and release them in
47 controlled manner, preferably in the stomach.
Various approaches have been pursued to increase the retention of an oral dosage form in the stomach including floating systems, swelling and expanding systems, bioadhesive systems, modified-shape systems, super porous hydrogel, magnetic systems, high-density systems, and delayed gastric emptying devices.
A. FLOATING DRUG DELIVERY
SYSTEM:
Floating systems are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period.
While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased GRT and reduces fluctuation in plasma drug concentration. (Arvind 2003)
Floating drug delivery systems (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. (Sanjay 2003) Most of the floating systems are single-unit, such as the HBS and floating tablets. These systems are unreliable and irreproducible in prolonging residence time in the stomach when orally administered. On the other hand, multiple-unit dosage forms appear to be better suited since they are claimed to reduce the inter-subject variability in absorption and lower the probability of dose-dumping. (Brahma N 2000) Floating systems can be classified as effervescent and non-effervescent systems.
i. Non-effervescent Systems:
This system, after swallowing, swells via imbibing gastric fluid to an extent that it prevents its exit from the stomach. These systems may be referred to as the
‘plug-type systems’ since they have a tendency to remain lodged near the pyloric sphincter. The air trapped by the swollen polymer confers buoyancy to these dosage forms. (Sanjay 2003) They maintain a relative integrity of shape and a bulk density of less than unity within the outer gelatinous barrier. The gel structure acts as a reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier.
Commonly used excipients in non-effervescent FDDS are gel-forming or highly swellable cellulose
type hydrocolloids, polysaccharides, and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate and polystyrene.
Colloidal gel barrier system:
These are designated as “Hydrodynamically balanced system”. They contain drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. They prolong GRT and maximize the amount of drug that reaches its absorption sites in the solution form for ready absorption. These systems incorporate a high level of one or more gel-forming highly soluble cellulose type hydrocolloid, matrix-forming polymer such as polycarbophil on coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloid gel barrier around its surface. The air trapped by the swollen polymer confers buoyancy to these dosage forms.
Figure 4: Intragastric floating tablet releasing drug via colloidal gel barrier
Microporous compartment system:
Drug reservoir is encapsulated inside a Microporous compartment with pores along its top and bottom walls. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric surface with the undissolved drug. In the stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric content. Gastric fluid enters through the aperture, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption.
48
Alginate beads:
Multi-unit floating dosage forms are developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate. The beads are then separated, snapfrozen in liquid nitrogen, and freezedried at -40ºC for 24 hours, leading to the formation of a porous system, which can maintain a floating force for over 12 hours. These floating beads give a prolonged residence time of more than 5.5 hours.
Evaluation:
Particle size and morphology of gel beads:
The mean diameters of dried beads are determined by optical microscopy. Morphological examination of the surface and internal structure of the dried beads was carried out using a scanning electron microscope. The samples are coated with gold to a thickness of about 30 nm in a vacuum evaporator.
The internal structures of the beads were examined by cutting them in half with a steel blade.
Buoyancy of gel beads:
The gel bead samples are placed in the Erlenmeyer flask filled with 50 ml of simulated gastric fluid USP without pepsin (SGF) test solution. The flask is shaken in a shaking incubator. The shaking speed is 100 rpm and the temperature is maintained at 37 ◦C.
Their buoyancy is observed for 24 h. The preparation is considered to have buoyancy in the test solution only when all of the gel beads floated in it. (Pornsak S 2005)
Hollow microspheres / Microballons:
Hollow microspheres loaded with drug in their outer polymer shelf were prepared by a novel emulsion solvent diffusion method. The solution of the drug and an enteric acrylic polymer is poured into an agitated solution of Poly Vinyl Alcohol (PVA) that was thermally controlled at 40ºC. The gas phase is generated in the dispersed polymer droplet by the evaporation of dichloromethane formed and internal cavity in the microsphere of the polymer with drug.
The Microballons floated continuously over the surface of an acidic dissolution media containing surfactant for more than 12 h. (Garg R 2008)
Evaluation:
Buoyancy:
Microballons are dispersed in solution containing Tween 20 (0.02 w/v %). Buoyancy is determined by the weight ratio of the floating particles to the sum of floating and sinking particles.
Apparent particle density:
Apparent particle density is determined by the projective image count method.
Drug release:
The drug release from Microballons is measured by performing dissolution test. (Yasunori S 2003)
Figure 5: Formulation of Microballons ii. Effervescent Systems:
These buoyant delivery systems utilize matrices prepared with swellable polymers such as polysaccharides, e.g., chitosan, and effervescent components, e.g., sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body temperature. The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the jellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. A decrease in specific gravity causes the dosage form to float on the chyme. The carbon dioxide generating components may be intimately mixed within the tablet matrix. Gas can also be introduced into the floating chamber by the volatilization of an organic solvent (e.g., ether or cyclopentane). These devices contain a hollow deformable unit that converts from a collapsed to an expanded position and returns to the collapsed position after a predetermined amount of
49 time to permit the spontaneous ejection of the inflatable system from the stomach
Carbonates, in addition to imparting buoyancy to these formulations, provide the initial alkaline microenvironment for polymers to gel. Moreover, the release of carbon dioxide helps to accelerate the hydration of the floating tablets which is essential for the formation of a bioadhesive hydrogel. This provides an additional mechanism (‘bioadhesion”) for retaining the dosage form in the stomach, apart from floatation.
a) Gas-generating Systems:
These are low density FDDS based on the formation of carbon-dioxide within the device following contact with body fluids. A single layer tablet or a Bilayer tablet may be compressed which contains the gas-generating mechanism in one hydrocolloid containing layer and the drug in the other layer formulated for a sustained release effect. The coating, is usually insoluble but permeable, allows permeation of water.
Figure 6: Gas-generating system
Intra Gastric Single Layer Floating Tablets or Hydrodynamically Balanced System (HBS):
These are formulated by intimately mixing the CO2 generating agents and the drug within the matrix tablet. These have a bulk density lower than gastric fluids and therefore remain floating in the stomach unflattering the gastric emptying rate for a prolonged period. The drug is slowly released at a desired rate from the floating system and after the complete release the residual system is expelled from the stomach. This leads to an increase in the GRT and a
better control over fluctuations in plasma drug concentration.
Intra Gastric Bilayer Floating Tablets:
These are also compressed tablets contain two layers i. Immediate release layer and
ii. Sustained release layer.
Multiple Unit type floating pills:
These systems consist of sustained release pills as
‘seeds’ surrounded by double layers. The inner layer consists of effervescent agents while the outer layer is of swellable membrane layer. When the system is immersed in dissolution medium at body temp, it sinks at once and then forms swollen pills like balloons, which float as they have lower density.
This lower density is due to generation and entrapment of carbon dioxide within the system.
Figure 7: A multiple-unit oral floating dosage system.
Evaluation of Multiple unit dosage form
Morphological and dimensional analysis: With the aid of scanning electron microscopy (SEM), the size can be measured using an optical microscope.
% yield of microspheres: This is calculated from weight of microspheres obtained ×100 total weight of drug and polymer.
Entrapment efficiency: The drug is extracted by a suitable method, analyzed and is calculated from:
Practical amount of drug present ×100 Theoretical drug content
50 In vitro floating ability (Buoyancy %):
A known quantity of microspheres are spread over the surface of a USP (Type II) dissolution apparatus filled with 900 ml of 0.1 N HCl containing 0.002%
v/v Tween 80 and agitated at 100 rpm for 12 hours.
After 12 hours, the floating and settled layers are separated, dried in a dessicator and weighed. The buoyancy is calculated from the following formula.
Buoyancy (%) = Wf / (Wf + Ws) X 100
Where Wf and Ws are the weights of floating and settled microspheres respectively.
Drug-excipient (DE) interactions:
This is done using FTIR. Appearance of a new peak, and/or disappearance of original drug or excipient peak indicate the DE interaction. Apart from the above mentioned evaluation parameters, granules (ex: Gelucire 43/01) are also evaluated for the effect of ageing with the help of Differential Scanning Calorimeter or Hot stage polarizing microscopy.
b) Volatile Liquid / Vacuum Containing Systems:
The device comprises of a hollow deformable unit that can be converted from a collapsed to an expanded position and returned to a collapsed position after an extended period of time. Housing is attached to the deformable unit and separated by an impermeable, pressure responsive movable bladder.
Intragastric Floating Gastrointestinal Drug Delivery System:
These systems can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a Microporous compartment.
Figure 8: Intragastric floating drug delivery device
Inflatable Gastrointestinal Delivery Systems:
In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach. These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug, impregnated polymeric matrix, then encapsulated in a gelatin capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber.
The inflatable chamber automatically inflates and retains the drug reservoir compartment in the stomach. The drug continuously released from the reservoir into the gastric fluid.
Figure 9: Gastro-inflatable drug delivery device
Intragastric Osmotically Controlled Drug Delivery System:
It is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule. In the stomach, the capsule quickly disintegrates to release the drug from the delivery device. The inflatable support inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body temperature to inflate the bag. The osmotic pressure controlled drug delivery device consists of two components; drug reservoir compartment and an osmotically active compartment. The floating support is also made to contain a Bioerodable plug that erodes after a predetermined time to deflate the support. The deflated drug delivery system is then emptied from the stomach. Although this type of sophisticated dosage form might be used to administer a drug at a controlled rate for a prolonged period of time, it could not be recommended for smokers because of safety reasons. (Amit K 2011)
51 Figure 10: Intragastric osmotic controlled drug delivery system
iii. Raft forming system:
Raft forming systems have been used for the delivery of drugs for gastrointestinal infections and disorders.
The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of carbon dioxide. Usually, the system ingredients include gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of carbon dioxide to make the system less dense and float on the gastric fluids. The raft floats on the gastric fluid and prevents the reflux of the gastric contents (i.e.
gastric acid) into the esophagus by acting as a barrier between the stomach and esophagus. (Praveen 2010) Evaluation of Floating tablets:
Evaluation of powder blend:
a) Angle of repose:
Angle of repose is defined as “the maximum angle possible between the surface of the pile of powder and the horizontal plane.” Lower the angle of repose, better the flow properties. The angle of repose may be calculated by measuring the height (h) of the pile and the radius of the base(r) with ruler.
Tan θ = h/r
b) Bulk density:
Bulk density denotes the total density of the material.
It includes the true volume of interparticle spaces and
intraparticle pores. The packing of particles is mainly responsible for bulk .Bulk density is defined as:
Bulk density = Weight of the powder Bulk volume of powder c) Percentage porosity:
Whether the powder is porous or nonporous, the total porosity expression for the calculation remains the same. Porosity provides information about hardness, disintegration, total porosity etc.
% porosity, € = void volume x100 Bulk volume
% porosity, € = (bulk volume-true volume) x100 True density
Evaluation of floating tablets:
a) Floating lag time:
The buoyancy lag time is determined in the U.S.P.
dissolution test apparatus II in an acid environment.
The time interval between the introduction of the tablet into the dissolution medium and its buoyancy to the top of the dissolution medium is buoyancy lag time or floating lag time.
b) In vitro drug release and duration of floating:
This is determined by using USP II apparatus (paddle) stirring at a speed of 50 or 100 rpm at 37 ± 0.2 °c in simulated gastric fluid (pH 1.2 without pepsin). Aliquots of the samples are collected and analyzed for the drug content. The time (hrs) for which the tablets remain buoyant on the surface of the dissolution medium is the duration of floating and is visually observed.
c) Tablet swelling indices:
Tablets were 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 regular time intervals, the tablets were removed and the excess surface liquid was carefully removed by a filter paper. The swollen tablets were then reweighed (W2). The swelling index (SI) was calculated using the formula:
SI = W2 – W1 / W1
d) In vivo evaluation for gastro-retention:
This is carried out by means of X-ray or Gamma scintigraphy monitoring of the dosage form transition in the GIT. X‐Ray/Gamma Scintigraphy is a very popular evaluation parameter for floating dosage form nowadays. It helps to locate dosage form in the
52 gastrointestinal tract (GIT), by which one can predict and correlate the gastric emptying time and the passage of dosage form in the GIT. Here the inclusion of a radio‐opaque material into a solid dosage form enables it to be visualized by X‐rays.
Similarly, the inclusion of a γ‐emitting radionuclide in a formulation allows indirect external observation using a γ‐camera or scinti-scanner. In case of γ‐scintigraphy, the γ‐rays emitted by the radionuclide are focused on a camera, which helps to monitor the location of the dosage form in the GIT
e) Hardness:
The Monsanto hardness tester is used to determine the tablet hardness. The tablets are held between affixed and moving jaw. Scale is adjusted to zero;
load is gradually increased until the tablet fractured.
The value of the load at that point gives a measure of the hardness of the tablet which is expressed in kg/cm2.
f) Friability:
Tablet strength is tested by Roche friabilator. Pre weighed tablets are allowed for 100 revolutions in 4 min and were dedusted. The percentage weight loss was calculated by reweighing the tablets. The % friability was then calculated by: -
F = (Winitial) – (Wfinal) X 100 / (Winitial) g) Weight variation:
Randomly selected 20 tablets are weighed individually and together in a single pan balance. The average weight is noted and standard deviation is calculated. The tablet passes the test if not more than two tablets fall outside the percentage limit and none of the tablet differs by more than double percentage limit.
PD= (Waverage) – (W initial) / (W average) X 100 PD= percentage Deviation (Prakash R 2009)
B. EXPANDABLE SYSTEMS:
These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their GRT. After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis. These systems are sometimes referred to as plug type systems because they tend to remain lodged at the pyloric sphincter.
Swelling GRDF’s:
These are comprised of an envelope from an elastic or non elastic non hydra -table polymeric membrane, which is drug and body fluid permeable. The envelope contains a drug reservoir and an expanding agent i.e. a swellable resin or hydrocolloid which causes expansion by osmotic pressure. Such devices of sizes larger than 1.531 cm were retained in the stomach for prolonged periods of time, typically than 12 h. The proposed mechanism of retention is not only due to large dimensions, but also by maintaining the stomach in the fed mode i.e. delaying the
‘housekeeper wave’ Administration of riboflavin-5-phosphate containing hydrogel to dogs maintained elevated blood concentrations for up to 54 h, thus yielding a 3.7-fold increase in bioavailability in comparison to oral bolus.
Figure 11: Swelling dosage form prior to administration
Unfolding GRDFs:
Unfolding devices are characterized by different erodibility, mechanical properties, sizes and geometries These devices have the following properties: sufficient resistance to forces applied by the stomach, thus preventing rapid passage through the pylorus; allowance of free passage of food while in residence in the stomach; and desired in vivo circumference larger than 5 cm, to ensure gastroretentivity. The median GRT achieved is apparently prolonged and accordingly, may improve drug therapy. (Eytan K 2003)
53 Figure 12: Unfolding dosage form
C. BIO/MUCOADHESIVE SYSTEMS:
Bio/Mucoadhesive systems bind to the gastric epithelial cell surface, or mucin, and extend the GRT by increasing the intimacy and duration of contact between the dosage form and the biological membrane. The concept is based on the self-protecting mechanism of the GIT. The epithelial
Bio/Mucoadhesive systems bind to the gastric epithelial cell surface, or mucin, and extend the GRT by increasing the intimacy and duration of contact between the dosage form and the biological membrane. The concept is based on the self-protecting mechanism of the GIT. The epithelial