Floating Drug Delivery Systems A Review

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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
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.

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
   . 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-
alginate     gels        ,  bioadhesive      or                      aminobenzoic        acid,       furosemide,
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

          S.Gopalakrishnan et al / Journal of Pharmaceutical Science and Technology Vol. 3 (2), 2011,548-554

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.

         S.Gopalakrishnan et al / Journal of Pharmaceutical Science and Technology Vol. 3 (2), 2011,548-554

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]

          S.Gopalakrishnan et al / Journal of Pharmaceutical Science and Technology Vol. 3 (2), 2011,548-554

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
Effervescent Floating Liquid        hydroxide,                    LIQUID
                                                                                         Glaxo Smith Kline,INDIA
alginate Preparation                Magnesium                     GAVISON
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

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.

         S.Gopalakrishnan et al / Journal of Pharmaceutical Science and Technology Vol. 3 (2), 2011,548-554

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

          S.Gopalakrishnan et al / Journal of Pharmaceutical Science and Technology Vol. 3 (2), 2011,548-554

stomach or the proximal part of the small                        [4]     Kawashinia, Y., Niwa. T. and Takcuchi, H.,
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