INTRODUCTION:
Oral drug delivery is the preferred route for drug administration because it is more
natural and less invasive than other traditional routes, such as intravenous and intramuscular
injections. This, in turn, increases patient compliance and improves safety compared with
other methods.[1]
Oral sustained drug delivery system is complicated by limited,
1. Gastric residence times (GRTs).
2. Rapid GI transit can prevent complete drug release in the absorption zone and reduce the
efficacy of the administered dose since the majority of drugs are absorbed in stomach or the
upper part of small intestine.[3]
These limits promoted the development of gastroretentive drug delivery systems
(GRDDSs). Gastroretentive dosage forms are drug delivery systems which remain in the
stomach for an extended period of time and allow both spatial and time control of drug
liberation. Basically gastroretentive systems swells following ingestion and is retained in the
stomach for a number of hours, while it continuously releases the incorporated drug at a
controlled rate to preferred absorption sites in the upper intestinal tract.[5]
ADVANTAGES: [7-9]
1. Swellable tablet will remains in the solution for prolonged time even at the alkaline
pH of the intestine.
2. It is advantageous for drugs meant for local action in the stomach eg: Antacids
3. Swellable dosage forms are advantageous in case of vigorous intestinal movement
and in diarrhoea to keep the drug in floating condition in stomach to get a relatively
better response.
4. Acidic substance like aspirin causes irritation on the stomach wall when come in
contact with it hence; swellable formulations may be useful for the administration of
aspirin and other similar drugs.
5. The GRDDS are advantageous for drugs absorbed through the stomach eg: Ferrous
salts, Antacids.
LIMITATIONS:[10]
More predictable and reproducible swellable properties should be achieved in all the
extreme gastric conditions.
1. Faster swelling properties are required and complete swelling of the system should be
achieved well before the gastric emptying time.
2. Bioadhesion in the acidic environment and high turnover of mucus may raise
questions about the effectiveness of this technique.
3. Not suitable for drugs that may cause gastric lesions e.g. Non- steroidal anti
inflammatory drugs.
4. Drugs that are unstable in the strong acidic environment, these systems do not offer
significant advantages over the conventional dosage forms for drugs that are absorbed
throughout the gastrointestinal tract.
5. The mucus on the walls of the stomach is in a state of constant renewal, resulting in
Unpredictable adherence.
6. In all the above systems the physical integrity of the system is very important and
primary requirement for the success of these systems.
APPROACHES TO GASTRIC RETENTION:-
FACTORS AFFECTING GRDDS:[11]
The gastric retention time of a dosage form is mainly depends upon the factors like
density, size of the dosage form, food nature, age, posture, sex and condition of the patient.
Density of the dosage form:
Dosage forms having a density lower than that of gastric fluid experience floating
behaviour and hence gastric retention. Density <1.0 gm/cm3 of the dosage form is required to
exhibit floating property. However, the floating tendency of the dosage form usually
decreases as a function of time, as the dosage form gets immersed into the fluid, as a result of
the development of hydrodynamic equilibrium.
Nature of food:
Food intake, viscosity and volume of food, caloric value and frequency of feeding
have a profound effect on the gastric retention of dosage forms. The presence or absence of
food in the GIT influences the gastric retention time of the dosage form. Usually the presence
of food in the GIT improves the gastric retention time of the dosage form and thus, the drugs
absorption increases by allowing its stay at the absorption site for a longer period. Again,
increase in acidity and caloric value shows down GET, which can improve the gastric
retention of dosage forms.
Fed or unfed state:
Under fasting conditions, the GI motility is characterized by periods of strong motor
activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 3 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 gastric retention time of the unit can be
expected to be very short. However, in the fed state, MMC is delayed and GRT is
considerably longer.
Gastrointestinal pH:
Gastric emptying is retarded at low stomach pH and promoted at higher or alkaline
pH. Chemicals that affect gastrointestinal pH also alters drug release. The inhibitory effect of
various acids on gastric emptying decreases with increase in molecular weight and is in the
following order: HCl > acetic > lactic > tartaric > citric. With alkaline solutions, a low base
concentration (1% NaHCO3) increases the gastric emptying rate more than the one of higher
concentration (5%).
GASTROINTESTINAL TRANSIT TIME AND MOTILITY:
Based on fasted and fed states of stomach, there are two distinct patterns of
gastrointestinal motility. The fasted state is associated with some cyclic contractile events
commonly known as Migrating Myoelectric Complex (MMC). Liquid components easily
pass through the partially constricted sphincter. On the contrary, an “antral-sieving” process
retains the large undigested materials. Usually a series of interdigestive events takes place in
stomach. The Migrating Myoelectric Complex (MMC), which governs the gastrointestinal
motility pattern has been described as an alternating cycles of activity and quiescence.
Apparently there are four consecutive phases of activity in MMC.
Fig. 1: Anatomy of the Stomach.
Phase I: It is a quiescent period lasting from 30 to 60 minutes with no contractions.
Phase II: It consists of intermittent contractions that gradually increase in intensity as
the phase progresses and it lasts about 20 to 40 minutes.
Phase III: This is a short period of intense distal and proximal gastric contractions (4
to 5 contractions per minute) lasting about 10 to 20 minutes; these contractions, also known
as “housekeeper wave” sweep gastric contents down to small intestine.
Phase IV: This is a short transitory period of about 0 to 5 minutes, and the
contractions dissipate between the last part of phase III and quiescence of phase I.
The fasted-state emptying pattern is independent of the presence of any indigestible solids in
the stomach. Patterns of contractions in the stomach occur such that solid food is reduced to
particles of less than 1mm diameter that are emptied through the pylorus as a suspension. The
duration of the contractions is dependent on the physiochemical characteristics of the
ingested meal.
Generally, a meal of ~450kcal will interrupt the fasted state motility for about three to
four hours. It is reported that the antral contractions reduce the size of food particles to ≤1mm
and propel the food through the pylorus. However, it has been shown that ingestible solids
≤7mm can empty from the fed stomach in humans.
Different features of stomach:Gastric pH: Fasted healthy subject 1.1 ± 0.15
Fed healthy subject 3.6 ± 0.4
Volume : Resting volume is about 25-50 ml
Gastric secretion: Acid, pepsin, gastrin, mucus and some enzymes about 60 ml with
approximately 4 mmol of hydrogen ions per hour. Effect of food on Gastric secretion: About
3 liters of secretions are added to the food.
Fig. 2: Migrating Myoelectric Complex (MMC).
Table 1: GIT specifications.
Transit
Microbial
Absorbing
Absorption
Section
Length
time
PH
count
surface area
pathway
Stomach
0.2
variable
1-4
<103
0.1
P, C, A
Small
6-10
3±1
5-7.5
103 – 1010
120-200
P, C, A, F,
intestine
I, E, CM.
P – Passive diffusion, C – Aqueous channel transport, A – Active transport
F – Facilitated transport, I – Ion-pair transport, E – Entero-or pinocytosis
CM – Carrier mediated transport.
DRUG CANDIDATES FOR GRDDS:[11]
There are so many drugs used in the gastroretantive dosage form due to some reasons,
the followings are the reasons for selecting criteria for gastroretantive dosage form,
1. Narrow absorption window at upper part of gastrointestinal tract (e.g. levodopa,
riboflavin, calcium, repaglinide, atenolol, theophylline, diltiazem, risedronate)
2. pH-dependant absorption from stomach (acidic drugs). (e.g. furosemide)
3. Drugs which are acting locally in the stomach. (e.g. antacids, antibiotics used for
bacterial ulcers)
4. Drugs which are primarily absorbed in the stomach. (e.g. albuterol, ciprofloxacin)
5. Degradation at higher pH (higher stability at lower pH) (e.g. captopril)
6. Drugs which are poorly soluble at an alkaline pH. (e.g. verapamil)
7. Drugs which are absorbed rapidly from the GI tract. (e.g. amoxicillin)
8. Drugs which degrade in the colon. (e.g. metoprolol).
SWELLING SYSTEMS.[13]
After being swallowed, these dosage forms swell to a size that prevents their passage
through the pylorus. As a result, the dosage form is retained in the stomach for a long period
of time. These systems are sometimes referred to as plug type systems because they tend to
remain lodged at the pyloric sphincter. These polymeric matrices remain in the gastric cavity
for several hours even in the fed state. Sustained and controlled drug release may be achieved
by selecting a polymer with the proper molecular weight and swelling properties. Upon
coming in contact with gastric fluid, the polymer imbibes water and swells. The extensive
swelling of these polymers is a result of the presence of physical–chemical crosslinks in the
hydrophilic polymer network. These cross-links prevent the dissolution of the polymer and
thus maintain the physical integrity of the dosage form. A balance between the extent and
duration of swelling is maintained by the degree of crosslinking between the polymeric
chains. A high degree of crosslinking retards the swelling ability of the system and maintains
its physical integrity for a prolonged period (see below figure). On the other hand, a low
degree of cross-linking results in extensive swelling followed by the rapid dissolution of the
polymer. An optimum amount of cross-linking is required to maintain a balance between
swelling and dissolution.
SWELLABLE POLYMERS:
Because of the peculiar hydration behaviour, both erodible and non-erodible swelling
polymers exhibit.[14]. In this respect, hydrophilic cellulose derivatives, alginic acid,
carrageenans as well as guar, xanthan and locust bean gums represent the most popular
examples, while polyvinyl alcohol (PVA) and polyethylene oxide (PEO) are non-saccharidic
swelling polymers in common use. Due to their consolidated safety, versatility and broad
availability profiles, cellulosic ethers, such as hydroxypropyl methylcellulose (HPMC),
hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and calcium or sodium
carboxymethylcellulose (CMC), have particularly been exploited.[15]
These are also used, Acacia, Pectin, Chitosan, Agar, Casein, Bentonite, Veegum,
Gellan gum.[16]
Fig. 3: Relationship between the degree of cross-linking of the polymeric chains and the
swelling behavior of swelling systems.[13]
PHARMACOKINETIC ASPACTS:[1-3]
Absorption window-validation that the drug is within the category of narrows
1. Absorption window agents:
Currently various experimental techniques are available that permit us to verify the
absorption properties of the tested molecule, to determine the mechanism of intestinal
absorption and to elucidate the permeability at different regions of the GI tract. In general,
appropriate candidates for CR-GRDF are molecules that have poor colonic absorption but are
characterized by better absorption properties at the upper parts of the GI tract. In the case of
absorption by active transporters that are capacity limited, the efficacy of the transport
activity may increase following sustained presentation of the drug to the transporting
enzymes in comparison to non CR mode of administration.
2. Enhanced bioavailability:
Once it has been ascertained that the compound in question is defined as narrow
absorption window, the possibility of improving bioavailability by continuous administration
of the compound to the specific site should be tested. For example, certain bisphosphonates,
including alendronate, are absorbed directly from the stomach. However, the magnitude of
this pathway remains modest even in the case where the prolonged gastric retention of the
bisphosphonate in rats is produced by experimental/surgical means. On the other hand, the
bioavailability of riboflavin and levodopa CR-GRDF is significantly enhanced in comparison
to administration of non-GRDF CR polymeric formulations. It may be concluded that several
different processes, related to absorption and transit of the drug in the gastrointestinal tract,
act concomitantly and influence the magnitude of drug absorption. Therefore, in vivo studies
are necessary to determine the release profile of the drug from the dosage form that will
provide enhanced bioavailability.
3. Reduced frequency of dosing:
For drugs with relatively short biological half-life, sustained and slow input from CRGRDF may result in a flip-flop pharmacokinetics and enable reduced dosing frequency. This
feature is associated with improved patient compliance, and thereby improves therapy.
4. Targeted therapy for local ailments in the upper GI tract:
The prolonged and sustained administration of the drug from the GRDF to the
stomach may be advantageous for local therapy in the stomach and the small intestine. By
this mode of administration, therapeutic drug concentrations may be attained locally while
the systemic concentrations, following drug absorption and distribution, are minimal.
EVALUATIONS:
1. Water uptake study.[6]
The swelling of the polymers can be measured by their ability to absorb water and
swell. The swelling property of the formulation can be determined by various techniques. The
water uptake study can be done by using USP dissolution apparatus II. Distilled water can be
used as medium, 900 ml rotated at 50 rpm. The temperature of medium should be maintained
at 37±0.5 ◦C throughout the study. After a selected time intervals, the tablets should be
withdrawn, blotted to remove excess water and weighed. Swelling characteristics can be
expressed in terms of water uptake (WU) as
𝑊𝑎𝑡𝑒𝑟 𝑢𝑝𝑡𝑎𝑘𝑒 =
(𝑊𝑡. 𝑜𝑓 𝑠𝑤𝑜𝑙𝑙𝑒𝑛 𝑡𝑎𝑏 − 𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑡. 𝑜𝑓 𝑡𝑎𝑏)
× 100
𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑡. 𝑜𝑓 𝑡𝑎𝑏
2. XRay/ gamma scintigraphy.[2]
X‐Ray/Gamma Scintigraphy is a very popular evaluation parameter for swelling
dosage form nowadays. It helps to locate dosage form in the gastrointestinal tract (GIT), by
which one can predict and correlate the gastric emptying time and the passage of dosage form
in the GIT. Here the inclusion of a radio‐opaque material into a solid dosage form enables it
to be visualized by X‐rays. Similarly, the inclusion of a γ‐emitting radionuclide in a
formulation allows indirect external observation using a γ‐camera or scintiscanner. In case of
γ‐scintigraphy, the γ‐rays emitted by the radionuclide are focused on a camera, which helps to
monitor the location of the dosage form in the GIT.
REFERENCES:
1. S. Tao, and T Desai. Gastrointestinal patch systems for oral drug delivery. DDT.
2005; 10(13).
2. A Surana. and R. Kotecha. An overview on various approaches to oral controlled drug
delivery system via gastroretention. International Journal of Pharmaceutical Sciences
Review and Research. 2010; 2(2): 68-72.
3. K Vinod, Vasa Santhosh, S Anbuazaghan, Banji David, A Padmasri, S Sandhya.
Approaches for gastrotentive drug delivery systems International Journal of Applied
Biology and Pharmaceutical Technology. 2010; I(2): 589-601.
4. http://www.pharmabiz.com, Basak S, Chronicle Specials, Floatable Gastroretentives:
Emerging Potentials, Mar- 2006.
5. Deshpande A.A., Shah N.H., Rhodes C.T., Malick W.,Development of a novel
controlled release system for gastric retention, Pharm. Res. 1997; 14: 815-819.
6. Joseph N.H. Laxmi S., Jayakrishnan A. A floating type oral dosage form for
piroxicam based on hollow polycarbonate microspheres: in vitro and in vivo
evaluation in rabbits. J Control Release. 2002; 79(1-3): 71-9.
7. Shinde A, Dr. More H, Gastroretentive Drug Delivery System: An Overview.
Pharmaceutical review. 2008; 6(1).
8. M V Srikanth, B J Ram, S A Sunil, N S Rao, K V R Murthy. Gastroretantive drug
delivery system: Novel approaches and its evaluation – A review. ISSN 0976 – 044X,
Volume 10, Issue 1, September – October 2011; Article-034.
9. A.Pandey, G.Kumar, P.Kothiyal, Y.Barshiliya. A Review on current approaches in
gastro retentive drug delivery system. Asian Journal of Pharmacy and Medical
Science. Vol 2 (4), 2012.
10. Chawla G, Gupta P, Koradia V, Bansal A. Gastroretention a Means to Address
Regional Variability in Intestinal Drug Absorption. Pharmaceutical Technology. July
2003, 50-68.
11. N.A. Peppas, P. Bures, W. Leobandung, H. Ichikawa, Hydrogels in pharmaceutical
formulations, Eur. J. Pharm. Biopharm. 50 (2000) 27–46.
12. Mathu P, Saroha K, Syan N, Verma S, Nanda S, Valecha V. An overview on recent
advancements and developments in gastroretentive buoyant drug delivery system. Der
Pharmacia Sinica.2011, 2 (1):161-169.
13. Hoffman A, Stepensky D, Lavy E, Klausner S, Michael Friedman. Pharmacokinetic
and pharmacodynamic aspects of gastroretentive dosage forms. International Journal
of Pharmaceutics .277 (2004) 141–153.