Current State and Future Perspectives on Gastroretentive Drug Delivery Systems
Abstract
:1. Introduction
2. Physiology of Stomach
3. Application of GRDDS
4. Critical Factors Affecting GRDDS Efficacy
4.1. Pharmacutical Factors
4.2. Physiological Factors
4.3. Patient-Related Factors
5. Current Pharmaceutical Technologies of GRDDS
5.1. Low-Density Systems
5.1.1. Non-Effervescent Floating Systems
5.1.2. Effervescent Floating Systems
5.2. High-Density Systems
5.3. Expandable Systems
5.4. Superporous Hydrogel Systems
5.5. Bioadhesive/Mucoadhesive Systems
5.6. Raft-Forming Systems
5.7. Magnetic Systems
5.8. Ion-Exchange Resin Systems
6. Evaluation Parameters of GRDDS
6.1. In Vitro Evaluation Parameters
6.2. In Vivo Evaluation Parameters
7. Future Perspectives of GRDDS
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Phase | Comments | Duration |
---|---|---|
Phase 1 | Quiescent period with rare contractions. | 30–60 min |
Phase 2 | Intermittent action potentials and contraction that gradually increases in intensity and frequency as the phase progresses. | 20–40 min |
Phase 3 | Short periods of intense, large, regular contractions. This phase is termed as “housekeeper wave” as it enables all undigested materials to be swept out of the stomach and down to the small intestine. | 10–20 min |
Phase 4 | Occurs between phase 3 and phase 1 of two consecutive cycles in a brief transitional phase. | 0–5 min |
Bioavailability Challenges | Drug | Therapeutic Indications | References |
---|---|---|---|
Local activity | Ranitidine, Amoxicillin, Levofloxacin, Metronidazole | Peptic ulcer and reflux esophagitis, eradication of H. pylori | [1,13,21,22,23,24] |
Plasma fluctuations | Ciprofloxacin, Clarithromycin | Urinary tract, respiratory, and GI infections | [1,25,26,27,28] |
Low solubility at alkaline pH | Ofloxacin | Urinary tract, respiratory, and GI infections | [1,10] |
Cinnarizine | Nausea, vertigo, and motion sickness | [15] | |
Narrow absorption window | Riboflavin | Essential nutrients, mouth ulcer and sore throat | [29,30] |
Cilostazol | Inhibits platelet aggregation | [4] | |
Pregabalin | Fibromyalgia, diabetic peripheral neuropathy, post-herpetic neuralgia, and adjunctive therapy for partial onset seizures | [5,31] | |
Short half-life, narrow absorption window | Levodopa | Parkinson’s disease | [32] |
Metformin | Type II diabetes mellitus | [7,9,33,34] | |
Poor absorption from lower GIT | Atenolol | Hypertension | [1] |
Lafutidine | Gastric and duodenal ulcers | [35] | |
Unstable at alkaline pH | Verapamil, Captopril | Hypertension | [1,11,14] |
Delivery Systems | Brand Name | Active Ingredient | Manufacturing Company |
---|---|---|---|
Bioadhesive tablets | Xifaxan® | Rifampicin | Lupin, India |
Bilayer floating capsule | Cytotec® | Misoprostol | Pfizer, UK |
Coated multi-layer & swelling system | Baclofen GRS® | Baclofen | Sun Pharma, India |
Colloidal gel forming floating system | Conviron® | Ferrous sulphate | Ranbaxy, India |
Effervescent floating system | Zanocin OD® | Ofloxacin | Ranbaxy, India |
Riomet OD® | Metformin hydrochloride | Ranbaxy, India | |
Cifran OD® | Ciprofloxacin | Ranbaxy, India | |
Effervescent floating liquid alginate preparation | Liquid Gaviscon® | Alginic acid and sodium bicarbonate | Reckitt Benckiser Healthcare, UK |
Effervescent and swelling based floating system | Prazopress XL® | Prazosin hydrochloride | Sun Pharma, Japan |
Erodible matrix based system | Cipro XR® | Ciprofloxacin hydrochloride and betaine | Bayer, USA |
Expandable system (unfolding) | Accordion Pill® | Carbidopa/levodopa | Intec Pharma, Israel |
Raft forming system | Topalkan® | Aluminum magnesium | Pierre Fabre Medicament, France |
Almagate FlatCoat® | Aluminium-magnesium antacid | Pierre Fabre Medicament, France | |
Floating system—controlled release capsule | Madopar HBS® | Levodopa and benserzide | Roche, UK |
Prolopa HBS® | Levodopa and benserzide hydrochloride | Roche, UK | |
Valrelease® | Diazepam | Roche, UK | |
Foam based floating system | Inon Ace Tables® | Simethicone | Sato Pharma, Japan |
Gastroretention with osmotic system | Coreg CR® | Carvedilol | GlaxoSmithKline, UK |
Minextab Floating®—floating and swelling system | Metformin HCl | Metformin hydrochloride | Galanix, France |
Cafeclor LP | Cefaclor | Galanix, France | |
Tramadol LP | Tramadol | Galanix, France | |
Polymer based swelling technology: AcuFormTM | Gabapentin GR | Gabapentin | Depomed, USA |
proQuin XR | Ciprofloxacin | Depomed, USA | |
Glumetza | Metformin hydrochloride | Depomed, USA | |
Metfromin GRTM | Metformin hydrochloride | Depomed, USA |
Gastroretentive Approach | Mechanism | References |
---|---|---|
Low-density systems/ floating systems | System causes buoyancy in gastric fluid. Density of pellets/tablets is lower than the density of stomach fluid. | [1,17,20,47] |
High density systems | Uses the density of dosage form as a strategy to produce the retention mechanism. Sinking system remains at the bottom of the stomach, where the density of the dosage form is greater than the gastric fluid. | [1] |
Expandable systems | Expansion of the dosage form occurs by swelling or unfolding in the stomach. Swelling usually occurs because of diffusion. Unfolding takes place due to mechanical shape memory. | [6,12,61] |
Bioadhesive systems | A very complex process with several mechanisms, including electrical theory, adsorption, wetting, diffusion, and fracture theories. The interaction between the negatively charged mucosal surface and positively charged polymers might facilitate the bioadhesive process. | [12,45] |
Raft forming systems | The polymer in presence of mono or di valent cations, absorbs water, swells and forms in situ gel layers, which float above gastric fluid and termed as raft. | [62,63] |
Super-porous hydrogel systems | Swells up to 100 times due to water update by capillary wetting through numerous pores. | [12,64] |
Magnetic systems | Consists of the small internal magnet mixed with the drug. Its position inside the stomach is controlled by an extracorporeal magnet. | [16] |
Ion-exchange resin systems | Drug is loaded into the resin to form the resin loaded drug complex, which can be combined with floating delivery or bioadhesive systems. | [16] |
Theories | Mechanisms of Mucoadhesion |
---|---|
Wettability | Bioadhesive polymers penetrate and develop intimate contact with the mucous layers. |
Diffusion | Physical entanglement of mucin strands and flexible polymer chains. Influenced by molecular weight, cross-linking density, chain flexibility, and expansion capacity of both networks. |
Adsorption | Bioadhesion is due to primary forces (ionic, covalent, and metallic) and secondary forces (van der Waals, hydrophobic and hydrogen bonds) between surfaces. |
Electronic | Attractive electrostatic forces between the glycoprotein mucin network and the bioadhesive material. |
Fracture | Detachment force needed to separate the mucus and polymer reflects the force of the adhesive binding. |
GRDDS | Evaluation | Comment | References |
---|---|---|---|
Low-density system, raft-forming system | Floating Lag Time (FLT), total floating time (TFT), floating strength | The test is carried out in a simulated gastric fluid (SGF) at 37 °C. The time between introduction of dosage form and its buoyancy on the SGF (FLT) and the time during which the dosage form remains buoyant (TFT) were measured. The floating strength is measured using specifically designed basket holder connected with analytical balance. The reduction of weight on the analytical balance over time determines the floating strength. | [9,17,19,31,97,98] |
Superporous hydrogel system, expandable system | Swelling studies | The test is carried out by placing the weighed amount of dosage form into the swelling medium (0.01 N HCl) and weight, diameter, and length of swollen samples are measured at predetermined time point. | [61,99] |
Raft-forming and Mucoadhesion systems | Viscosity and Rheology | Viscosity of polymer affects the consistency of the dosage form upon contact with the gastric fluid. Brookfield/Ostwald’s viscometer and texture analyzer are commonly used. | [100] |
Expandable system | In vitro unfolding study | The test is carried out by placing the folded dosage form into the dissolution medium and examining its unfolding behavior in different time interval. | [101] |
Ion-exchange resin system | Particle size, ion exchange capacity, moisture content | Particle size analysis is carried out using a sieve shaker, laser diffraction, and coulter counter analyzer. The ion exchange capacity depends upon the functional group available for crosslinking. Moisture content can be measured with Karl Fischer. | [96,102,103,104] |
Applicable for all GRDDS | In vitro drug release | The test is carried out in SGF at a predefined time interval (generally 0 to 12 h) using USP type-II apparatus at 50 rpm and maintained at 37 °C. | [9,27,72,80] |
Gel strength | The high gel strength is desirable for better mechanical integrity. | [9,105] | |
Drug-excipient interaction study | It can be studied by using FT-IR spectroscopy, Differential scanning calorimetry, and High Performance Liquid Chromatography. | [17,106] |
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Tripathi, J.; Thapa, P.; Maharjan, R.; Jeong, S.H. Current State and Future Perspectives on Gastroretentive Drug Delivery Systems. Pharmaceutics 2019, 11, 193. https://doi.org/10.3390/pharmaceutics11040193
Tripathi J, Thapa P, Maharjan R, Jeong SH. Current State and Future Perspectives on Gastroretentive Drug Delivery Systems. Pharmaceutics. 2019; 11(4):193. https://doi.org/10.3390/pharmaceutics11040193
Chicago/Turabian StyleTripathi, Julu, Prakash Thapa, Ravi Maharjan, and Seong Hoon Jeong. 2019. "Current State and Future Perspectives on Gastroretentive Drug Delivery Systems" Pharmaceutics 11, no. 4: 193. https://doi.org/10.3390/pharmaceutics11040193