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S.Gopalakrishnan et al / Journal of Pharmaceutical Science and Technology Vol. 3 (2), 2011,548-554
Floating Drug Delivery Systems: A Review
S. Gopalakrishnan and A. Chenthilnathan
Department of Pharmaceutical Chemistry, Manonmaniam Sundaranar University, Tirunelveli – 627 012,
Tamil Nadu, India
Abstract
In the recent years, scientific and technological advancements have been made in the research and
development of novel drug delivery systems by overcoming physiological troubles such as short gastric
residence times and unpredictable gastric emptying times. Several approaches are currently utilized in the
prolongation of the gastric residence times, including floating drug delivery systems, swelling and
expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems and
other delayed gastric emptying devices. This review explains briefly about formulation aspects,
evaluation various floating drug delivery systems and application of these systems.
Keywords: Gastric residence time, Floating drug delivery system, Effervescent, Non-effervescent.
INTRODUCTION
The oral route is the most preferred route of is released slowly at the desired rate from
administration of drugs because of low cost the system. After release of drug, the
of therapy, ease of administration, patient residual system is emptied from the
compliance and flexibility in formulation, stomach. This results in an increased GRT
etc. During the past few decades, numerous and a better control of the fluctuations in
oral drug delivery systems have been plasma drug concentration. However,
developed to act as drug reservoirs from besides a minimal gastric content needed to
which the active substance can be released allow the proper achievement of the
over a specific period of time at a buoyancy retention principle, a minimal
predetermined and controlled rate [1]. It is level of floating force (F) is also required to
evident from the recent scientific and patent keep the dosage form reliably buoyant on
literatures that an increased interest in novel the surface of the meal . Many buoyant
oral controlled release dosage forms that systems have been developed based on
designed to be retained in the granules, powders, capsules, tablets,
gastrointestinal tract (GIT) for a prolonged laminated films and hollow microspheres.
and predictable period of time exists today Table 1 enlists examples of various drugs
[2]
. Several approaches are currently utilized formulated as different forms of FDDS.
in the prolongation of the gastric residence
times (GRT) , including floating drug Drug Candidates Suitable for FDDS
delivery systems (FDDS) [3], low- density Drugs that have narrow absorption
systems [4], raft systems incorporating window in GIT (e.g. L-DOPA, p-
[5]
alginate gels , bioadhesive or aminobenzoic acid, furosemide,
[6]
mucoadhesive systems , high-density riboflavin) [2]
systems [7], superporous hydrogels [8] and Drugs those are locally active in the
magnetic systems [9]. The current review stomach (e.g. misroprostol, antacids) [10]
addresses briefly about the FDDS that is one Drugs those are unstable in the intestinal
of the most leading methodologies in or colonic environment (e.g. captopril,
gastroretentive drug formulations. ranitidine HCl, metronidazole) [11]
Floating drug Delivery System Drugs that disturb normal colonic
Floating drug delivery systems (FDDS) or microbes (e.g. antibiotics used for the
hydrodynamically controlled systems are eradication of Helicobacter pylori, such
low-density systems that have sufficient as tetracycline, clarithromycin,
buoyancy to float over the gastric contents amoxicillin) [12]
and remain buoyant in the stomach without Drugs that exhibit low solubility at high
affecting the gastric emptying rate for a pH values (e.g. diazepam,
prolonged period of time. While the system chlordiazepoxide, verapamil) [13]
is floating on the gastric contents, the drug
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Table 1 - List of Drugs Formulated as Single Disadvantages of FDDS
and Multiple Unit Forms of Floating Drug 1. Floating system is not feasible for those
Delivery Systems drugs that have solubility or stability
problem in G.I. tract.
Dosage Drugs 2. These systems require a high level of
Form fluid in the stomach for drug delivery to
Tablets Cholrpheniramine maleate, float and work efficiently coat, water.
Theophylline, Furosemide, 3. The drugs that are significantly absorbed
Ciprofloxacin, Captopril, through out gastrointestinal tract, which
Acetylsalicylic acid, undergo significant first pass
Nimodipine, Amoxycillin metabolism, are only desirable
trihydrate, Verapamil HCI, candidate.
Isosorbide di nitrate,
Isosorbide mononitrate, FACTORS AFFECTING FLOATING
Acetaminophen, Ampicillin, DRUG DELIVERY SYSTEM
Cinnarazine, Dilitiazem, a. Density: Density of the dosage form
Florouracil, Prednisolone, should be less than the gastric contents
Capsules Nicardipine, (1.004gm/ml).
Chlordiazepoxide HCI, b. Size and Shape: Dosage form unit with
Furosemide, Misoprostal, a diameter of more than 7.5 mm are
Diazepam, Propranlol, reported to have an increased GRT
Urodeoxycholic acid. competed to with those with a diameter
Microspheres Aspirin, Griseofulvin, and of 9.9 mm. The dosage form with a
p-nitroanilline, Ketoprofen, shape tetrahedron and ring shape devises
Iboprufen, Terfenadine. with a flexural modulus of 48 and 22.5
Granules Indomethacin, Diclofenac kilopond per square inch (KSI) are
sodium, Prednisolone reported to have better GIT for 90 to 100
Films Cinnarizine % retention at 24 hours compared with
other shapes. [16]
Advantages of FDDS [14, 15] c. Fed or Unfed State: Under fasting
1. The Floating systems are advantageous conditions, the GI motility is
for drugs meant for local action in the characterized by periods of strong motor
stomach. E.g. antacids. activity or the migrating myoelectric
2. Acidic substances like aspirin cause complexes (MMC) that occurs every 1.5
irritation on the stomach wall when to 2 hours. The MMC sweeps
come in contact with it. Hence FDDS undigested material from the stomach
may be useful for the administration of and if the timing of administration of the
aspirin and other similar drugs. formulation coincides with that of the
3. The Floating systems are advantageous MMC, the GRT of the unit can be
for drugs absorbed through the stomach. expected to be very short. However, in
E.g. Ferrous salts, antacids. the fed state, MMC is delayed and GRT
4. Administration of prolongs release is considerably longer. [17]
floating dosage forms, tablet or d. Nature of the meal: Feeding of
capsules, will result in dissolution of the indigestible polymers of fatty acid salts
drug in the gastric fluid. They dissolve can change the motility pattern of the
in the gastric fluid would be available stomach to a fed state, thus decreasing
for absorption in the small intestine after the gastric emptying rate and prolonging
emptying of the stomach contents. the drug release. [18]
5. It is therefore expected that a drug will e. Caloric Content: GRT can be increased
be fully absorbed from floating dosage between 4 to 10 hours with a meal that
forms if it remains in the solution form is high in proteins and fats.
even at the alkaline pH of the intestine.
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f. Frequency of feed: The GRT can from system while the another sustained
increase by over 400 minutes when release layer absorbs gastric fluid, forming
successive meals are given compared an impermeable colloidal gel barrier on its
with a single meal due to the low surface, and maintain a bulk density of less
frequency of MMC. [19] than unity and thereby it remains buoyant in
g. Gender: Mean ambulatory GRT in the stomach
meals (3.4±0.4 hours) is less compared c. Alginate Beads: Multi-unit floating
with their age and race-matched female dosage forms were developed from freeze-
counterparts (4.6±1.2 hours), regardless dried calcium alginate. Spherical beads of
of the weight, height and body surface. approximately 2.5 mm diameter can be
h. Age [20]: Elderly people, especially those prepared by dropping sodium alginate
over 70 years have a significantly longer solution into aqueous solution of calcium
GRT. [21] chloride, causing precipitation of calcium
i. Posture [20]: GRT can very between alginate leading to formation of porous
supine and upright ambulatory states of system, which can maintain a floating force
the patients for over 12 hours. When compared with
j. Concomitant drug administration: solid beads, which gave a short residence
Anticholinergic like atropine and time of 1 hour, and these floating beads
propentheline opiates like codeine and gave a prolonged residence time of more
prokinetic agents like metoclopramide than 5.5 hours.
and cisapride. d. Hollow Microspheres: Hollow
microspheres (microballoons), loaded with
TYPES OF FLOATING DRUG drug in their outer polymer shells are
DELIVERY SYSTEMS prepared by a novel emulsion-solvent
Based on the mechanism of buoyancy, two diffusion method. The ethanol:
distinctly different technologies have been dichloromethane solution of the drug and an
utilized in the development of FDDS. enteric acrylic polymer is poured into an
i) Non-Effervescent FDDS [19, 22] agitated aqueous solution of PVA that is
The Non-effervescent FDDS is based on thermally controlled at 40 ˚C. The gas phase
mechanism of swelling of polymer or generated in dispersed polymer droplet by
bioadhesion to mucosal layer in GI tract. evaporation of dichloromethane forms an
The most commonly used excipients in non- internal cavity in microsphere of polymer
effervescent FDDS are gel forming or with drug. The microballoons float
highly swellable cellulose type continuously over the surface of acidic
hydrocolloids, hydrophilic gums, dissolution media containing surfactant for
polysaccharides and matrix forming more than 12 hours.
materials such as polycarbonate,
polyacrylate, polymethacrylate, polystyrene ii) Effervescent FDDS
as well as bioadhesive polymers such as a.Volatile liquid containing system: The
Chitosan and carbopol. GRT of a drug delivery system can be
The various types of this system are as: sustained by incorporating an inflatable
a. Single Layer Floating Tablets: They are chamber, which contains a liquid e.g. ether,
formulated by intimate mixing of drug with cyclopentane, that gasifies at body
a gel-forming hydrocolloid, which swells in temperature to cause the inflatation of the
contact with gastric fluid and maintains bulk chamber in the stomach. The device may
density of less than unity. They are also consist of a bioerodible plug made up
formulated by intimate mixing of drug with of Poly vinyl alcohol, Polyethylene, etc. that
low-density enteric materials such as gradually dissolves causing the inflatable
HPMC. chamber to release gas and collapse after a
b. Bi-layer Floating Tablets: A bi-layer predetermined time to permit the
tablet contain two layer one immediate spontaneous ejection of the inflatable
release layer which releases initial dose systems from the stomach. [23]
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Table 2 - Marketed Products of FDDS
Dosage Form Drugs Brand Name Company, Country
Floating Controlled Release Levodopa,
MODAPAR Roche Products,USA
Capsule Benserazide
Floating Capsule Diazepam VALRELEASE Hoffmann-LaRoche,USA
Aluminium
Effervescent Floating Liquid hydroxide, LIQUID
Glaxo Smith Kline,INDIA
alginate Preparation Magnesium GAVISON
carbonate
Floating Liquid alginate Aluminium -
TOPALKAN Pierre Fabre Drug,FRANCE
Preparation Magnesium antacid
Colloidal gel forming FDDS Ferrous sulphate CONVIRON Ranbaxy,INDIA
Gas-generating floating
Ciprofloxacin CIFRAN OD Ranbaxy,INDIA
Tablets
Bilayer floating Capsule Misoprostal CYTOTEC Pharmacia,USA
b. Gas-generating Systems: These buoyant it should be hydrodynamically balanced to
delivery systems utilize effervescent have a bulk density of less than one to
reactions between carbonate/bicarbonate assure buoyancy.
salts and citric/tartaric acid to liberate CO2, Inert fatty materials: Edible, pharmaceutical
which gets entrapped in the gellified inert fatty material, having a specific gravity
hydrocolloid layer of the systems thus less than one can be added to the
decreasing its specific gravity and making it formulation to decrease the hydrophilic
to float over chyme. [23, 24] property of formulation and hence increases
Some FDDS products available in the the buoyancy. Eg. Purified grades of
market are listed in Table 2. beeswax, fatty acids, long chain alcohols,
glycerides, and mineral oils can be used.
FORMULATION OF FLOATING Release rate accelerant: The release rate of
DOSAGE FORM the medicament from the formulation can be
The following types of the ingredients can modified by including excipient like lactose
be incorporated in to FDDS [21] and/or mannitol. These may be present from
Hydrocolloids about 5-60% by weight.
Inert fatty materials Release rate retardant: Insoluble substances
Release rate accelerants such as dicalcium phosphate, talc,
Release rate retardant magnesium strearete decresesd the solubility
Buoyancy increasing agents and hence retard the release of
Miscellaneous medicaments.
Hydrocolloids: Suitable hydrocolloids are Buoyancy increasing agents: Materials like
synthethics, anionic or non ionic like ethyl cellulose, which has bulk density less
hydrophilic gumes, modified cellulose than one, can be used for enhancing the
derivatives. Eg. Accasia, pectin, agar, buoyancy of the formulation. It may be
alginates, gelatin, casein, bentonite, adapted up to 80 % by weight.
veegum, MC, HPC, HEC, and Na CMC can Miscellaneous: Pharmaceutically acceptable
be used. The hydrocolloids must hydrate in adjuvant like preservatives, stabilizers, and
acidic medium i.e. gastric fluid is having pH lubricants can be incorporates in the dosage
1.2.Although the bulk density of the forms as per the requirements. They do not
formulation may initially be more than one, adversely affect the hydrodynamic balance
but when gastric fluid is enter in the system, of the systems.
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EVALUATION OF FLOATING After 12 hours, the floating and settled
DOSAGE FORMS layers are seperated, dried in a dessicator
A. For Single Unit Dosage Forms [25] (Eg: and weighed. The buoyancy is calculated
tablets) from the following formula.
(i) Floating lag time: It is the time taken by Buoyancy (%) = Wf / ( Wf + Ws) x 100
the tablet to emerge onto the surface of Where Wf and Ws are the weights of
dissolution medium and is expressed in floating and settled microspheres
seconds or minutes. respectively.
(ii) In vitro drug release and duration of (v) Drug-excipient (DE) interactions: This is
floating: This is determined by using USP II done using FTIR. Appearance of a new
apparatus (paddle) stirring at a speed of 50 peak, and/or disappearance of original drug
or 100 rpm at 37 ± 0.2 °c in simulated or excipient peak indicates the DE
gastric fluid (pH 1.2 without pepsin). interaction. Apart from the above mentioned
Aliquots of the samples are collected and evaluation parameters, granules are also
analysed for the drug content. The time (hrs) evaluated for the effect of ageing with the
for which the tablets remain buoyant on the help of Differential Scanning Calorimeter or
surface of the dissolution medium is the Hot stage polarizing microscopy.
duration of floating and is visually
observed. APPLICATION OF FLOATING DRUG
(iii) In vivo evaluation for gastro-retention: DELIVERY SYSTEM
This is carried out by means of X-ray or Floating drug delivery offers several
Gamma scintigraphic monitoring of the applications for drugs having poor
dosage form transition in the GIT. The bioavailability because of the narrow
tablets are also evaluated for hardness, absorption window in the upper part of the
weight variation, etc. gastrointestinal tract. It retains the dosage
B. For Multiple Unit Dosage Forms [26] form at the site of absorption and thus
(Eg: microspheres) enhances the bioavailability. These are
Apart from the In vitro release, duration of summarized as follow:
floating and in vivo gastro-retention tests, i) Sustained Drug Delivery: FDDS can
the multiple unit dosage forms are also remain in the stomach for long periods and
evaluated for: hence can release the drug over a prolonged
(i) Morphological and dimensional analysis period of time. The problem of short gastric
with the aid of scanning electron residence time encountered with an oral CR
microscopy (SEM). The size can also be formulation hence can be overcome with
measured using an optical microscope. these systems. These systems have a bulk
(ii) % yield of microspheres: This is density of <1 as a result of which they can
calculated from float on the gastric contents. These systems
Weight of microspheres obtained are relatively large in size and passing from
× 100 the pyloric opening is prohibited.
Total weight of drug and polymer
Eg. Sustained release floating capsules of
(iii) Entrapment efficiency: The drug is nicardipine hydrochloride were developed
extracted by a suitable method, analysed and were evaluated in vivo. The formulation
and is calculated from compared with commercially available
Practical amount of drug present MICARD capsules using rabbits. Plasma
× 100 concentration time curves showed a longer
Theoretical drug content duration for administration (16 hours) in the
(iv) In vitro floating ability (Buoyancy %): sustained release floating capsules as
A known quantity of microspheres are compared with conventional MICARD
spread over the surface of a USP (Type II) capsules (8 hours). [27]
dissolution apparatus filled with 900 ml of ii) Site-Specific Drug Delivery: These
0.1 N HCl containing 0.002% v/v Tween systems are particularly advantageous for
80 and agitated at 100 rpm for 12 hours. drugs that are specifically absorbed from
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