To avoid this
limitation, the development of oral sustained-controlled release formulations
is an attempt to release the drug slowly into the gastrointestinal tract (GIT)
and maintain an effective drug concentration in the systemic circulation for a
long time. After oral administration, such a drug delivery would be retained in
the stomach and release the drug in a controlled manner, so that the drug could
be supplied continuously to its absorption sites in the gastrointestinal tract
(GIT). These drug delivery systems suffer from mainly two adversities: the
short gastric retention time(GRT) and unpredictable short gastric emptying time
(GET), which can result in incomplete drug release from the dosage form in the
absorption zone (stomach or upper part of small intestine) leading to
diminished efficacy of administered dose . To formulate a site-specific orally
administered controlled release dosage form, it is desirable to achieve a
prolong gastric residence time by the drug delivery. Prolonged gastric retention
improves bioavailability, increases the duration of drug release, reduces drug
waste, and improves the drug solubility that are less soluble in a high pH
environment. Also prolonged gastric retention time (GRT) in the stomach could
be advantageous for local action in the upper part of the small intestine e.g.
treatment of peptic ulcer, etc. Gastro retentive drug delivery is an approach
to prolong gastric residence time, thereby targeting site-specific drug release
in the upper gastrointestinal tract (GIT) for local or systemic effects.
NEED FOR
GASTRORETENTIVE DRUG DELIVERY SYSTEM
1. Drugs acting locally in the stomach
E.g. Antacids and drugs for H. Pylori viz., Misoprostol
2. Drugs that are primarily absorbed in the stomach
E.g. Amoxicillin
3. Drugs that is poorly soluble at alkaline pH
E.g. Furosemide, Diazepam, Verapamil, etc.
4. Drugs with a narrow window of absorption
E.g. Cyclosporine, Methotrexate, Levodopa, etc.
5. Drugs which are absorbed rapidly from the GI tract.
E.g. Metonidazole, tetracycline.
6. Drugs that degrade in the colon.
E.g. Ranitidine, Metformin HCl.
7. Drugs that disturb normal colonic microbes
E.g. antibiotics against Helicobacter pylori.
1. Drugs acting locally in the stomach
E.g. Antacids and drugs for H. Pylori viz., Misoprostol
2. Drugs that are primarily absorbed in the stomach
E.g. Amoxicillin
3. Drugs that is poorly soluble at alkaline pH
E.g. Furosemide, Diazepam, Verapamil, etc.
4. Drugs with a narrow window of absorption
E.g. Cyclosporine, Methotrexate, Levodopa, etc.
5. Drugs which are absorbed rapidly from the GI tract.
E.g. Metonidazole, tetracycline.
6. Drugs that degrade in the colon.
E.g. Ranitidine, Metformin HCl.
7. Drugs that disturb normal colonic microbes
E.g. antibiotics against Helicobacter pylori.
DRUGS THOSE ARE UNSUITABLE FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS
1.Drugs that have very limited acid solubility.
E.g. phenytoin etc.
2.Drugs that suffer instability in the gastric environment.
E.g. erythromycin etc.
3.Drugs intended for selective release in the colon.
E.g. 5- amino salicylic acid and corticosteroids etc.
E.g. phenytoin etc.
2.Drugs that suffer instability in the gastric environment.
E.g. erythromycin etc.
3.Drugs intended for selective release in the colon.
E.g. 5- amino salicylic acid and corticosteroids etc.
Physiology of the Stomach
The GI tract is essentially a tube about nine metres long that runs through the middle of the body from the mouth to the anus and includes the throat (pharynx), oesophagus, stomach, small intestine (consisting of the duodenum, jejunum and ileum) and large intestine (consisting of the cecum, appendix, colon and rectum).
The GI tract is essentially a tube about nine metres long that runs through the middle of the body from the mouth to the anus and includes the throat (pharynx), oesophagus, stomach, small intestine (consisting of the duodenum, jejunum and ileum) and large intestine (consisting of the cecum, appendix, colon and rectum).
Drug absorption in the case of-
(a) Conventional dosage forms,
(b) Gastroretentive drug delivery systems
(a) Conventional dosage forms,
(b) Gastroretentive drug delivery systems
Gastric
Emptying
Gastric emptying occurs during fasting as well as fed states. Gastric emptying occurs s a result of gastric contraction, the nature of which depends on the contents of the stomach. Thus gastric emptying can be conveniently classified into gastric emptying of liquid, digestible solids, and indigestible solids. Liquids empty from the stomach as a result of Intragastric pressure generated by slow muscular contractions occurring mainly from the proximal stomach (i.e. the upper body of the stomach). The removal of liquid is First order, i.e., the volume of liquid emptied per unit time is directly proportional to the volume remaining in the stomach. Digestible solids are known to be emptied only when they have been changed to a thick, creamy substance called chyme.
Indigestible solids including oral dosage forms are known to be emptied from the stomach in fasting state by a distinct cycle of Myoelectrical activity known as the Interdigestive Migrating myoelectric complex (IMMC).
Gastric emptying occurs during fasting as well as fed states. Gastric emptying occurs s a result of gastric contraction, the nature of which depends on the contents of the stomach. Thus gastric emptying can be conveniently classified into gastric emptying of liquid, digestible solids, and indigestible solids. Liquids empty from the stomach as a result of Intragastric pressure generated by slow muscular contractions occurring mainly from the proximal stomach (i.e. the upper body of the stomach). The removal of liquid is First order, i.e., the volume of liquid emptied per unit time is directly proportional to the volume remaining in the stomach. Digestible solids are known to be emptied only when they have been changed to a thick, creamy substance called chyme.
Indigestible solids including oral dosage forms are known to be emptied from the stomach in fasting state by a distinct cycle of Myoelectrical activity known as the Interdigestive Migrating myoelectric complex (IMMC).
FACTORS CONTROLLING GASTRIC RETENTION OF
DOSAGE FORMS
Density of dosage forms
A density of <1.0 gm/cm3 is required to exhibit floating property.
A density of <1.0 gm/cm3 is required to exhibit floating property.
Shape and size of the dosage form
Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. Ring-shaped and tetrahedron-shaped devices have a better gastric residence time as compared with other shapes.
Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. Ring-shaped and tetrahedron-shaped devices have a better gastric residence time as compared with other shapes.
Food intake and its nature
The presence or absence of food in the gastrointestinal tract (GIT) influences the gastric retention time (GRT) of the dosage form. Usually the presence of food in the gastrointestinal tract (GIT) improves the gastric retention time (GRT) 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 gastric emptying time (GET), which can improve the gastric retention of dosage forms.
The presence or absence of food in the gastrointestinal tract (GIT) influences the gastric retention time (GRT) of the dosage form. Usually the presence of food in the gastrointestinal tract (GIT) improves the gastric retention time (GRT) 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 gastric emptying time (GET), which can improve the gastric retention of dosage forms.
Fed or unfed state
Under fasting conditions: GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (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. However, in the fed state, MMC is delayed and GRT is considerably longer.
Under fasting conditions: GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (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. However, in the fed state, MMC is delayed and GRT is considerably longer.
Nature of meal
Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
Disease state
Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT.
Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT.
FACTORS CONTROLLING GASTRIC RETENTION OF
DOSAGE FORMS
Density of dosage forms
A density of <1.0 gm/cm3 is required to exhibit floating property.
A density of <1.0 gm/cm3 is required to exhibit floating property.
Shape and size of the dosage form
Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. Ring-shaped and tetrahedron-shaped devices have a better gastric residence time as compared with other shapes.
Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. Ring-shaped and tetrahedron-shaped devices have a better gastric residence time as compared with other shapes.
Food intake and its nature
The presence or absence of food in the gastrointestinal tract (GIT) influences the gastric retention time (GRT) of the dosage form. Usually the presence of food in the gastrointestinal tract (GIT) improves the gastric retention time (GRT) 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 gastric emptying time (GET), which can improve the gastric retention of dosage forms.
The presence or absence of food in the gastrointestinal tract (GIT) influences the gastric retention time (GRT) of the dosage form. Usually the presence of food in the gastrointestinal tract (GIT) improves the gastric retention time (GRT) 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 gastric emptying time (GET), which can improve the gastric retention of dosage forms.
Fed or unfed state
Under fasting conditions: GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (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. However, in the fed state, MMC is delayed and GRT is considerably longer.
Under fasting conditions: GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (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. However, in the fed state, MMC is delayed and GRT is considerably longer.
Nature of meal
Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
Disease state
Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT.
Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT.
ADVANTAGES OF GASTRORETENTIVE DELIVERY SYSTEMS
1) Improvement of bioavailability and therapeutic efficacy of the drugs and possible reduction of dose e.g. Furosemide
2) Maintenance of constant therapeutic levels over a prolonged period and thus reduction in fluctuation in therapeutic levels minimizing the risk of resistance especially in case of antibiotics. E.g. b-lactam antibiotics (penicillins and cephalosporins)
3) For drugs with relatively short half life, sustained release may result in a flip- flop pharmacokinetics and also enable reduced frequency of dosing with improved patient Compliance.
4) They also have an advantage over their conventional system as it can be used to overcome the adversities of the gastric retention time (GRT) as well as the gastric emptying time (GET).
5) Gastro retentive drug delivery can produce prolongs and sustains release of drugs from dosage forms which avail local therapy in the stomach and small
intestine. Hence they are useful in the treatment of disorders related to stomach and small intestine.
6) The controlled, slow delivery of drug form gastro retentive dosage form provides sufficient local action at the diseased site, thus minimizing or eliminating systemic exposure of drugs. This site-specific drug delivery reduces undesirable Effects of side effects.
7) Gastro retentive dosage forms minimize the fluctuation of drug concentrations and effects. Therefore, concentration dependent adverse effects that are associated with peak concentrations can be presented. This feature is of special importance for drug with a narrow therapeutic index.
8) Gastro retentive drug delivery can minimize the counter activity of the body leading to higher drug efficiency.
Future Prospects
While
the control of drug release profiles has been a major aim of pharmaceutical
research and development in the past two decades, the control of GI transit
profiles could be the focus of the next two decades and might result in the
availability of new products with new therapeutic possibilities and substantial
benefits for patients.
Comments
Post a Comment