3. INTRODUCTION
•
•
•
•
Drug delivery systems are used for maximizing therapeutic index of the drug and
also for reduction in the side effects.
The oral route is considered as the most promising route of the drug delivery and
effective oral drug delivery may depend upon many factors such as gastric
emptying process, gastrointestinal transit time of the dosage form, drug release
from the dosage form and site of absorption of drug.
To modify the GI transit time is one of the main challenge in the development of
oral controlled drug delivery system.
Gastric emptying of pharmaceuticals is highly variable and dependent on the
dosage form and the fed/fasted state of the stomach. Normal gastric residence
time usually ranges between 5 minutes to 2 hours. In the fasted state the electrical
activity in the stomach – the inter digestive myoelectric cycle or migrating
myoelectric complex (MMC) governs the activity and the transit of dosage forms. It
is characterized by four Phases:
5. •
•
•
•
•
Drugs having a short half-life are eliminated quickly from the blood circulation.
Various oral controlled delivery systems have been designed which can overcome
the problems of unpredictable gastric emptying due to physiological problems and
presence of food and also release the drug to maintain its plasma concentration
for a longer period of time. This has led to the development of oral gastroretentive
floating dosage forms.
This dosage form improves bioavailability, therapeutic efficacy and may allow a
reduction in the dose because of steady therapeutic levels of drug.
Drug absorption from the GIT is a complex procedure and is subject to many
variables.
Controlled release drug delivery systems that retain in the stomach for a long time
have many advantages over sustained release formulations.
GRDDS are advantageous for drugs like
Antacids
Poorly soluble in intestine
absorbed in stomach
Narrow absorption window and site specific delivery
From the formulation and technological point of view, floating drug delivery
system (FDDS) is considerably easy and logical approach in development of GRDFs.
6. FACTORS AFFECTING FDDS
•
•
•
•
•
•
•
•
•
•
•
•
•
Density
Size : 7.5 mm
Shape : Tetrahedron and ring-shaped devices
Single or multiple unit formulations
Fed or fasted state
Nature of the meal
Caloric content
Frequency of feeding
Gender
Age
Posture
Biological factors
Concomitant drug administration
9. NON EFFERVESCENT FDDS
HYDRODYNAMICALLY BALANCED SYSTEMS
Excipients
Gel forming hydrocolloid
Shape and bulk density
Buoyancy
Sustained drug release
Receding boundary
Working principle of the hydrodynamically balanced systems (HBS)
10. •
A recent patent issued to G.D. Searle and Co. described a bilayer buoyant dosage
form consisting of a capsule, which included a non-compressed bilayer
formulation.
• Each layer included a hydrocolloid gelling agent such as hydroxy
propylmethylcellulose (HPMC), gums, polysaccharides and gelatin, which upon
contact with gastric fluid formed a gelatinous mass, sufficient for cohesively
binding the drug release layer and floating layer.
• CR floating tablets of theophylline using agar and light mineral oil :
Preparation : Tablets were made by dispersing a drug/ mineral oil mixture in a
warm agar gel solution and pouring the resultant mixture into tablet molds, which
on cooling and air drying formed floatable CR tablets.
• A multilayered, flexible, sheet-like medicament device that was buoyant in the
gastric juice of the stomach and had SR characteristics.
• The device consisted of at least one dry, self supporting carrier film a barrier film
overlaying the carrier film.
• SR floating tablets that were hydrodynamically balanced in the stomach for an
extended period of time until all the drug-loading dose was released.
12. HALLOW MICROSPHERES
•
•
•
•
Hollow microspheres are considered as one of the most promising buoyant
systems as they possess the unique advantages of multiple unit systems as well as
better floating properties, because of the central hollow space inside the
microsphere.
The general techniques involved in their preparation include simple solvent
evaporation, and solvent diffusion and evaporation.
The drug release and better floating properties mainly depend on the type of
polymer, plasticizer and the solvents employed for the preparation.
Polymers used are Cellulose acetate, Chitosan, Eudragit, Acrycoat, Methocil,
Polyacrylates, Polyvinyl acetate, Agar, Polyethylene oxide, Polycarbonates, Acrylic
resins and Polyethylene oxide.
13. •
•
•
•
•
•
Drug-loaded polycarbonate microspheres using a solvent evaporation technique.
Polymers such as polycarbonate has been used to develop hollow microspheres
that were capable of floating on the gastric fluid and released their drug contents
for prolonged period of time.
Hollow microspheres (microballoons) with drug in their outer polymer shells,
prepared by a novel emulsion solvent diffusion method.
Invitro testing, the microballoons floated continuously over the surface of an
aqueous or an acidic dissolution medium containing surfactant for more than 12 hr
A patent assigned to Eisai Co. Ltd. of Japan described a floatable coated shell
which consisted essentially of a hollow globular shell made from polystyrene. The
external surface of the shell was coated with an under-coating and a final coating.
While the former was a layer of a cellulose acetate phthalate, the latter consisted
of a layer of ethyl cellulose and HPMC in combination with an effective amount of
a pharmaceutically active ingredient selected from the group consisting of a gastric
acid secretion inhibitor, a gastric acid neutralizer and an anti-pepsin inhibitor.
15. •
•
•
•
•
•
A multiple-unit floating dosage form from freeze-dried calcium alginate beads
Spherical beads of approximately 2.5 mm in diameter were produced by dropping
a sodium alginate solution into aqueous calcium chloride.
After the internal gelation was complete, beads were separated from the solution
and snap-frozen in liquid nitrogen before being freeze-dried at -40°C for 24h.
The results of resultant-weight measurements suggested that these beads
maintained a positive floating force for over 12 h.
A multiple-unit system that contained an air compartament was prepared . The
units forming the system were composed of a calcium alginate core separated by
an air compartment from a membrane of calcium alginate or calcium alginate
/PVA.
The porous structure generated by leaching of the PVA, which was employed as a
water-soluble additive in the coating composition, was found to increase the
membrane permeability, preventing the collapse of the air compartment.
The in vitro results suggested that the floating ability increased with an increase in
PVA concentration and molecular weight.
17. EFFERVESCENT FDDS
•
•
•
•
•
These buoyant delivery systems utilize matrices prepared with swellable polymers
such as Methocel or 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.
Single unit type : Includes single layered or bilayered tablet for sustained release.
Also formulated as capsule.
Multiple-unit type : The system was found to float completely within 10 min and
approximately 80% remained floating over a period of 5 h irrespective of pH and
viscosity of the test medium.
While the system was floating, a drug (p-amino- benzoic acid) was released. A
variant of this approach utilizing citric acid (anhydrous) and sodium bicarbonate as
effervescing agents and HPC-H grade as a release controlling agent has also been
reported
In vitro results indicated a linear decrease in the FT of the tablets with an increase
in the amount of effervescing agents in the range of 10–20%.
18. (a) A multiple unit dosage form. (b) Stages of floating mechanism: (A)
penetration of water; (B) generation of CO2 and floating; (C) dissolution of
drug. Key: (a) conventional 2 SR pills; (b) effervescent layer; (c) swellable
layer; (d) expanded swellable membrane layer; (e) surface of water in the
beaker 37°C).
20. •
•
•
•
•
Floating bioadhesive system : The carbonates, in addition to imparting buoyancy to
these formulations, provide the initial alkaline microenvironment for polymers to gel .
Moreover, the release of CO2 helps to accelerate the hydration of the floating tablets,
which is essential for the formation of a bioadhesive hydrogel.
Floating ion exchange resin beads :
componets : Resin beads,
bicarbonate,
negatively charged drug,
semipermeable membrane.
Floating dosage forms with an in situ gas generating mechanism are expected to have
greater buoyancy and improved drug release characteristics.
However, the optimization of the drug release may alter the buoyancy and, therefore, it
is sometimes necessary to separate the control of buoyancy from that of drug release
kinetics during formulation.
It is noteworthy here that release kinetics for effervescent floating systems significantly
deviate from the classical Higuchi model and approach zero-order kinetics systems
23. RAFT FORMING SYSTEMS
Raft forming systems have received much attention for the
delivery of antacids and drug delivery for gastrointestinal
infections and other disorders.
Mechanism of raft formation
Ingredients – gel forming agents and alkaline bicarbonates.
Antacid raft forming floating system – alginic acid ,
sodium bicarbonate, and an acid neutralizer .
A patent assigned to Reckitt and Colman Products Ltd.,
describes a raft forming formulation for the treatment of
Helicobacter pylori (H. Pylori) infections in the GIT.
24. EVALUATION OF FLOATING DRUG DELIVERY
SYSTEMS
Measurement of buoyancy capabilities of the FDDS
•
•
•
•
It was given by the vectorial sum of buoyancy F(b) and gravitational forces F(g) acting
on the test object.
F = Fb - Fg
F = ( df – ds ) gV = (df – W/V) gV
Dissolution tests generally performed using USP dissolution apparatus. USP 28
states the dosage unit is allowed to sink to the bottom of the vessel before
rotation of the blade is started.
A helical wire sinker was applied to the swellable floating system of theophylline,
which is sparingly soluble in water and concluded that the swelling of the system
was inhibited by the wire helix and the drug release also slowed down.
To overcome this limitation a method was developed in which the floating drug
delivery system was fully submerged under a ring or mesh assembly and an
increase in drug release was observed.
25. •
Surface morphology was observed by SEM, which serves to confirm qualitatively a
physical observation relating to surface area.
•
Hollow structure of microspheres made of acrylic resins was estimated by by measuring
particle density (Pp) by a photographic counting method and a liquid displacement
method.
•
An image analyzer was used to determine the volume (v) of particles (n) of weight (w):
P = w/v
where porosity Ε = ( 1 – Pp – Pt) × 100
•
Bulgarelli et al., developed casein gelatin beads and determined their porosity by
mercury intrusion technique.
•
The principle of this technique is that pressure (P) required to drive mercury through a
pore decreases as described by the Washburn equation:
P = (– 4 σ cos θ) d
26. Floating time and dissolution
•
•
•
Done in stimulated gastric fluid or 0.1 mol/l HCl maintained at 37˚C.
Floating lag-time and floation time
It is determined using USP dissolution apparatus containing 900 ml 0.1 mol/l HCl
as the dissolution medium at 37˚C.
Drug release
Content uniformity, hardness, friability (tablets)
Drug loading, drug entrapment efficiency, particle size
analysis, surface characterization (for floating microspheres
and beads)
•
•
•
The percentage drug loading is calculated by dividing the amount of drug in the
sample by the weight of total beads or microspheres.
The particle size and the size distribution of the beads or microspheres are
determined in the dry state by optical microscopy.
The external and cross-sectional morphology (surface characterization) is carried
out by scanning electron microscopy (SEM).
27. X-ray/gamma scintigraphy
•
•
It helps to locate the dosage form in the GIT and it can be used to predict and
correlate the gastric emptying time and the passage of the dosage form in the GIT.
The inclusion of a λ-emitting radio-nuclide in a formulation allows indirect external
observation using a λ-camera or scintiscanner.
Pharmacokinetic studies
•
•
•
Sawicki studied the pharmacokinetics of verapamil, from floating pellets
containing the drug, filled into a capsule, and compared with conventional
verapamil tablets with a similar dose (40 mg).
The tmax and AUC values for floating pellets were comparatively higher than those
obtained for the conventional verapamil tablets .
Very little difference was found between the Cmax values of both formulations,
suggesting the improved bioavailability of the floating pellets compared with the
conventional tablets.
Specific gravity
28. Drug and polymers
Floating media/Dissolution medium and method
Pentoxyfylline (HPMC K4M)
500ml simulated gastric fluid pH 1.2 (with out enyzme), USP
XXIII dissolution apparatus
Amoxicillin (Calcium alginate)
900ml of deaerated 0.1 M HCl pH 1.2, USP XXII apparatus
Ketoprofen
S100)
(Eudragit
RL
& 20 ml simulated gastric fluid pH 1.2 (with out enyzme), 50 mg
microparticles in 50 ml beaker % of floating is calculated.
900ml of 0.1N HCl or pH 6.8 Phosphate buffer, USP apparatus
1
Verapamil (Propylene foam, 30ml of 0.1N HCl pH 1.2, floatation was studied by placing 60
Eudragit RS, ethyl cellulose)
particles in 30 ml flask
Captopril (HPMC K4M)
900ml 0.1 N HCl pH 1.2 (with out enyzme), USP XXIII
dissolution apparatus II
Theophylline (HPMC K4M, 0.1 N HCl pH 1.2, USP XXIII dissolution apparatus II
PEO)
Furosemide (HPMC 4000 & 100, Gastric fluid pH 1.2, flow through cell flow rate 9ml/min
CMC, PEG)
Piroxicam (Polycarbonate)
Ampicillin (Sodium alginate)
900ml dissolution medium in USP apparatus II
500ml distilled water, JP XII disintegration test medium pH 1.2
and pH 6.8 in JP XII dissolution apparatus with paddle
29. List of drugs explored for various floating dosage forms
Microspheres
Aspirin, griseofulvin,
p-nitroaniline , Ibuprofen,
Terfenadine , Tranilast
Granules
Diclofenac sodium Indomethacin, Prednisolone
Films
Cinnarizine, Drug delivery device
Capsules
Chlordiazepoxide HCl , Diazepam , Furosemide , L-Dopa and
benserazide , Misoprostol
Tablets /Pills
Acetaminophen, Ampicillin , Atenolol ,Chlorpheniramine
maleate, Fluorouracil .
Powders
Several basic drugs.
35. APPLICATIONS
•
•
•
•
•
•
•
•
The administration of diltiazem floating tablet twice a day might be more effective
compared to normal tablets in controlling the blood pressure of hypertensive
patient.
Madopar HBS- containing L-dopa and benserazide - here drug was released and
absorbed over a period of 6-8 hour and maintain substantial plasma concentration
for parkinson’s patients.
Cytotech — containing misoprostol, a synthetic prostaglandin- E1 analog, for
prevention of gastric ulcers caused by non-steroidal anti-inflammatory drugs
(NSAIDS).
As it provides high concentration of drug within gastric mucosa, it is used to
eradicate pylori (A causative organism for chronic gastritis and peptic ulcers).
5-Fluorouracil has been successfully evaluated in patients with stomach neoplasm.
Developing HBS dosage form for tacrine provides a better delivery system and
reduces its GI side effects in alzheimer’s patients.
Treatment of gastric and duodenal cancers.
Alza corporation has developed a gastroretentive platform for the OROS system,
which showed prolong residence time
36. RECENT ADVANCES
•
•
•
•
Ninan Ma et al developed a type of multi-unit floating alginate (Alg) microspheres
by the ionotropic gelation method with calcium carbonate (CaCO3) being used as
gas forming agent.
Rajnikanth and Mishra have developed a floating in situ gelling system for
clarithromycin (FIGC) using gellan as the gelling polymer and calcium carbonate as
the floating agent for the treatment of gastric ulcers, associated with Helicobacter
pylori.
Sher et al have proposed a specific technology, based on combining floating and
pulsatile principles, to develop a drug delivery system, intended for chronotherapy
of arthritis.
Jang et al prepared a gastro-retentive drug delivery system of DA-6034, a new
synthetic flavonoid derivative, for the treatment of gastritis using an effervescent
floating matrix system (EFMS).
37. CONCLUSION
•
The currently available polymer-mediated noneffervescent and effervescent FDDS,
designed on the basis of delayed gastric emptying and buoyancy principles, appear to
be an effective and rational approach to the modulation of controlled oral drug delivery.
• The FDDS become an additional advantage for drugs that are absorbed primarily in the
upper segments of GI tract, i.e., the stomach, duodenum, and jejunum.
• Some of the unresolved, critical issues related to the rational development of FDDS
include
the quantitative efficiency of floating delivery systems in the fasted and fed states;
the role of buoyancy in enhancing GRT of FDDS; and
the correlation between prolonged GRT and SR/PK characteristics.
•
Finally, with an increasing understanding of polymer behavior and the role of the
biological factors mentioned above, it is suggested that future research work in the
floating drug delivery systems should be aimed at discovering means to accurately
control the drug input rate into the GI tract for the optimization of the pharmacokinetic
and toxicological profiles of medicinal agents.
38. REFERENCES
1.
Brahma N. Singh, Kwon H. Kim. A review of floating drug delivery systems: an
approach to oral controlled drug delivery via gastric retention . Journal of
Controlled Release .2000; 63 , 235-259.
2.
Shweta Arora, Javed Ali, Alka Ahuja, Roop K. Khar, and Sanjula Baboota. Floating
Drug Delivery Systems: A Review. AAPS PharmSciTech 2005; 6 (3) : Article 47
(http://www.aapspharmscitech.org).
S. H. Shahaa, J. K. Patel, K. Pundarikakshudu, N. V. Patel. An overview of a gastroretentive floating drug delivery system. Asian Journal of Pharmaceutical Sciences
2009; 4 (1): 65-80
3.
4.
Pooja Mathur, Kamal Saroha, Navneet Syan , Surender Verma and Vipin Kumar
Floating drug delivery system: An innovative acceptable approach in
gastroretentive drug delivery. Archives of Applied Science Research, 2010; 2
(2):257-270. (http://scholarsresearchlibrary.com/archive.html)
39. 5. Bulgarelli E, Forni F, Bernabei MT. Effect of matrix composition and process
conditions on casein gelatin beads floating properties. Int J Pharm.
2000;198:157Y165.
6. Ninan M; Lu X; Wanga Q; Zhanga X. Int J Pharm, 2008, 358, 82-90.
7. Sawicki W. Eur J Pharm Biopharm, 2002, 53, 29-35.
8. Janga S; Lee J; Park S. Int J Pharm, 2008, 356, 88-94.
9. Rajinikanth P; Mishra B. J Cont Rel, 2008, 25, 33-41.
