In comparison to other systems floating drug delivery system have less density that creates ability to float. Because of buoyancy it can float over gastric contents and remains in stomach for longer time (3-4 hours). It is an important approach towards sufficient drug bioavailability because of efficient gastric retention.There are two requirements of FDDS:Slow Release: It should release contents very slowly and act as reservoir.
Specific Gravity: It should maintain specific gravity lower than gastric contents (1.003-4 to 1.01 gm/cm3). Gel barrier: It must form well integrated gel barriers. It is also known as low density system.
Mechanisms of Floating drug delivery systems:The drug is released slowly at required rate from the system floating on the gastric contents.After the drug is released the residual system is emptied from the stomach. Fig: Mechanism of Floating SystemsFloating force is required to keep dosage form buoyant on the surface of meal.
A novel apparatus is used to measure floating force kinetics. This apparatus works by measuring continuously the force “F” as a function of time that is required to maintain the objects intermingle. The apparatus in accessing FDDS to stability and durability of floating forces produced in order to prevent drawbacks of unforeseeable intra-gastric buoyancy ability of variations.F = F buoyancy – F gravity = (D f – D s) g v Where, F = Total vertical force D f = Fluid Density D s = Object Density V = VolumeIn approach to design the various floating dosage form there are two types of floating Dosage systems:Single unit floating dosage systemMultiple unit floating dosage systemThese two systems have been designed by using the following approaches:SINGLE UNIT DOSAGE FORMSLow density approach;As the name indicates in low-density approach the globular shells with lower density than that of gastric fluids are used as drug carrier for making single-unit floating dosage form Popcorn, polystyrol and poprice have been used as drug carriers in coated shells26. For the undercoating of these shells sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been exploited. These shells are further coated with a mixture of drug polymer.
Depending upon the type of release the polymer is ethyl cellulose or hydroxy propyl cellulose. Product floats on the gastric fluid and slowly releases the drug for a longer period of time.Fluid- filled floating chamber; Agas-filled floatation chamber is blend into a microporous component that covers the drug reservoir. Along the top and bottom walls there is supply for opening through which the GIT fluid enters into the device to dissolve the drug. The side walls came in contact with the fluid is sealed to ensure un-dissolved drug remains in the device.
Air, gas, liquid or solid that has specific gravity and that should be inert can be used as a system for floatation. This device should be of swell able size. Device remains floating within the stomach for a longer duration and slowly releases the drug. After the complete release of the drug, the shell unravel, goes to the intestine and finally excreted from body.Hydro-dynamically balanced systems (HBS); These systems have more capacity of absorption because they are designed in a way that they stays in GIT for long time. Drugs which are capable especially in acidic environment and site-specific absorption in the upper part of GIT are most appropriate for such systems. These dosages form must have more density of ? 1.
It should maintain its structural probity should resolute release the drug. The solubility of chlordiazepoxide hydrochloride29 is 150 mg/mL at pH 3-6 and is ~0.1 mg/ml at neutral pH. So, HBS capsule drug is better than conventional to solve the solubility problem.Bilayer and matrix tablets; Some types of Bilayer and matrix tablets shows floatable characteristics. The polymers which have been exploited are sodium carboxymethyl cellulose (CMC), hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose and Crosspovidone.
3-layer principle; As the development of asymmetric arrangement drug delivery system, 3-layer principle has improved 3-layer principle helps to control the release extent and for getting zero-order release kinetics. The design of the system works as it floats on the stomach content and gastric ability to keep contents for longer time which further results in longer total transit time which increases the absorptive capacity and hence better bioavailability is the result. PH-dependent solubility’s drugs get benefit from it, drugs which are absorbed by the active transport mechanism from the small intestine or the drugs with narrow or thin absorption window.Problems with single-unit formulations; Major problem with this formulation is that the Single-unit formulations can stick together or been obstructed in the GIT, which can cause irritation or un-comfort.MULTIPLE-UNIT DOSAGE FORMS Multiple-unit dosage form is designed to create a formulation which should be reliable that provide all the benefits of a single-unit form and to overcome the hazards of single-unit formulations. High loading capacity microspheres are used in it. The polymers i.e.
polyacrylamine, albumin, gelatin, starch, polymethacrylate and polyalkylcyanoacrylate haave been used to form microspheres. Because of its internal hollow structure characteristic microspheres shows excellent in-vitro floatability. After administration several devices of carbon dioxide multiple unit oral formulations have been described in the recent patent literatures with features that; unfold, extend or are inflated by carbon dioxide generated in the devices.CLASSIFICATION OF FLOATING DRUG DELIVERY SYSTEMEffervescent system:-In effervescent matrix type of system swell able polymers especially methylcellulose and chitosan and effervescent compounds mainly tartaric acid, citric acid, and sodium bicarbonate are used. Liberation of Carbon dioxide occurs in these formulations when come in contact with gastric contents and gas is trapped in swollen hydrocolloids which provide buoyancy to the dosage form.
Volatile liquid containing systems:In volatile liquid drug delivery system liquids are present in the inflatable chambers, liquids mainly ether and cyclopentane, these liquids causes inflammation in stomach when gasified at body temperature. This matrix may also comprises of a bio-erodible plug made up of PVA, Polyethylene etc. that slowly liquefies and causing the inflatable chamber to discharge gas and collapse after a predetermined period to permit the spontaneous discharge of the inflatable systems from stomach.Intra-gastric floating gastrointestinal drug delivery system Intra-gastric floating gastrointestinal drug delivery system: this system floats in stomach, because of the floating chamber, which may be a vacuum filled with air or a harmless gas, while drug reservoir is captured in a micro porous section.Inflatable gastrointestinal delivery system Inflatable gastrointestinal in these systems inflatable chamber is incorporated, which have liquid ether that gasifies at body temperature to cause the chamber to inflatable in the stomach. These systems are build by loading the chamber with drug reservoir, which can be a drug impregnated polymeric matrix, than incorporated in a gelatin capsule. After oral administration the drug’s reservoir is released due to dissolving of capsule along with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir into the gastric fluid.
b) Gas generating systems: In these systems effervescent reactions occurs between carbonates/bicarbonates salts and tartaric/citric acids to liberate CO2, which gets trapped in the gel matrix of the systems. Thus decrease in it specific gravity and to make it float over the gastric fluid.I) Floating pills: These systems consists of two layers, inner effervescent layer containing tartaric acid and sodium bicarbonate , the outer swell able polymeric membrane and the inner layer which is further divided into two sub layers to avoid contact between tartaric acid and sodium bicarbonate. When this pill is immersed in buffer solution at 37°C, it settles down at bottom and the buffer solution enters into the effervescent layer through the outer swell able membrane.
Generation of carbon dioxide forms swollen pills or balloons as a result of reaction between sodium bicarbonates and tartaric acid. The carbon dioxide generation entrapped within the delivery system to make the device float. These systems were found to float completely within 10 minutes and have good floating ability independent of pH, controlled viscosity of the medium and the drug is released.II) Floating capsules: Floating capsules are formed by mixing of sodium alginate and sodium bicarbonate solution, generation of carbon dioxide make it to float, which gets trapped in the hydrating gel network when exposed to an acidic environment.III) Floating systems with ion exchange resins: These systems are formulated by using ion exchange resin which is loaded with bicarbonate and by mixing the beads with sodium bicarbonate solution, to avoid the sudden loss of carbon dioxide loaded beads are surrounded by semi permeable membrane. When it came in contact with gastric contents there is an exchange of chloride and bicarbonate ions in result carbon dioxide generates thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads, which releases the drug at a predetermined quantity. IV) Tablet a) Intra-gastric single layer floating tablets or Hydrodynamic ally balanced system: These formulations have bulk density lower than gastric fluids and thus it float in the stomach that cause increase in gastric emptiness rate for a prolonged period.
These are formulated by intimately mixing the gas (CO2) generating agents and the drug within the matrix tablet. The drug is released at slow desired rate from the floating system & the residues emptied from the stomach after the complete release of the drug. This leads to and increases the gastric residence time & a better control on fluctuations in plasma drug concentration.b) Bi-layer tablet Bi-layer tablet can also prepared by gas generating matrix in one layer and in second layer with drug for its sustained release effect.c) Triple layer tablet Triple layer tablet also have first swell-able floating layer, second sustained release layer of two drugs and third rapid dissolving layerB) Non-effervescent systems: This type of system after swallowing swells abandonment via Imbibitions of gastric fluid to an extent that it stops their exit from the stomach. These systems may be referred as the “plug type system” since they have capability to remain bestow near the pyloric sphincter. One of the formulation methods of such dosage forms involve the mixing of drug with a gel, which swells in contact after oral administration and maintains a relative shape and a bulk density of less than 1.
This is based on the mechanism of swelling of polymer or bio adhesion to mucosal layer in GIT. The most commonly used recipients are gel forming materials such as polycarbonate, poly acryl ate, polystyrene etc. this hydrocolloid starts to hydrate by first forming a gel at the surface of the dosage form. The resultant gel structure then have control on the rate of diffusion of solvent-in and drug-out of the dosage form. The various types of this system are as follows:Single layer floating tablets: This can be formulated by indirect mixing of drug with gel forming hydrocolloid, which swells in and have contact with gastric fluid and maintain bulk density of less than 1. The air trapped by the swollen polymer confers floating capacity to these dosage forms.Bi-layer floating tablets: A bi-layer tablet contains two layers, one is immediate release layer which releases the initial dose from system while the other is sustained release layer which absorbs the gastric fluid and maintains a bulk density of less than 1 and it remains floating in the stomach. Fassihi and Yang developed a zero-order controlled release.
Multilayer tablet composed of at least 2 layers and one drug layer. All the layers are made of swell-able, erodible polymers and the tablet was found to swell on having contact with aqueous medium. As the tablet dissolved, the barrier layers eroded away to expose more of the drug. Agents which evolve gases are added in either of the barrier layers; this become the cause for tablet to float and increased the retaining capability of tablet in a patient’s stomach.Colloidal gel barrier systems: It contains drug with gel forming hydrocolloids meant to remain floating on stomach contents. This system assimilates a high level of one or more gel forming highly swell-able cellulose type hydrocolloids.
When it comes in contact with gastric fluid, the hydrocolloids in the system hydrates and forms a colloidal gel barrier around the gel surface. The air trapped by the swollen polymer maintains a density less than unity and confers floating to this dosage forms.Micro porous Compartment System This technology is based on the encapsulation of drug reservoir inside a micro porous compartment with aperture along its top and bottom wall. The peripheral walls of the drug reservoir compartments are sealed to prevent it from direct contact of the gastric mucosal surface with the un-dissolved drug. In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters from apertures, dissolves the drug, and carries the dissolved drug for continuous transport it through the intestine for absorption.
Alginate beads: To develop Multi-unit floating dosage forms the freeze-dried calcium alginate is used. Spherical beads of approximately 2.5 mm in diameter can be prepared through precipitation of calcium alginate via dropping sodium alginate solution into solution of calcium chloride. The beads are then separated and frozen in liquid nitrogen, and freeze dried at -40°C for 24 hours, leading to the formation of porous system, which can maintain a floating force over 12 hours. On the other hand, multiple-unit dosage forms appear to be better suited since they claimed to reduce the inter subject variability in absorption and lower the chances of dose-dumpingHollow microspheres: Preparation of hollow microspheres is done through emulsion solvent diffusion which (hollow microsphere) loaded with drug in their outer polymer shelf. The ethanol: dichloromethane solution of the drug andenteric acrylic polymers is poured in to an agitated aqueoussolution of PVA that was thermally controlled at 40°C.The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed in internal cavity in microspheres of thepolymer with drug. The micro ballons floated continuously over the surface of acidic dissolution media containing surfactant greater than 12 hours.
The drug released has high pH 7.2. Hollow microspheres (micro balloons), loaded with ibuprofen in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method.Ideal drug candidates for floating drug delivery:Drugs those are locally active in the stomach. E.g.
Misoprostol, antacids etc.Drugs which have narrow absorption window in the GIT. E.g. Furosemide, L-dopa, Para-amino benzoic acid, riboflavin.
etc.Drugs that shows low solubility at high pH values. E.g. Diazepam, Chlordiazepoxide, Verapamil hydrochloride.
Drugs those have instability in the intestinal or colonic environment. E.g. Captopril, ranitidine HCl, Metronidazole.Drugs which disturbs normal colonic microbes. E.g. antibiotics against Helicobacter pylori.
Drugs that have specific site of absorption in the upper part of small intestine.Drugs having a bulk density of less than 1 to remain in the stomach for longer period of time.FACTORS AFFECTING GASTRIC RETENTION: A) PHYSIOLOGICAL FACTORS:-a) Density: Gastric retention time is a function of dosage form floating is density dependent. A buoyant dosage form having a density less than that of the gastric floating fluid, since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a longer period of time. A density having less than 1.004g/ml i.
e. less than that of gastric contents has been reported.b) Size: 7.5mm diameter unit dosages are reported to have an increased GRT compared with those with a diameter of 9.9mm.c) Shape of dosage form: Tetrahedron and ring shaped devices with a bend modulus of 49 pounds or 22.
5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes.B) BIOLOGICAL FACTORS:a) Fed or unfed state: Under fasting conditions, GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach.
However, in the fed state, MMC delayed and GRT comparatively longer.b) Nature of meal: Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach is changed, thus decreasing in the gastric emptying rate and prolonging drug release.c) Caloric content: GRT can be increased with the meal high in protein and fats by 4 to 10 hours.d) Frequency of feed: When successive meals are given compared with a single meal due to the low frequency of MMC the GRT can increase by over 400 minutes.e) Gender: Mean ambulatory GRT in males (3.
4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), having no conditions of the weight, height and body surface.f) Age: Low gastric emptying time is observed in elders than do in younger subjects. Intra subject and inter subject variations also are observed in gastric and intestinal transit time.
Elderly people, especially over 70 years have a significantly longer GRT.g) Posture: GRT can vary between supine and upright ambulatory states of the patient. An upright position protects floating forms against postprandial emptying because the floating form remains above the gastric contents irrespective of size.
In supine subjects large dosage forms have prolonged retention. The gastric retention of floating forms appear to remain floating anywhere between the low and high curvature of the stomach. On moving distally, these units may be moved away by the peristatic movements that propel the gastric contents towards the pylorus, leading to significant reduction in GRT compared with upright subjects.h) Concomitant drug administration: Anti cholinergic like atropine and propentheline opiates like codeine and prokinetic agents like meto clopramide and cisapride, affect the gastric emptying and hence gastric residence time of an oral dosage form.Methods for Preparing Floating Dosage Form:Direct compression technique Involves compressing tablets directly from powdered material without changing the physical nature of the material itself.
Direct compression carriers must have good flow and compressible characters these properties are imparted by predisposing these vehicles to slugging, spray drying or crystallization. Most common carriers are di calciumphosphate trihydrate, tri calcium phosphate etc.Melt granulation technique: This is a process by which the pharmaceutical powders are massed (making a ball) by using a melt able binder and no water or organic solvents are required for granulation. Because there is no step of drying, the process is less time consuming and uses less energy. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 °c and an impeller speed of 20000 rpm.Melt solidification technique: This process involves emulsification of the molten mass in the aqueous phase followed by its solidification by cooling. The carriers used for this technique are lipids, waxes, polyethylene glycols. Drug is inserted into these carriers to achieve controlled release.
Wet granulation technique: Wet granulation process involves the wet massing of powders, wet sizing or milling and drying. Wet granulation forms the granules by attaching the powders together with an adhesive instead of compaction. The wet granulation technique employs a solution suspension or slurry containing a binder which is usually added to the powder mixture however the binder may be incorporated into the dry powder mix and the liquid may be added by itself.
The method of introducing the binder depends on the solubility and on the components of the mixture since, in general, the mass should merely be moist rather than wet, and there is a limit to the amount of solvent that may be used. Once the granulating liquid is added, mixing continues until a uniform dispersion is attained and all the binder has been activated. Then the wet mass undergoes wet screening by passing through a hammer mill or multi mill equipped with screens having large perforation. The milled wet mass is dried by either using tray drier or fluidized bed drier, after completion, the drying lubrication materials is blended with dried granules. This lubricated granule is made to experience compression.Effervescent technique: The floating chamber of the drug delivery system filled with inert gas CO2 by the effervescent reaction between organic acid citric acid and bicarbonate salts.
Spray drying techniques: It involves dispersing the core material in a liquefied coating material and solidification effect of coating is done through spraying the core-coating mixture in environment. Solidification is achieved by rapid evaporation of the solvent in which coating material is solubilised.Advantages of FDDS: FDDS have many advantages in the treatment of the disorders related to the stomach, as the prime objective of such systems is to produce a gastro retentive product.Drugs with considerably short half life can be administered in this manner to get an appreciable therapeutic activity.Improvement of the bioavailability for drugs which can metabolized in the upper GIT.They also have advantages over the conventional system as it can be used to overcome the adversities of gastric retention time as well as the gastric emptying time.
The duration of treatment through a single dose, which releases an active ingredient over an extended period of timeThe active entity is delivered to the site of action, thus minimizing or eliminating the side effectsDisadvantages of FDDS: The major disadvantage of floating system is the requirement of high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bio-adhesive polymers that easily adhere to the mucosal lining of the stomach.Gastric retention influenced by many factors such as gastric movement, pH and presence of food.
These factors are not constant and hence the floating cannot be predicted.Drugs that cause irritation to gastric mucosa are not suitable to be formulated as floating drug delivery systems.High variability in gastric emptying time due to its all (or) non-emptying process.Patients should not be dosed with floating forms just before sleeping.Floating system is not suitable for those drugs that have solubility (or) stability problem in gastric fluids.
The dosage form should be administered with a minimum of glass full of water (200-250 ml).The drugs, which are absorbed throughout GIT, which under go first-pass metabolism (Nifedipine, Propranolol etc.) are not suitable priority.
CONCLUSION: Drug absorption in the gastrointestinal tract is a highly variable procedure and increases gastric retention of the dosage form increase the time for drug absorption. FDDS promises to be a potential approach for gastric retention. Number of commercial products and patents issued in this field are the evidence of it. The aim is to improve the bioavailability of the drug with less absorption window in gastrointestinal tract region. By increasing the drug staying time in GI region improves the solubility of drug that is less soluble in high PH and decreases drug waste, reduction in plasma level fluctuation.
Although there are number of problems to be worked on to achieve prolonged gastric retention, Now a day’s many companies have focus on commercializing this technique.