Peptic ulcer (gastric or duodenal ulcer) is one of the most common disorders affecting the gastrointestinal system. The lifetime cumulative incidence of peptic ulcer disease is more than 10% of adult population in western countries (Ofman et al., 2000). The pathophysiology of peptic ulcer disease is an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide and other peptides and growth factors) and injurious factors (acid and pepsin). The management and prevention of these acid-related disorder are possible either by decreasing the level of gastric acidity or by enhancing mucosal protection (Brunton et al., 2008). Various factors, including genetic, diet, pharmacologic and psychologic might contribute to peptic ulcers (Wyatt, 1989).
Nowadays it is believed that,
Not surprisingly, the wide range of effective medicinal agents available today is one of the greatest scientific achievements. Regardless of the effectiveness and safety of the medicines embedded in dosage forms, the pharmaceutical concept of the latter is growing to be ever more eminent in the management of different diseases. The oral dosage forms of the medications available for
2. Prolongation of GI retention
Scientific and technological advancements have been made in the research and development of different types of drug delivery systems. Keeping up with the rapid development in designing novel drug delivery systems, it is advisable to explore the existing delivery concept and new intra gastric delivery systems which would be expected to overcome the current medication limitations of the treatment of
The most feasible method for achieving a prolonged and predictable drug delivery in the GI tract is to control the gastric residence time by gastro retentive and sustained release dosage forms that have some beneficial in safety and efficacy over normal release systems. This method of application is especially helpful in delivery of sparingly soluble and insoluble drugs used in
One of the advantages of the sustained release dosage forms is that medication is administered less often than other dosage forms reducing fluctuations of drug concentration in the bloodstream. As a result, the patient is not repeatedly subjected to different levels of drug which are less or more than adequate. Nor does the blood chemistry undergo frequent chemical imbalances, which might be risky to the patient's health. Additionally, through gastroretentive dosage forms not only the bioavailability and therapeutic efficacy of drugs are improved but also it may allow for a possible reduction in the dose because of the steady therapeutic levels of drugs. Drugs that have poor solubility in higher pH, absorption windows in stomach, requiring local delivery in stomach could be delivered ideally to the site of action by the gastroretentive formulations. On the other hand, drugs that cause irritation to gastric mucosa and the ones meet first-pass metabolism or have stability problems in gastric fluids are not appropriate for these kinds of drug delivery systems (JavadzadehHamedeyazdan, 2012; Pahwa et al., 2012a; Pawar et al., 2012).
In brief, gastric retention is a means to enable a delivery strategy that will function irrespective of the digestive state, clinical condition, or GI motility of the individuals with longer drug residence time in the stomach being advantageous in superior drug bioavailabilities and also in certifying local action of some drugs in the upper part of the GI tract, that are used in
H. pylori associated peptic ulcer
3.1. Acidic condition of stomach
The human stomach can produce and secrete about 2.2 to 3 L of gastric acid per day with basal secretion levels being typically highest in the evening. Normally no bacteria or viruses can survive in this medium that is composed of digestive enzymes and concentrated hydrochloric acid. Consequently, stomach has been regarded as a sterile ingestion organ for its hostile and acidic environment that could be considered as a barrier for invasion of various microorganisms. However, this notion has been totally changed since
3.2. Pathogenesis of
3.3. Treatments for
H. pylori associated peptic ulcer disease
Basically, the goals for peptic ulcer treatments have been defined as: alleviation of symptoms, healing of the ulceration, prevention of recurrence of ulcer. Primarily, before the bacterium was found, it was believed that stomach ulcers occur when excess acid damaged the gastric mucosa so the treatment was based on reduction or neutralization of that acid (Gisbert et al., 2010; GisbertPajares, 2010). Patients were treated with long-term suppressive therapy by giving acid-blocking medications, for instance, H2-blockers and, more recently, proton pump inhibitors (BreuerGraham, 1999). This kind of treatment could certainly relieve ulcer-related symptoms, heal gastric mucosal inflammation and even heal the ulcer. Unfortunately, it has a high recurrence rate just owing to the lack of basic treatment of the infection and eradication of the bacterium,
3.3.1. Combination therapy
3.3.2. Triple combination therapy
Triple combination therapy, using two antibacterial antibiotics and a proton pump inhibitor, had achieved a high eradication rate and seems to be the most effective regimens for
3.3.3. Quadruple combination therapy
In the case of
3.4. Drug delivery systems for
H. pylori eradication
3.4.1. Importance of drug delivery systems in treatment of diseases
It is judicious to be reminiscent of the GI tract being a primary site for the absorption of drugs with a variety of limitations making the
3.4.2. Stomach and drug delivery systems
As far as we know, the stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the human body located between the esophagus and the small intestine. Surface epithelium of stomach retains its integrity throughout the course of its lifetime, even though it is constantly exposed to a high concentration of hydrochloric acid and powerful enzymes. This self protection mechanism is due to the fact that the specialized goblet cells located in the stomach and continuously secrete a large amount of mucus that remains closely applied to the surface epithelium (Chein, 1992). In general, stomach is an important site of enzyme production with small surface area, offering an imperfect site of absorption (Chein, 1992). The main function of stomach is to store food temporarily, grind it, and then release it slowly in to the duodenum. The process of gastric emptying occurs both during fasting and fed states; however, the pattern of motility differs markedly in the two states. Fasted state is characterized by an inter-digestive series of electrical events which cycle both through the stomach and small intestine every 2–3 h which is called the inter-digestive myoelectric cycle or migrating myoelectric complex (Fell, 1996). In the fed state, the gastric emptying rate is slowed since the feeding results in a lag time prior to the onset of gastric emptying, depending upon the physiological state of the subject and the design of pharmaceutical formulation, the emptying process can last from a few minutes to 12 h. Alterations in gastric emptying occurs due to factors such as age, race, sex, and disease states, as they may seriously affect the release of a drug from the drug delivery system (SinghKim, 2000).
The complex and highly variable nature of gastric emptying process making the
3.4.3. Floating drug delivery systems
One of the approaches followed to extend the residency of medications in the stomach is floating dosage forms with lower density than the gastric fluids to be capable of floating on the gastric juice in the stomach (SinghKim, 2000; Adibkia, Hamedeyazdan et al., 2011). According to the mechanism of buoyancy, two evidently different technologies are applied in development of floating dosage forms, effervescent and non-effervescent systems. In general, the principle rule is indelible in all approaches and that is to float on gastric juice with a specific density of less than 1.004 g/cm of the gastric juice in the stomach.
Besides, multi-particulates of floating dosage forms consisting of small discrete units in which the active substance is offered as a number of small independent subunits are less reliant on gastric emptying, bringing about less inter and intra-subject variability in GI transit time. Moreover, they are also well distributed and less likely to cause local irritation. Nowadays, much emphasis is being laid on the development of multi particulate dosage forms rather than single unit systems due to potential benefits of them such as increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation as well as predictable gastric emptying (MohamadDashevsky, 2007; GuptaPathak, 2008).
A number of factors that affect gastric emptying of a dosage form, such as density, size, and shape of dosage form, concomitant intake of food and drugs such as anticholinergic agents (e.g., atropine, propantheline), opiates (e.g., codeine), prokinetic agents (e.g., metoclopramide, cisapride), and biological factors like gender, posture, age, body mass index, and disease states (e.g., diabetes, Crohn’s disease) could be controlled by these floating dosage forms providing a more convenient medication therapy (SinghKim, 2000).
These systems are also appropriate for drugs which are locally active to the gastric mucosa in the stomach, such as administration of metronidazole (MZ) as an antibiotic for
Considering the fact that prolongation of the local availability of the antibacterial agents show positive effects of increasing in the effectiveness of
Hence, developing an efficient floating dosage form is reliant to a better understanding of the relation among the physiological properties of the GI tract, formulation variables and the performance of these floating systems
Overall, developing an efficient floating dosage form for
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