Yashwantrao Bhonsale College of Pharmacy, Sawantwadi, dist – Sindhudurg, Maharashtra, India
Oral absorption of drugs with narrow absorption window in the upper small intestine shows poor bioavailability with conventional dosage forms due short residence time. To overcome this restriction and to increase the bioavailability of these drugs, controlled drug delivery systems with a prolonged residence time in the stomach can be used. Gastric retention drug delivery system can be used to prolonged residence times of the drug in the upper part of the gastrointestinal tract. The current review deals with formulation developments of gastric retentive drug delivery systems which is prolonged residence time and enhancing oral bioavailability of the drugs. Similarly, drugs which produce their local action in stomach get rapidly emptied and do not get enough residence time in stomach. So, frequency of dose administration in such cases is increased. To avoid this problem, various efforts have been made to prolong the retention time of drug delivery system. In this review, we will discuss about the various approaches to produce gastro retention of drug delivery system, with special emphasis to floating in situ gel system for stomach specific drug delivery.
In recent years, scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times and unpredictable gastric emptying times.1,2 The oral bioavailability of drugs with an absorption window in the upper part of the gastro intestinal tract is generally limited with conventional dosage forms such as tablet, capsules and granules. These drugs can be delivered ideally by slow release from the stomach to give a localized effect at the site of action.3,4 Improved efficacy is expected for drugs that are used in the treatment of gastric disorders like ulcers and H. pylori infections.5 Many drugs categorized as oncea-day delivery have been demonstrated to have suboptimal absorption due to dependence on the transit time of the dosage form, making traditional extended release development challenging. Therefore, a system designed for longer gastric retention will extend the time within which drug absorption can occur.6 These hydrogels are liquid at room temperature but undergo gelation when in contact with body fluids or change in pH7. These have a characteristic property of temperature dependent, pH dependent and cation induced gelation8. Compared to conventional controlled release formulations, in situ forming drug delivery systems possess potential advantages like simple manufacturing process, ease of administration, reduced frequency of administration, improved patient compliance and comfort9.
Floating drug delivery system
Oral administration is the most convenient mode of drug delivery and is associated with superior patient compliance as compared to other modes of drug intake. However, oral administration has only limited use for important drugs, from various pharmacological categories, that have poor oral bioavailability due to incomplete absorption and/or degradation in the gastrointestinal (GI) tract. Some of these drugs are characterized by a narrow absorption window (NAW) at the upper part of the gastrointestinal tract. This is because of proximal part of the small intestine exhibits extended absorption properties (including larger gaps between the tight junctions, and dense active transporters). Despite the extensive absorption properties of the duodenum and jejunum, the extent of absorption at these sites is limited because the passage through this region is rapid. Enhancing the gastric residence time (GRT) of a NAW the drug may significantly improve the net extent of its absorption10.
Figure 1: (a) Drug release mechanism and (b) Floating drug delivery systems
Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables. It is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa11. Thus small intestinal transit time is an important parameter for drugs that are incompletely absorbed.Floating drug delivery systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion12, flotation13, sedimentation14, expansion15, modified shape systems16, or by the simultaneous administration of pharmacological agent17 that delay gastric emptying. Floating systems or hydrodynamically controlled systems are low-density systems that have sufficient buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal.Many buoyant systems have been developed based on granules, powders, capsules, tablets, laminated films and hollow microspheres.
Advantages of floating drug delivery system18,19
Disadvantages or Limitation of Gastroretentive Drug Delivery Systems20
Need of Gastroretentive Drug Delivery Systems21
Oral dosage forms often face challenges with low bioavailability due to rapid gastric emptying from the stomach, especially for drugs that are less soluble in the alkaline pH of the intestine. Additionally, drugs intended for local action in the stomach are quickly emptied, leading to increased dosing frequency. To overcome these issues, floating drug delivery systems have been developed.
Main types of gastro retentive drug delivery systems
Gastro retentive delivery systems are designed to be retained in the stomach for a prolonged time and release their active ingredients and thereby enable sustained and prolonged input of the drug to the upper part of the gastrointestinal (GI) tract. This technology has generated enormous attention over the last few decades owing to its potential application to improve the oral delivery of some important drugs for which prolonged retention in the upper GI tract can greatly improve their oral bioavailability and/or their therapeutic outcome. Gastro retentive delivery system can be classified as follows.
Bioadhesive systems
Bioadhesive drug delivery systems are used as a delivery device within the lumen to enhance drug absorption in a site specific manner. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach.22 Bioadhesive systems adhere to gastric epithelial cells or mucous and extend the gastric retention by increasing the intimacy and duration of contact between gastro retentive drug delivery system (GRDDS) and the biological membrane. Some of the most promising excipients that have been used commonly in these systems include polycarbophil, carbopol, lectins, chitosan and gliadin and alginate etc. Bioadhesive systems are those which bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending the gastric residence time of drug delivery system in the stomach, by increasing the intimacy and duration of contact of drug with the biological membrane. The surface epithelial adhesive properties of mucin have been well recognized and applied to the development of GRDDS based on bioadhesive polymers. The ability to provide adhesion of a drug to the mucous layer provides a longer residence time in a particular organ site, thereby producing an improved effect in terms of local action or systemic effect.
Figure 1 Mechanism of bioadhesion of drug molecules on mucus layer.
Expandable systems
Expandable gastric retentive delivery systems are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time.23 After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastro-retentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. Expansion mechanism of this system is swelling to an extent that prevents their exit from the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be named as “plug type system”, since they exhibit the tendency to remain logged at the pyloric sphincter if that exceed a diameter of approximately 12-18mm in their expanded state. The formulation is designed for gastric retention and controlled delivery of the drug into the gastric cavity. Such polymeric matrices remain in the gastric cavity for several hours even in the fed state. A balance between the extent and duration of swelling is maintained by the degree of cross-linking between the polymeric chains. A high degree of cross-linking retards the swelling ability of the system maintaining its physical integrity for prolonged period. The following schematic presentation (Figure 2) explained the mechanism of expandable drug delivery system.
Floating drug delivery systems
Floating drug delivery systems have bulk density less than gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time.12 While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system, after release of drug; the residual system is emptied from the stomach. This results in an increased gastric retention time and a better control of the fluctuations in plasma drug concentration. Floating drug delivery system can be divided into (i) Non-effervescent and (ii) Gas-generating system.24
Figure 2 Represents expandable drug delivery system. A) The device significantly swells on contact with gastric fluids (to a few hundred times of the original volume); B – D) the gastric contraction pushes the hydrogel to the pylorus; E) the gastric contraction slips over the surface of the hydrogel; and F) the hydrogel is pushed back into the body of the stomach.
Non-effervescent systems
This type of system, after swallowing, swells unrestrained via imbibitions of gastric fluid to an extent that it prevents their exit from the stomach. One of the formulation methods of such dosage forms involves the mixing of the drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms.25Excipients used most commonly in these systems include hydroxypropyl methyl cellulose (HPMC), polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates. Various types of non-effervescent system are discussed below (a-c).
a. Colloidal gel barrier system
Such a system contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. This system incorporates a high level of one or more gel-forming highly soluble cellulose type hydrocolloid, e.g., hydroxypropyl cellulose, hydoxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), polysaccharides and matrix-forming polymer such as polycarbophil, polyacrylate and polystyrene. On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloid gel barrier around its surface. The schematic diagram of colloidal gel barrier system is shown in Figure 3.
b. Microporous compartment system
This technology is based on the encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls (Figure 4). In the stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric content. Gastric fluid enters through the aperture, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption.
c. Alginate beads
Multi-unit floating dosage forms have been developed from dried calcium alginate complex.26 Spherical beads of approximately 2.5mm in diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate. The beads are then separated, snap-frozen in liquid nitrogen, and freeze-dried at -40ºC for 24 hours, leading to the formation of a porous system, which can maintain a floating force for over 12 hours. Schematic diagram for preparation of alginate beads is shown in Figure 5.
Figure 3 Colloidal gel barrier system.
Figure 4 Microporous compartment system.
Figure 5 Schematic diagram for preparation of alginate beads.
Hollow microspheres/Microballons
Kawashima et al.27 was developed hollow microspheres loaded with drug in their outer polymer shell were prepared by a novel emulsion solvent diffusion method. The ethanol/dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated solution of Poly Vinyl Alcohol (PVA) that was thermally controlled at 40ºC. The gas phase is generated in the dispersed polymer droplet by the evaporation of dichloromethane formed and internal cavity in the microsphere of the polymer with drug. The microballoon floated continuously over the surface of an acidic dissolution media containing surfactant for more than 12 hours. Various types of effervescent system are discussed below (a-c).
a. Gas-generating (effervescent) systems
These buoyant systems utilize matrices prepared with swellable polymers such as methocel, polysaccharides (e.g., chitosan), effervescent components (e.g., sodium bicarbonate, citric acid or tartaric acid). The system is so prepared that upon arrival in the stomach; carbon dioxide is released, causing the formulation to float in the stomach.28,29 Other approaches and materials that have been reported are a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology. These mini capsules contain a central core and a coating. The central core consists of a granule composed of sodium bicarbonate, lactose and a binder, which is coated with HPMC. Pepstatin is coated on the top of the HPMC layer. The system floats because of the CO2 release in gastric fluid and resides in the stomach for prolonged period.30
b. High density systems
Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture.31 Dense pellets (approx. 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours. Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase density by up to1.5–2.4g/cm3.
c. Multiple unit type floating system
Multiple unit type floating system is sustained release pills, known as ‘seeds’, which are surrounded by two layers. The outer layer is of swellable membrane layer and inner layer consists of effervescent agents. This system sinks at once and then it forms swollen pills like balloons which float as they have lower density, when it is immersed in the dissolution medium at body temperature. The lower density of the system is due to generation and entrapment of CO2 within the system.32
Ion exchange resins
A coated ion exchange resin bead formulation has been shown to have gastric retentive properties, which was loaded with bicarbonates. Ion exchange resins are loaded with bicarbonate and a negatively charged drug is bound to the resin. The resultant beads were then encapsulated in a semi-permeable membrane to overcome the rapid loss of carbon dioxide. Upon arrival in the acidic environment of the stomach, an exchange of chloride and bicarbonate ions take place. As a result of this reaction carbon dioxide was released and trapped in the membrane thereby carrying beads towards the top of gastric content and producing a floating layer of resin beads in contrast to the uncoated beads, which will sink quickly.
Osmotic regulated systems
It is comprised of an osmotic pressure-controlled drug delivery device and an inflatable floating support in a bio erodible capsule.32 The osmotic controlled drug delivery device consists of two components– drug reservoir compartment and osmotically active compartment. In the stomach the capsule quickly disintegrates to release the intragastric osmotically controlled drug delivery device. The inflatable support inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body temperature to inflate the bag.
Suitable drug candidates for gastro retention delivery system
It is evident from the recent scientific and patient literature that an increased interest in novel dosage forms that are retained in stomach for a prolonged and predictable period of time exists today in academic and industrial research groups. One of the most feasible approaches for achieving a prolonged and predictable drug delivery in the GI tract is to control the gastric residence time, i.e. gastro retentive delivery system. Gastric retention is enhanced the therapeutic effect of the drugs due to improve the oral drug absorption in the stomach. Drugs are released from the formulations in controlled manner so that reduce dosing frequency and improve patience compliance. Suitable drug candidates for gastric retention delivery system are shown in (Table 1).
Table 1 Pharmaceutical and pharmacokinetics classification of drug candidates for gastro retentive delivery system
Poorly soluble at an alkaline pH |
|
|
Ranitidine |
Anti-Histamine |
|
Good absorption at stomach chlordiazepoxide |
Antipsychotic |
|
Cinnarizine |
Anti allergy |
|
Narrow absorption window Levodopa |
Ani epilepsy |
|
Riboflavin |
Vitamin |
|
Drug degradation at colon Ranitidine HCl |
Antiulcer |
|
Metronidazole |
Antimicrobial |
|
Amoxicillin |
Antibiotic |
|
Poor solubility in water Acyclovir |
Antiviral |
|
Silymarin Norfloxacin |
Antibiotic |
|
Ciprofloxacin |
Antibiotic |
|
Locally acting at stomach Misoprostol |
Anti-Ulcer |
|
Application of gastric retention delivery systems on treatment of H. pylori infection
Helicobacter pylori (H. pylori) is one of the most common pathogenic bacterial infections, colonizing an estimated half the world’s population. It is associated with the development of serious gastro duodenal disease—including peptic ulcers, gastric lymphoma and acute chronic gastritis.33 Figure 6 is shown clear representation of mechanism of H. pylori induced gastric ulcer. H. pylori reside mainly in the gastric mucosa or at the interface between the mucous layer and the epithelial cells of the antral region of the stomach. H. pylori
Genomes have been linked to altered gastric acid secretion and premalignant histological features.
The discovery of this microorganism has revolutionized the diagnosis and treatment of peptic ulcer disease. Most antibacterial agents have low minimum inhibitory concentrations (MIC) against H. pylori in culture. And, single antibiotic therapy is not effective for the eradication of H. pylori infection in vivo. This is because of the low concentration of the antibiotic reaching the bacteria under the mucosa, instability of the drug in the low pH of gastric fluid and short residence time of the antibiotic in the stomach. Combination of more than one antibiotics and anti-secretory agent are required for complete eradication of H. pylori, but these regimens are not fully effective. Patient compliance, side effects and bacterial resistance are the other problems. Other than the multi-antibiotic therapy, different therapeutic strategies have been examined to completely eradicate H. pylori from the stomach.34
Drug delivery strategies for treatment of H. pylori
One way to improve the efficacy in eradicating the infection is to deliver the antibiotic locally in the stomach. Better stability and longer residence time will allow more of the antibiotic to penetrate through the gastric mucus layer to act on H. pylori. The reason for the incomplete eradication of H. pylori is probably due to short residence time of antimicrobial agents in the stomach so that effective antimicrobial concentration cannot be achieved in the gastric mucous layer or epithelial cell surfaces where H. pylori exists.35 The other reason may be the degradation of antibiotics in gastric acid. Access of antimicrobial drugs to the site is restricted from both the lumen of the stomach and the gastric blood supply. H. pylori may also have acquired resistance to the commonly used antimicrobial agents. As conventional drug delivery systems do not remain in the stomach for prolonged periods, they are unable to deliver the antibiotics to the site of infection in effective concentrations and in fully active forms. Therefore, it is necessary to design drug delivery systems that not only alleviate the shortcomings of conventional delivery vehicles but also deliver the antimicrobials to the infected cell lines. The absorption of an antibiotic into the mucus through the mucus layer (from the gastric lumen) is believed to be more effective for H. pylori eradication than absorption through the basolateral membrane (from blood). Scientists have focused on development of new drug delivery systems which were able to reside in stomach for an extended period for more effective H. pylori eradication34-35.
CONCLUSION
H. pylori are the major causative factor in the pathogenesis of gastritis and peptic ulcer disease. During the last few years researchers tested many different anti H. pylori agents and their combinations in the search for the most effective regimen for eradicating H. pylori. However, the therapy regimens suggested, including several patents, have given disappointing eradication rates in several countries especially, developing countries. This could be attributed partly to the poor patient compliance due to side effects associated with anti H. pylori agents and partly to the location of the organism which does not appear to allow for adequate antimicrobial levels to be achieved when given orally. One of the research goals to treat H. pylori infection is to deliver the medication at the bacterium location in high concentration for local action followed by absorption of these agents to provide systemic action. In early 90’s concept of gastro-retentive drug delivery provided a logical way to improve the effectiveness of therapeutics. Among the investigated GRDDS, some provide interesting solutions leading to filing of various patents, although many of them present drawbacks. The promise offered by GRDDS can still become a reality but it requires judicious selection of polymeric carriers, dosage forms, selection of drugs based on potential drug-receptor targets on the microorganism together with proper optimization of system parameters. In our opinion unit drug delivery systems like hydrodynamically balanced capsules based on natural or biodegradable polymers like chitosan, super-porous hydrogels, in-situ gelling systems, floating and mucoadhesive systems and targeted nano-particulate systems have sufficient potential to be developed as potential GRDDS to treat H. pylori infection in humans. All these systems are simple to fabricate, patient compliant.
REFERENCE
Pooja Mokashi, Rohan Barse, Vijay Jagtap, A Novel Approach Of GRDDS For Treatment Of H. Pylori: In Situ Gel, Int. J. Sci. R. Tech., 2024, 1 (12), 199-212. https://doi.org/10.5281/zenodo.14569510