Patel Geeta M
Oral delivery of the drug is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in the formulations. From immediate release to site-specific delivery, oral dosage form has really progressed. It is evident from the recent scientific and patented literature that an increased interest in novel dosage forms that are retained in the stomach for the prolong and predictable period of time exist today in academic and industrial research groups. Various attempts have been made to develop Gastroretentive delivery systems. For example floating, swelling, mucoadhesive, and high-density system shave been developed to increases gastric retention time of the dosage forms. These systems have more flexibility in dosage design than conventional dosage form. Several new approaches have recently been developed to extend gastrointestinal transit time by prolonging residence time in drug delivery system in the GIT.
The design of oral control drug delivery systems (DDS) should be primarily aimed to achieve more predictable and increased bioavailibility.1 Nowadays most of the pharmaceutical scientist is involved in developing the ideal DDS. This ideal system should have advantage of single dose for the whole duration of treatment and it should deliver the active drug directly at the specific site. Scientists have succeeded to develop a system and it encourages the scientists to develop control release systems. Control release implies the predictability and reproducibility to control the drug release, drug concentration in target tissue and optimization of the therapeutic effect of a drug by controlling its release in the body with lower and less frequent dose.2,3
Under certain circumstances prolonging the gastric retention of a delivery system is desirable for achieving greater therapeutic benefit of the drug substances. For example, drugs that are absorbed in the proximal part of the gastrointestinal tract 4,and the drugs that are less soluble or are degraded by the alkaline pH may benefit from the prolong gastric retention 5,6.In adition, for local and sustained drug delivery to the stomach and the proximal small intestine to treat certain conditions, prolonging gastric retention of the therapeutic moiety may offer numerous advantages including improved bioavailibility, therapeutic efficacy and possible reduction of the dose size.7,8.
Approaches To Gastric Retention
Various approaches have been paused to increase the duration of oral dosage form in the stomach, including floating systems, swelling and expanding system, modified shape system, high density systems and other delayed gastric emptying devices. (Magnetic systems, Super porous –biodegradable hydrogel systems).
ØHydrodynamically balanced systems (HBS) –incorporated buoyant materials enable the device to float.9,10
ØRaft systems incorporate alginate gels – these have a carbonate component and, upon reaction with gastric acid, bubbles form in the gel, enabling floating.9,10
ØSwelling type of dosage form are such that after swelling, this product swell to extent that prevent their exit from the stomach through the pylorus. As, a result, the dosage form retained in the stomach for a longer period of time. These systems may be referred to as a “Plug type system”, since they exhibit tendency to remain logged in the pyloric sphincters.11
ØBioadhesive or mucoadhesive systems are used to localize a delivery device within the lumen and cavity of the body to enhance the drug absorption process in a site-specific manner. The approaches involves the use of bioadhesive polymers that can be adhere to the epithelial surface of the GIT.The proposed mechanisms of bioadhesive is the formation of hydrogen and electrostatic bonding at the mucus polymer boundary.
ØModified shape systems are non-disintegrating geometric shapes molded from silastic elastomer or exuded from polyethylene blends and extended the GTT depending on the size, shape and flexural modulus of the drug delivery device.
ØHigh density formulations include coated pallets, and have density greater than that of the stomach content (1.004 gm/cm3). This is accomplishing by coating the drug with a heavy inert material such as barium sulphate, ZnO, titanium dioxide. This formulation of high-density pellet is based on assumption that heavy pellets might remain longer in the stomach, since they are position in the lower part of the antrum.12
ØAnother delayed gastric emptying approaches of interest include sham feeding of digestible polymers or fatty acid salts that charges the motility pattern, of the stomach to a fed stage thereby decressing the gastric emptying rate and permitting considerable prolongation of the drug release.
ØBut some of this has certain drawbacks, which could limit their uses described in the following table: 13 (Table-1)
Table-1: Drawback Associated with Different Types of GRDDS 13
Incorporation of passage delaying food excipient such as fatty acids
Affect the emptying mechanism of the entire content
Bio adhesive drug delivery systems
Biodegradable and non biodegradable (swelling) formulation in which the size and shape retain in the dosage form.
Present the hazard of permanent retention and might lead to serious life threatening effects if multiple dosing is predicted.
Floating systems, first described by Davis in 1968,have bulk density lower than that of the gastric fluid, and thus remain buoyant in stomach for a prolong period.
1.Volatile liquid containing systems:
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 PVA, 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 stomach.14
2. 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 gellified hydrocolloid layer of the systems thus decreasing its specific gravity and making it to float over chyme. 1,17,40 How the dosage form float is shown in the following figure (Figute-1) 15
Figure-1:The Mechanism of Floating Systems19
1. Colloidalgel barrier systems
Hydrodymamically balance system (HBSTM) was first design by Sheth and Tossounian in 1975.Such systems contains drug with gel forming hydrocolloids meant to remain buoyant on stomach contents. This systems incorporate a high level of one or more gel forming highly swellable cellulose type hydrocolloids.e.g.HEC, HPMC, NaCMC, Polysacchacarides and matrix forming polymer such as polycarbophil, polyacrylates and polystyrene, incorporated either in tablets or in capsule. On coming in contact with gastric fluid, the hydrocolloid 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 buoyancy to this dosage forms.16
2.Microporous Compartment System
This technology is based on the encapsulation of drug reservoir inside a Microporous compartment with aperture along its top and bottom wall. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug. In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the apertures, dissolves the drug, and carries the dissolve drug for continuous transport across the intestine for absorption.
Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium alginate. The beads are then separated snap 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 fource over 12 hours.14, 16
4. Hollow microspheres
Hollow microspheres (microballons), loaded with ibuprofen in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ehanol: dichloromethane solution of the drug and an enteric acrylic polymers was poured in to an agitated aqueous solution 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 the polymer with drug. The microballons floated continuously over the surface of acidic dissolution media containing surfactant for greater than 12 hours in vitro.16
Factors Affecting Gastric Retention
Density of the dosage form should be less than the gastric contents (1.004gm/ml).
Size and Shape
Dosage form unit with a diameter of more than 7.5 mm are reported to have an increased GRT competed to with those with a diameter of 9.9 mm. The dosage form with a shape tetrahedron and ring shape devises with a flexural modulus of 48 and 22.5 kilopond per square inch (KSI) are reported to have better GIT @ 90 to 100 % retention at 24 hours compared with other shapes.1
Fed or Unfed State
Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complexes (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. Howevwer, in the fed state, MMC is delayed and GRT is considerably longer.12,12
Nature of the meal
Feeding of indigestible polymers of fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging the drug release.18
GRT can be increased between 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 due to the low frequency of MMC.16
Mean ambulatory 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 surface.
Elderly people, especially those over 70 years have a significantly longer GRT.20
GRT can very between supine and upright ambulatory states of the patients
Concomitant drug administration
Anticholinergic like atropine and propentheline opiates like codeine and prokinetic agents like metoclopramide and cisapride.
Formulation Of Floating Dosage Form
Following types of the ingredients can be incorporated in to HBS dosage form 20
·Inert fatty materials
·Release rate accelerants
·Release rate retardant
·Buoyancy increasing agents
Suitable hydrocolloids are synthethics, anionic or non ionic like hydrophilic gumes, modified cellulose derivatives. E.g. Accasia, pectin, agar, alginates, gelatin, casein, bentonite, veegum, MC, HPC, HEC, and Na CMC can be used. The hydrocolloids must hydrate in acidic medium i.e. gastric fluid is having pH 1.2.Although the bulk density of the formulation may initially be more than one, but when gastric fluid is enter in the system, it should be hydrodynamically balanced to have a bulk density of less than one to assure buoyancy.
Inert fatty materials
Edible, pharmaceutical inert fatty material, having a specific gravity less than one can be added to the formulation to decrease the hydrophilic property of formulation and hence increases the buoyancy. Example: Purified grades of beeswax, fatty acids, long chain alcohols, glycerides, and minaral oils can be used.
Release rate accelerant
The release rate of the medicament from the formulation can be modified by including excipient like lactose and/or mannitol. These may be present from about 5-60% by weight.
Release rate retardant
Insoluble substances such as dicalcium phosphate, talc, magnesium strearete decresesd the solubility and hence retard the release of medicaments.
Buoyancy increasing agents
Materials like ethyl cellulose, which has bulk density less than one, can be used for enhancing the buoyancy of the formulation. It may be adapted up to 80 % by weight.
Pharmaceutically acceptable adjuvant like preservatives, stabilizers, and lubricants can be incorporates in the dosage forms as per the requirements. They do not adversely affect the hydrodynamic balance of the systems.
In Vitro And In Vivo Evaluation Of Floating Systems
Age, sex, posture, food, bioadhesion, health of subject and GIT condition
Diametrical size, flexibility and density of matrices
Floating time, specific gravity, dissolution, content uniformity, hardness and friability
The test for buoyancy is usually performed in simulated gastric and intestinal fluid maintained at 37°C.The floating time is determined by using USP dissolution apparatus containing 900 ml of o.1 N HCl as the testing medium maintained at 37°C.The time for which the dosage form floats is termed as the floating or floatation time.1
Specific Gravity of the floating system can be determined by the displacement method using benzene as a displacing medium.17,21
The in vitro measuring apparatus has been conceived to determine the real floating capabilities of buoyant dosage forms as a function of time. It operates by fource equivalent to the fource F required to keep the object totally submerged in the fluid. This fource determines the resultant weight of the object when immersed and may be used to quantify its floating or nonfloating capabilities. The magnitude and direction of the fource and the resultant weight corresponds to the Victoria sum of buoyancy (Fbuoy) and gravity (Fgrav) forces acting on the objects as shown in the equat
F = Fbuoy – F grav
F = dfgV – dsgV = (df-ds) gv
F =(df – M/V)gV
In which the F is total vertical fource (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.20
Advantages Of Floating Dosage Form 22
ØThe Principle of HBS may not limited to any particular medicament or class of medicament
ØThe HBS formulations are not restricted to medicaments, which are absorbed from stomach, since it has been found that these are equally efficacious with medicament, which absorbed from the intestine.
ØAcidic substances like aspirin cause irritation on the stomach wall when come in to contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs.
ØThe HBS are advantageous for drugs absorbed through the stomach.e.g. Ferrous salts, antacids.
ØThe efficacy of the medicaments administered utilizing the sustained release principle of HBS formulation has been found to be independent of the site of particular medicaments.
ØThe HBS are advantageous for drugs meant foe local action in the stomach.e.g.Antacids.
ØAdministration of prolongs release floating dosage forms, tablet or capsules, will results in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is therefore expected that a drug will be fully absorbed from the floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine.
ØWhen there is vigorous intestinal movement and a shorted transit time as might occur in certain type of diarrhea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.
ØThese systems require a high level of fluid in the stomach for drug delivery tom float and work efficiently-coat, water.
ØNot suitable for drugs that have solubility or stability problem in GIT.
ØDrugs such as nifedipine which is well absorbed along the entire GIT and which undergoes first pass metabolism, may not be desirable.
ØDrugs which are irritant to Gastric mucosa is also not desirable or suitable.1
ØThe drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems.1
ØThe dosage form should be administered with a full glass of water (200-250 ml).3
ØThese systems do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed through out the gastrointestinal tract.
Application Of Floating Drug Delivery System 5
ØRecent study indicated that the administration of Diltiazem floating tablets twice a day may be more effective compared to normal tablets compared to normal tablets in controlling the B.B of hypertensive patients.
ØModapar® HBS containing L-Dopa and Benserazide, here the drug was absorbed over a period of 6-8 hours and maintained substantial plasma concentration for Parkinsonian patients. Cytotech®- containing Misoprostol, a synthetic prostaglandin –EL analogue, for prevention of gastric ulcer caused by non-steroidal anti-inflammatory drugs (NSAIDS).
ØAs it provides high concentration of drug within gastric mucosa, it is used to eradicate H.pylori (a causative organism for chronic gastritis and peptic ulcers).
Ø5-fluorouracil have been successfully evaluate in the patients with stomach neoplasm.
ØDeveloping HBS dosage form for tacrin provide better delivery systems and reduced its GI side effects.
ØTreatment of gastric and duodenal ulcer.
ØFloating dosage form offers various future potential as evident from several recent publication. The reduced fluctuations in the plasma level of drug results from delayed gastric emptying.
ØDrugs that have poor bioavailibility because of their limited absorption to the upper gastrointestinal tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavalability.
ØBuoyant delivery system considered as a beneficial strategy for the treatment of gastric and duodenal cancers.
ØThe floating concept can also be utilized in the development of various anti-reflux formulations.
ØDeveloping a controlled release system for the drugs, which are potential to treat the Parkinson’s disease.
ØTo explore the eradication of Halico-bector pylori by using the narrow spectrum antibodies.
Table-2: Commercial Gastroretentive Floating Formulations 3,23,24
Type and Drug
Floating capsule, Levodopa and benserazide
Floating CR capsules
Floating capsule, Diazepam
Floating Antacid, aluminum and magnesium mixture
Effervescent floating liquid alginate preparation
Amalgate Float Coatâ 35
Floating dosage form
Colloidal gel forming FDDS
Ciprofloxacine (1 gm)
Gas generating floating form
Misoprostol (100 mcg/200 mcg)
Bilayer floating capsule
Mixture of alginate
Suppress gastro esophageal reflux and alleviate the heart burn
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Patel Geeta M is presently working as Lecturer in the department of Pharmaceutics and Pharmaceutical Technology at S. K. Patel college of Pharmaceutical education and research, Kherva, Ganpat University, Mehsana, India. She worked on floating drug delivery system during her post graduation. She has 9 publications in different journals. She further focuses her research activity in the novel drug delivery system
*Corresponding Author: E-mail – firstname.lastname@example.org
Patel Hitesh R is presently working as Lecturer in the department of Pharmaceutics and Pharmaceutical Technology at S. K. Patel college of Pharmaceutical education and research, Kherva, Ganpat University, Mehsana, India. he worked on oral mucosal drug delivery system during his post graduation. He has 4 publications in different journals. He further focuses her research activity in the same.
Dr. Madhabhai Patel is currently Principal of Kalol institute of Pharmacy, Kalol India. He earned his PhD in Pharmaceutics and Pharmaceutical Technology. Dr. Madhabhai Patel has 25 years of academic and research experience. He has 40 national and intentional research papers to his credit. He is an approved PhD guide at Hemchandrachayra North Gujarat University, Patan, and Ganpat University, Kherva, India.
Patel Jayvadan K