1、胃内滞留漂浮给药系统中使用草药根除幽门螺旋杆菌的研究进展作者：Shreeraj H. SHAH, Jayvadan K. PATEL, Nirav V. PATEL 【关键词】 幽门螺旋杆菌 ; 胃滞留剂; 漂浮剂型; 草药; 黑柯子; 黄连素Helicobacter pylori are very common pathogenic bacteria colonizing about half of all populations and associated with the development of serious gastroduodenal diseases like gastr
2、ic lymphoma, peptic ulcers and acute chronic gastritis. Current drug regimes are not wholly effective. Other problems related with the current drug regimes are lack of patient compliance, side effects and bacterial resistance. Thus, drug delivery to the site of residence in the gastric mucosa may he
3、lp in solving the problems associated with the current drug therapy. Gastric retentive delivery systems potentially allow increased penetration and thus increased drug concentration at the site of action. Floating drug delivery systems, expandable or swellable drug delivery systems and bioadhesive s
4、ystems are the major areas of interest to formulate gastroretentive drug delivery system against H. pylori. Generally, problems with these formulations are lack of specificity and the dependence on mucus turnover, so they fail to persist in the stomach. Gastric mucoadhesive systems are hailed as a p
5、romising technology to address this issue, penetrating the mucus layer and prolonging activity at the mucusepithelial interface. Gastroretentive delivery strategies, specifically with regard to their application as a delivery system to target Helicobacter, are a very attractive field which can cure
6、these troublesome infections.H. pylori is a Gramnegative, microaerophilic, spiral and flagellated bacterium, with unipolarsheathed flagella that provides motility. Its spiral shape and high motility allows it to penetrate mucus, resist gastric emptying and remain in the host gastrointestinal (GI) tr
7、act. It is now firmly established that infection with this bacterium is the cause of chronic active gastritis. Its isolation radically changed the conceptualisation of several chronic gastrointestinal illnesses including gastritis and peptic ulcers, and elimination of the causative organism became t
8、he goal of therapies 1. Estimates from the WHO in 1994 claimed that about half of the worlds population was infected with H. pylori and although most infections are silent, a portion of the infected population will subsequently present with associated disease including chronic gastritis, peptic and
9、duodenal ulcers. About 550 000 new cases a year of gastric cancerabout 55% of the worldwide totalwere attributed to H. pylori, and it was predicted that by 2020 to enter the top ten of leading causes of death worldwide 2, 3. H. pylori is a very diverse specy and cancer risks may be increased with st
10、rains having virulenceassociated genes (cytotoxinassociated gene, CagA), host genetics and environmental factors. The incidence of infection is higher in developing countries with up to 80%90% of adults being infected whereas in developed countries prevalence ranges from 10%50%4.1 Mechanism of H. py
11、lori infectionsInfection with H. pylori occurs predominately in childhood mainly between the ages 1 to 5, via oral ingestion of the bacterium, and lasts until the end of life with intrafamilial transmission being the major route in developed countries. The possible routes of transmission are food an
12、d water. The major feature of H. pylori infection is progressive injury to the gastric mucosa and its function5, 6. The bacterium adheres to the gastric epithelial cells, producing a direct injurious effect that is then amplified by production and release of a vacuolating cytotoxin (VacA)7, 8. H. py
13、lori produces a variety of enzymes and is characterised by a high urease activity. Urea is broken down into bicarbonate and ammonia that protects the bacterium in the acid environment of the stomach. The ammonium ions produced can be toxic to the gastric superficial epithelial cells. Urease stimulat
14、es inflammatory cytokine production and activates mononuclear phagocytes. Although, after colonisation, the host immune defences are stimulated, and there is increased secretory IgA (sIgA) detected in the gastric mucosa and raised specific IgG, while the infected host is not able to eliminate the or
15、ganism. Colonisation results in persistent gastric inflammation but the clinical course of infection can be very variable9.2 Current treatment of H. pylori infectionsThe treatment for eradication of H. pylori is complicated, requiring a minimum of two antibiotics in combination with gastric acid inh
16、ibitors. Although H. pylori is sensitive to many antibiotics in vitro, no single agent is effective alone in vivo. Firstly, the bacterium resides below the gastric mucus adherent to the gastric epithelium and thus access of drugs to this site is limited. Secondly, the strain may have acquired resist
17、ance to the commonly used antimicrobial drugs10. These infections are currently treated with a firstline triple therapy treatment, consisting of one proton pump inhibitor (PPI) and two antibiotics. None of the antibiotics used achieves sufficient eradication when used alone and also require adjuvant
18、 therapy11. This consists of agents increasing pH within the stomach to allow local action of antibiotics not active at low pH, and PPIs are used at a dose equivalent to 20 mg omeprazole twice daily. It was suggested that ranitidine bismuth citrate (RBC) regimens may be less influenced by antibiotic
19、 resistance than PPIbased therapies12.The most effective therapies combine two antibiotics including clarithromycin and amoxicillin with a gastric acid inhibitor. However, increasing resistance to current antibiotics is driving research to produce alternatives to the commonly used therapies. In addi
20、tion to increasing levels of antibiotic resistance, the hostile environment of the stomach, reducing antibiotic bioavailability at the site of action, contributes to failures in treatment13. Current recommended regimes are not wholly effective, for example, triple therapy with bismuth, metronidazole
21、 and amoxicillin or tetracycline has an eradication efficiency of 60%80%, and patient compliance, sideeffects and bacterial resistance can be problematic with this regime14. Alternatives proposed include quadruple therapies, based on, for example, colloidal bismuth subcitrate, tetracycline, metronid
22、azole and omeprazole15. Patient compliance with such a complicated dosage regime could be improved by combining the therapies in a single dosage form, and a capsule containing bismuth biskalcitrate, metronidazole and tetracycline (Helicide) has been developed in an effort to improve patient complian
23、ce and has currently received approval16. There is concern regarding acquired resistance to two of the commonly prescribed antibiotics: clarithromycin and metronidazole. Although not as widespread, resistance to metronidazole can also be problematic but it can be overcome in some cases by lengthenin
24、g the duration of treatment17.3 Drug delivery systems for gastric retentionMajor problems in the eradication of H. pylori are the presence of antibioticresistant bacteria requiring multiple drugs with complicated dosing schedules and bacterial residence in an environment where high drug concentratio
25、ns are difficult to achieve. In order to ensure that the therapy is adequately delivered to the unique niche of the gastric mucosa, development of oral dosage forms with prolonged gastric residence is desirable. Gastric retentive delivery systems have been studied for a number of years, and generall
26、y requirements of such strategies are that the vehicle maintains a controlled release of drug and exhibits prolonged residence time in the stomach. Overcoming the physiological barriers of the human GI tract is a major challenge facing successful development of gastric retentive systems and leads to
27、 problems with reproducibility. In addition to the thick protective mucus layer, gastrointestinal motility patterns are another obstacle facing drug delivery to the stomach. In the fasted state, the interdigestive myoelectric motor complex (IMMC) is a 2hour cycle of peristaltic activity that regulat
28、es motility patterns18. Phase of the IMMC is also called the housekeeper wave and consists of strong, intense contractions designed to remove debris such as undigested food from the stomach19, 20. Gastric residence time will depend on which phase of IMMC is active. In the fed state, the stomach chur
29、ns food to sizes less than 1 mm, which is then emptied to the duodenum. Type of the food determines its residence time in the stomach with liquids emptying rapidly and solids much more slowly. Gastric residence time is generally longer in the fed rather than fasted state. The gastric residence time
30、of dosage forms is also influenced by posture, age, gender, disease status and concomitant medication. A number of different techniques have been explored to increase gastric retention including high density and magnetic systems, but the three main systems are floating systems, bio/mucoadhesive syst
31、ems and swelling systems.4 Floating drug delivery systemsVarious approaches had been made since the late 1970s to utilise floating behaviour in order to prolong residence. Designs include hydrodynamically balanced systems (HBS), microspheres, gasgenerating systems and raftforming systems. Originally
32、, such systems were proposed to reduce fluctuations in drug levels and provide sustained release as the duration of most oral sustained release preparations is 812 hours, due to a relatively short GI transit time21, 22. HBS has a bulk density lower than gastric fluids and contain one or more colloid
33、s formulated into a single unit with the drug and other additives, which swell on contact with water and facilitate floating23, 24. A density of less than 1.0 g/mL is required. A triplelayer floating tablet system was proposed containing a swellable gasgenerating layer, a swellable drugcontaining la
34、yer (with tetracycline and metronidazole) and a rapidly dissolving layer containing bismuth salts. The system was capable of providing sustained release of the antibiotics in vitro at pH 1.8 and demonstrated buoyancy in vitro, however no in vivo results are reported. Tablets containing a 12 ratio of
35、 hydroxypropylcellulose to amoxicillin, with a gasgenerating system, failed to improve efficacy. These large singlelayer tablets remained buoyant in vitro but bioavailability was reduced to 80.5% as compared with conventional capsules in fasted humans25. Intersubject variability in gastric transit t
36、imes with floating tablets and HBS results in unreliable and irreproducible residence times in the stomach and remains a significant problem with such systems. This can be addressed by using multipleunit divided systems such as microspheres. As these can spread evenly through the stomach contents, t
37、hey can avoid the problems of variable and early gastric emptying or bursting associated with the singleunit systems. Polymers used in formulation of floating multipleunits include caesingelatin acrylic polymers such as Eudragits and alginates26. Alginic acid is a polysaccharide consisting of Dmannu
38、ronic acid and Lguluronic acid. It forms a bioadhesive and stable gel with divalent cations such as calcium and the sodium salt been used in a variety of oral and topical formulations. Floating alginate systems such as Gaviscon form a buoyant gel which floats on the gastric contents alleviating symp
39、toms of heartburn. Its stability in acidic media has made it a popular choice for gastric retentive delivery systems. For example, floating multiple units consisting of a calcium alginate core, separated from a calcium alginate/polyvinyl alcohol (PVA) membrane by an air compartment displayed prolong
40、ed gastric retention after a meal. Alginate beads are commonly prepared by extruding alginate, dropwise, into a solution containing Ca2+. The resultant beads are porous and can be used to encapsulate a variety of drugs with a wide range of physicochemical properties27. Adequate control of drug release from such formulations often requires some modification to the matrix. For example, foambased floating microspheres can be prepared by adding polypropylene foam powder to an organic solution
