P S Goudanavar1*, B. Ramesh1, S. R. Fattepur2
1Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B.G. Nagara, Nagamangala Tq., Mandya Dist., 571448 Karnataka.
2Management and Science University, Malaysia.
Peptic ulcer (gastric ulcer and duodenal ulcer) is very common chronic disorder of stomach which is mainly caused by the damage or impairment of stomach lining. Various factors such as pepsin, gastric acid, H. pylori, NSAIDs, prostaglandins, mucous, bicarbonate and blood flow to mucosa play an important role in causing peptic ulcer. In this review article, our main focus is on some important approaches (floating, bioadhesive, high density, swellable and magnetic systems) which are helpful in gastro retention of different dosage forms for treatment of peptic ulcer. Various factors such as composition of meal, nature of meal, gender, age, posture, size, shape, density of the dosage form influence the efficiency of above approaches. Currently, a lot of work is running to improve different types of gastro retentive delivery systems of a wide range of drugs and compensate the effects of above factors. In the future, it is anticipated that they will become of growing significance, finally leading to improved efficiency of various types of pharmacotherapies.
Peptic ulcer is very common disorder of stomach which mainly caused by the damage or impairment of stomach lining. If peptic ulcer found in stomach, they are known as gastric ulcer or if they are found in duodenum (first part of your small intestine), they are known as duodenal ulcer1.
As according to WHO, approximately 4.6 million of people suffer from this disease and according to report of U.S census bureau almost 1.83 % of the total population of the world is affected by this chronic disease2. A peptic ulcer principally occurs due to difference between aggressive factors like pepsin, gastric acid, H. pylori, NSAIDs, prostaglandins, mucous, bicarbonate and blood flow to mucosa etc. An increased use of NSAIDs, alcohol, smoking, and improper eating habits may play as contributing factor. The symptoms related to peptic ulcer are burning pain in the abdomen, heavy felling, stomach pain, nausea, vomiting, weight loss, hematemesis or melena3.
Chemotherapy and surgery is available options to control and treat this disease conditions. Different classes of drugs such as antibiotics (Amoxicillin, Tetracycline, Clarithromycin, Ciprofloxacin, Metronidazole), proton pump inhibitors (Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole), H2 receptor antagonists (Famotidine, Cimetidine, Ranitidine, Nizatidine), prostaglandin analogue (Bismith subcitrate, Bismith subsalcilyate, Sucralfate), and antacids (Magnesium carbonate, Calcium Carbonate, Magnesium hydroxide) are successfully used to treat peptic ulcer4. Various formulations are available in the market for the treatment of the peptic ulcer such as Prilosec (Omeprazole), Prevacid (Lansoprazole), Tagamet (Cimetidine), Zantac (Ranitidine), Amoxil (Amoxicillin) etc. These formulations are available in different forms such as tablets, capsules, liquid, suspensions, emulsions, solutions and parenteral. The above chemotherapy heals ulcers quickly as well as effectively, abolition of H. pylori, and prevents most ulcers from recurring5. The second most important option for treatment for the same is surgery. This option is adopted on those conditions when people don’t respond to medication or to develop critical complications due to disease or chemotherapy. Over three decades, numerous efforts have made in designing a dosage form which can be retained in the upper part of GIT. After the numerous efforts, scientists develop gastro retentive dosage forms (GRDF), which have the ability to retain in the stomach for longer duration of time and produce greatest therapeutic effects against peptic ulcer. In this review article, our major focus on properties as well as applications of GRDF against peptic ulcer.
Need for Gastro retention (GRT)6-9
Gastro retention means retention of dosage forms in the stomach for longer duration of period and continuously releases the drug to the target site. Following situations needs gastro retention which is describe below:
· When the desired action produced only in the stomach part such as antacid and misoprostol.
· When the drug release continuously in controlled manner for longer duration of period.
· When without the need for repeated dosage or high dose frequency.
· When the drug have narrow therapeutic window in GIT such as Riboflavin and Levodopa.
· When the drug primarily absorbed from the stomach or upper part of the GIT such as Calcium supplements, chlordiazepoxide and Cinnarizine.
· When the drug disturb normal colonic bacteria such as Amoxicillin Trihydrate.
· When drugs show low solubility at high pH values such as diazepam, chlordiazepoxide, verapamil HCl.
Gastro retentive Dosage Forms (GRDF):
GRDF stay in the gastric regions for longer duration of period and prolong gastric residence time, so targeting site-specific drug release in the upper GIT for local or systemic effects. GRDF available as Floating systems, Bio adhesive or mucoadhesive systems, Swellable systems, High density systems, Magnetic system etc. to achieve their goal successfully. Numerous factors/elements such as meal, posture, age, gender, size and shape of dosage form, and food frequency etc.10 mainly affects the gastric retention of the dosage forms in the stomach. Table 1 shows the major advantages of GRDF along with their some limitations.
Table 1. Advantages and limitations of gastro retentive delivery systems11-14.
ADVANTAGES OF GRDF
LIMITATIONS OF GRDF
· Biocompatible and biodegradable nature.
· Provides sufficient local action at the diseased site.
· Enhance the bioavailability of encapsulated bioactive molecules.
· Minimum dosing frequency with excellent patient compliance.
· Minimizes the fluctuations of the drug concentrations (narrow therapeutic index) and their side effects.
· Necessitate a satisfactorily high level of liquids in the stomach for the drug delivery maintain to float therein and to work proficiently.
· Drugs which have very narrow acid solubility such as phenytoin etc. are poor candidate for GRDF.
· Drugs that suffer instability in the gastric environment such as erythromycin etc. are unsuitable candidate for GRDF.
Factors Affecting Gastro retention (GRT):
The stomach structure, composition and functioning comprise parameters to be considered in the development of GRDF. There are numerous factors/elements which are responsible for the gastric retention of the dosage forms in the stomach. Table 2 shows the effects of various factors on gastro retention.
Table 2. Factors affecting the gastro retention15-19.
AFFECT THE GASTRORETENTION (GRT)
· High density pellets will shrink to the bottom of the stomach and withstand the peristaltic waves of the stomach wall.
· A density of < 1.0 gm/ cm3 is required to exhibit floating property.
· Approximately 3g/cm3 density have significant gastric residence time.
· Dosage form units with a diameter of more than 7.5 mm are reported to have a GRT.
· Tetrahedron and ring shaped devices have better GRT 90 % to 100 % retention at 24 hours as compared with other shapes.
· Multiple unit formulation show a more expectable release profile.
· Multiple unit formulation permits a large margin of safety.
· Can change the motility pattern of the stomach to a fed state.
· Successive meals increased the GRT by over 400 minutes due to low frequency of MMC.
· GRT is less in males as compare to female as according to the weight, height and body surface.
· Elederly people (over 70) have a significantly longer GRT.
Concomitant drug administration
· Anticholinergics like Atropine, Propantheline
· Opiates like Codeine,
· Prokinetic agents like Metoclopramide, Cisapride.
Approaches of Gastro retentive Dosage Forms:
Over the three decades numerous effort have made in designing a dosage form which can retained in the upper part of GIT. Numerous approaches are successfully used for longer retention of dosage form in the target site. Some important approaches were shown in Figure 1.
Figure 1. Approaches to achieve gastric retention.
(A) Floating Drug Delivery System (FDDS):
These systems remain afloat in the stomach for the longer duration of time with the prospective release of drug to the target place. The two main possible reasons for floating are (i) their low density than gastric contents or (ii) formation of gaseous phase inside the stomach subsequently they come in contact with gastric environment. Finally, the drug is released slowly at the desired rate from the system and better control of the fluctuation in plasma drug concentration. FDDS can be divided into effervescent and non- effervescent systems17.
(A.1) Effervescent systems:
In these systems, drugs are incorporated into an inflatable chamber which contain a liquid such as ether, cyclopentane etc. This device also consist of biodegradable plugs made up of biocompatible polymers such as polyvinyl alcohol, polyvinyl chloride etc. that was gradually dissolves and release the gas from the inflatable chamber and collapse after predetermined time to permit the spontaneous ejection of the inflatable system from the stomach. Gas – generating systems also include in these systems which utilizes effervescent reaction between carbonate /bicarbonate salts and tartaric acid /citric acid to liberate carbon-di-oxide. Finally they entrapped in the jellified hydrocolloids layers of the system thus decreasing the specific gravity and making it float over chime20.
(A.2) Non effervescent systems:
These systems incorporate high levels of swellable cellulosic hydrocolloids such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polysaccharide, polycarbophil, Polyacryaltes and polystyrene into a suitable dosage form. These gel formers form a colloidal gel barrier in contact with gastric fluid and control the rate of fluid penetration into the device as well as drug release. Exterior surface of the dosage form dissolves the gel layer and lower the density due to air entrapment into swollen polymers which provide buoyancy to the dosage form 21.
(B) Bioadhesive / mucoadhesive drug delivery system:
These systems are mainly used to enhance the drug absorption in a site specific control manner on the target site. Various bioadhesive polymers such as poly acrylic acid, chitosan, cholestyramine, sodium alginate, HPMC, Tragacanth, dextrin, polyethylene glycol (PEG), polylactic acids etc. are mainly used for prolongation of the gastric retention on to the epithelial surface in the stomach.22,23. Another basic mechanism behind for dosage form can stick to the mucosal surface are:
(B.1) The wetting theory
· Based on the ability of the bioadhesive polymers to spread on the mucous layers.
· Hydrophilic polymers become sticky due to high absorption of large amount water and achieved bioadhesive properties.
(B.2) Bonding mediated theory
· Mainly two types of bonds such as physical as well as chemical bond involved in polymer adhesion with mucin.
· Physical bonding involved the physical entanglement of the polymer with the mucin.
· Chemical bond may be covalent, or ionic in nature.
· Secondary chemical bonds consist of dispersive interactions such as Vander wall interactions.
(B.3) Receptor mediated adhesions:
· Some polymers increase their gastric retention of dosage forms by binding to specific receptor sites on the surface of the cells.
· For example, Tomato lectin specially interacts with the sugar group of mucous.
(C) Expandable / Swellable drug delivery systems:
A dosage form will survive gastric transit in the stomach if it is bigger than the pyloric sphincter but may cause gastric obstruction. These systems incorporate 3 important configurations to avoid such problems.
· A small configuration for oral intake
· An expanded gastro retentive form
· Enable evacuation following drug release.
In these systems, carrier such as capsules incorporated into biodegradable polymers compressed systems which extend in the stomach. The swelling is commonly outcome from osmotic absorption of the water 24. The device regularly decreased in volume and firmness as a result of drug and expanding agents and /erosion of the polymer envelope, enabling its elimination. The major advantages of these systems are the dosage form is small enough to be swallowed and swells in gastric liquids 25, 26.
(D) High density drug delivery system:
High density pellets will shrink to the bottom of the stomach as well as entrapped in the folds of the antrum and withstand the peristaltic waves of the stomach wall 52. Sedimentation has working a retention mechanism for high density system. Various polymers such as barium sulfate, zinc oxide, iron oxide, titanium dioxide successfully used to fabricate these types of delivery systems due to their high density. Approximately 3g/cm3 density have significant gastric residence time but these systems are very difficult to prepare with a large amount of drugs (50%) and to achieve the required density of 2.4-2.8g/cm2. Effectiveness of this system in human beings was not observed and no system has been marketed27,28.
(E) Magnetic drug delivery system:
This system contains small internal magnet into the dosage form and deliver to the target site by using magnet which was placed on the abdomen over the portion of the stomach29. The main advantages of these systems are absolute drug targeting, increase the absorption and bioavailability of encapsulated drug as well as dosage forms. However, a degree of correct position on the stomach is a very hard work and it needs a lot of practice30. Saravanam et al (2009) try to make localize ranitidine loaded microspheres in the stomach by magnetic means. In this technique, they formulated gelatin magnetic microspheres loaded with ranitidine hydrochloride by using emulsification-cross linking technique. The in vivo study showed the efficiency of microspheres to be retained in the stomach over a period of 8 hours in the experimental rats31.
The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body and also to achieve and maintain the desired plasma concentration of the drug for a particular period of time. However, incomplete release of the drug, shorter residence times of dosage forms in the upper GIT leads to lower oral bio-availability. Gastro retentive drug delivery systems provide the benefit of better absorption of drugs that are absorbed from upper part of stomach. Local action of drug is increased as the system rests in stomach for longer time. This leads to less frequent dosing and enhanced efficiency of the treatment. Good stability and better drug release as compared to other conventional dosage forms make such system more reliable.
CONFLICT OF INTEREST:
Authors declare no conflict of interest.
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Received on 07.04.2020 Modified on 15.06.2020
Accepted on 04.08.2020 © RJPT All right reserved