INTRODUCTION:
Recently, significant attempts have been made to target a medication or drug delivery system in a specific area of the body for an extended period of time, not only for local drug targeting but also for improved systemic drug delivery control. The desired plasma level for a medication should be produced and maintained for a lengthy period of time by oral administration using a controlled drug delivery system.1
Despite significant improvements in drug delivery, the oral route is still favoured because it is simple to administer and has a low cost of therapy, which results in good patient compliance. Drug release from oral controlled-release drug delivery devices occurs at a planned, predictable, and controlled rate and has attracted a lot of interest. However, some drugs have demonstrated poor bioavailability because of incomplete absorption or degradation in the gastrointestinal tract.
Therefore, a gastroretentive drug delivery system (GRDDS) is developed, because prolonging the gastric retention is sometimes desirable for drugs that:
1) Are locally active in the stomach,
2) Have a narrow absorption window in GIT,
3) Are unstable in the intestinal or colonic environment,
4) Exhibit low solubility at high pH regions.2
GRDDS can be approached by:
1) Low density dosage form that causes buoyancy above gastric fluid;
2) A high density dosage form that sinks in the bottom of the stomach;
3) A bioadhesion to the stomach mucosa; or
4) A limited emptying of the dosage form through the pyloric sphincter by swelling or unfolding to a larger size.
Advantages:
1) Improves patient compliance by decreasing dosing frequency.
2) Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.
3) Better therapeutic effect of short half-life drugs can be achieved.
4) Gastric retention time is increased because of buoyancy.
5) Releases in controlled manner for prolonged period.
6) Site-specific drug delivery to stomach can be achieved.
7) Enhanced absorption of drugs, which solubilized only in stomach.
8) Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug.1
The successful development of oral controlled drug delivery systems requires an understand ding of the three aspects of the system, namely;
1) The physiochemical characteristics of the drug.
2) Anatomy and physiology of GIT
3) Characteristics of Dosage forms.3
i. Physiochemical characteristics of the drug:
1) Acting locally in the stomach;
2) Primarily absorbed in the stomach;
3) Poorly soluble at an alkaline pH;
4) With a narrow window of absorption; and
5) Degrade in the colon.
ii. Basic anatomy and physiology of stomach:
Processing and moving food is the stomach's primary function. In the stomach, significant enzymatic digestion, especially of proteins, begins. The stomach is anatomically divided into three parts: the fundus, the body, and the antrum (pylorus). While the antrum is the primary location for mixing motions and serves as a pump for stomach emptying via pushing action, the proximal portion made of the fundus and body serves as a reservoir for undigested material. Both when one is eaten and when one is fasting, the stomach empties. However, there are differences between the 2 states' motility patterns. An interdigestive series of electrical events occurs while fasting, cycling through the stomach and intestine every two to three hours.This is called the inter digestive myloelectric cycle (IMC) or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.4
1) Phase i (base phase): lasts 40 to 60 minutes with occasional contractions
2) Phase ii (pre-burst): lasts 40-60 minutes, with intermittent action potential and contractions. The intensity and frequency increase gradually as the phase advances.
3) Phase iii (burst phase): lasts 4–6 minutes. It consists of brief periods of severe and regular contractions. All undigested material is carried out of the stomach and into the small intestine by this wave. The housekeeping wave is another name for it.
4) Phase iv: lasts between phases III and I of two consecutive cycles and lasts 0 to 5 minutes.
Fig. 1. Four phase
2) Floating system:
Because floating drug delivery systems (FDDS) have a lower bulk density than gastric fluids, they float in the stomach for a longer time without slowing down the rate at which the stomach empties. The medicine is removed from the system slowly and at the desired pace while the body is floating on the contents of the stomach. The leftover system from the stomach is evacuated following medication release.
2.1) Non-effervescent system:
2.2) Effervescent system
Fig. 2. Classification of floating tablets
2.1) Non-effervescent system:
The non-effervescent FDDS is based on the mechanism of polymer swelling or bioadhesion to the mucosal layer of the GI tract. Gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene, and bio-adhesive polymers such as chitosan and carbopol are the most widely utilised excipients in non-effervescent FDDS. The following are the numerous types of these systems:
2.1.1) Colloidal Gel Barrier System Hydrodynamically balanced system:
One of the several gel-forming materials employed in this system is hydroxyethyl cellulose, which is very soluble, along with hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polysaccharides, and matrix-forming polymers including polycarbophil and polystyrene.
2.1.2) Bilayer floating tablet:
A bilayer tablet contain two layer immediate release layer which release initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach.
2.1.3) Micro porous Compartment System:
Encapsulated drug reservoir is located inside the microporous compartment, which features pores on its top and bottom walls. Because the peripheral walls of the drug reservoir are entirely sealed, undissolved drugs cannot directly access the stomach surface. The system is stimulated to float over stomach content by air that has been confined inside the floating chamber. Gastric fluid enters through a hole, dissolving the medication for intestinal absorption.
2.1.4) Alginate beads:
period Dropping a sodium alginate solution into an aqueous solution of calcium chloride causes precipitation of calcium alginate, resulting in the construction of a porous system that can maintain a floating force for more than 12 hours. These floating beads provided a Calcium alginate that has been freeze dried is used to create multi-unit floating dosage forms. By adding a sodium alginate solution to a calcium chloride aqueous solution, calcium alginate precipitates and forms a porous system that can sustain a floating force for more than 12 hours, yielding spherical beads with a diameter of around 2.5When compared to solid beads, which had a one-hour residence duration, these floating beads had a greater than S5.5-hour residence.
2.1.5) Hollow microspheres:
Hollow microspheres (microballons), loaded with drug in their outer polymer shells were prepared by a novel emulsion solvent diffusion method. The ethanol: dichloromethane solution of drug and enteric acrylic polymer was poured into an agitated aqueous solution of PVA that was thermally controlled at 400 C. The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed an internal cavity in microsphere of polymer with drug. The microballons floated continuously over the surface of acidic dissolution media containing surfactant for more than 12 hours in vitro.
2.2) Effervescent system:
Carbonates (such as sodium bicarbonate) and other organic acids (such as citric acid and tartaric acid) contained in the formulation are used in effervescent systems to produce carbon dioxide (CO2) gas, which lowers the system's density and causes it to float above the contents of the stomach. The integration of a matrix with a liquid part that produces gas that evaporates at body temperature is an alternative .There are two further categories for these effervescent systems.
Fig. 3. Effervescent system
2.2.1) Volatile liquid containing systems:
The drug delivery system incorporates an inflatable chamber filled with a liquid that enables sustained gastric retention. The liquids used in this system, such as cyclopentane and ether, undergo gasification at body temperature, resulting in the inflation of the chamber within the stomach. These systems consist of hollow deformable units that function as osmotically controlled floating systems. The system is divided into two compartments, with the drug being housed in the first compartment and the second compartment containing the volatile liquid.
2.2.2) Gas generating systems:
Gas-generating systems consist of polymers that undergo gasification at body temperature, combined with effervescent compounds like sodium bicarbonate, citric acid, tartaric acid, as well as swellable polymers such as methocel, and polysaccharides like chitosan. The most widely utilized method for preparing these systems involves resin beads that are loaded with bicarbonate and coated with ethylcellulose. The ethylcellulose coating is both insoluble and permeable to water, allowing the release of carbon dioxide, which leads to the buoyancy and floating properties of the system.
2.2.3) Raft forming systems:
The development of raft forming systems has sparked significant interest in the delivery of antacids and medicines for gastrointestinal diseases and infections. The formation of rafts is primarily driven by the creation of a cohesive, viscous gel upon contact with gastric contents, leading to the expansion and formation of a continuous layer known as a raft. The inclusion of alkaline bicarbonates or carbonates, along with a gel-forming agent, facilitates the production of CO2, which imparts buoyancy to the raft and acts as a barrier, preventing the reflux of gastric contents such as HCl and enzymes into the oesophagus. This buoyancy enables the system to float on gastrointestinal fluids, making it less dense and more effective in its intended function.5
3) Swellable system:
For effective gastric transit, it is important that the size of a dose form is smaller than the pyloric sphincter, which regulates passage from the stomach to the small intestine. However, the dose form should still be large enough to be easily taken and should not cause any obstruction in the stomach. This necessitates the design of a small oral dosage form that can later expand into a larger gastroretentive form, followed by a final small form to facilitate evacuation after drug release .Research has focused on developing systems that can fold and swell. Biodegradable polymers are utilized to create unfoldable systems, often in the form of a capsule. This compressed system stretches in the stomach, taking advantage of its mechanical properties to ensure retention.
Swellable systems are also commonly employed due to their ability to expand. One common mechanism for swelling is osmotic absorption of water. Gastric fluids cause the dose form to swell, while still remaining small enough to be ingested. The bulk of the system serves as a drug reservoir, promotes gastric retention, and keeps the stomach in a "fed" state, surrounded by an expandable, swellable substance. The entire system is coated with an elastic outer polymeric membrane that is permeable to both the drug and bodily fluids. This membrane regulates drug release. Over time, as the medication and expanding agent are depleted, and/or due to bioerosion of the polymer envelope, the device gradually loses volume and rigidity, facilitating its eventual removal.
Fig. 4. Swellable System
3.1) Superporous hydrogels:
These systems are swellable, but they differ from more typical varieties in a way that justifies a different classification. With pores between 10nm to 10Am in size, traditional hydrogels absorb water very slowly and may take several hours to achieve an equilibrium condition, at which point the dosage form may prematurely evacuate. Due to rapid water uptake by capillary wetting through multiple interconnected open holes, superporous hydrogels with average pore sizes > 100 Am expand to equilibrium size in under a minute. They also swell to a large size (swelling ratio of 100 or more), and their mechanical strength is designed to be sufficient to withstand pressure from gastric contraction.6
Fig. 5. Superporous Hydrogel
4) Factors Affecting Gastric Residence Time of GRDDS:
Density, size, and shape of the dosage form, food status, and biological parameters like age, gender, posture, body mass index, disease state, etc. are among the few of the variables that might affect how quickly an oral dosage form is emptied from the stomach.7
4.1) Effect of Dosage Form Size and Shape:
Researchers discovered that floating units with a diameter equal to or less than 7.5 mm had longer gastric residence times (GRT) than non-floating units, but the GRT was similar for floating and non-floating units having a large diameter of 9.9 mm. Small size tablets are emptied from the stomach during the digestive phase, while large size units are expelled during the housekeeping waves. They observed that the GRT of non-floating units, which are distributed in the range of tiny to large, was significantly more variable. Additionally, size affects both the floating and non-floating forms of GRT in supine patients. Devices in the tetrahedron and ring shapes have higher GRTs than those in other shapes.8
4.2) Gender Posture and Age:
regardless of their weight, height, or body surface, males' mean ambulatory GRT (3.40.6 hour) is lower compared to that of their age- and race-matched female counterparts (4.61.2 hour). Even when menstrual cycle-related hormonal changes were kept to a minimum, women nevertheless emptied their stomachs more slowly than males did. The difference between the mean GRT in the supine state (3.40.8hours) and the upright, ambulatory state (3.50.7hours) was not statistically significant. The GRT was prolonged in cases of the elderly, particularly in subjects older than 70 (mean GRT: 5.8hours).9
4.3)Effect of Food and Specific Gravity:
The density of the dose form must be smaller than the gastric content, or 1.0 g/cm3, in order for FDDS to float in the stomach. Since the extent of a dosage form's floating strength may change as a function of time and gradually diminish after immersion in a fluid due to the formation of its hydrodynamic equilibrium, the bulk density of a dosage form is not the only way to explain its buoyant capabilities. Numerous studies have indicated that food intake, as opposed to food, is the primary predictor of stomach emptying. The presence of food has a greater impact on GRT than buoyancy. Due of the delayed start of MMC, GRT is greatly boosted when fed. Studies show that GRT for both floating and non-floating single unit are shorter in fasted subjects (less than 2 hour), but significantly prolonged after a meal (around 4 hour)10
4.4) Natural of Meal & Frequency of Food:
Feeding the stomach with indigestible polymers or fatty acid salts can cause the stomach's motility pattern to change to a fed state, speeding up gastric emptying and delaying the release of drugs. Protein and fat-rich diets can extend GRT by 4–10 hours.11
5) Methods of preparation:
1) Direct compression,
2) Dry granulation,
3) Wet granulation.
5.1) Direct compression method:
Direct compression is the procedure of creating tablets straight from powdered ingredients without changing the raw components' physical properties. This method is utilised for crystalline substances with good flow and compressibility characteristics, such as ammonium chloride, sodium chloride, methenamine, potassium salt (chloride, chlorate, and bromide). Employing tablet machines, compressed tablets are created through single compression. The upper and lower punches of the tablet machine compress the material at a high pressure after an amount of powdered or granulated tableting material has flowed into a die.
5.2) Dry granulation method:
If the tablet contents are sensitive to moisture and/or unable to tolerate high temperatures during drying, it is termed as the formation of granules by slugging.
5.3) Wet granulation method:
In a rapid mixer granulator (RMG), the active ingredient, diluents, and disintegrants are thoroughly mixed or blended. The RMG is a multi-purpose chopper used for high speed dispersion of dry powders and aqueous or solvent granulations. It is made up of an impeller and a chopper. Large trays with wet materials from wet milling processes are placed inside drying chambers with thermostable heat controllers and circulating air current. Dryers like tray dryers and fluidized beds are frequently utilised. The granules undergo a smaller mesh screen after drying to minimise their particle size. The lubricant or glidant is then applied as a fine powder to encourage granule flow. The resulting compacted granules are subsequently formed into tablets. When opposed to wet granulation, the manufacturing method for dry granulation is quicker and more affordable. Dry granulation is particularly suited for active substances that are sensitive to solvents or labile to moisture and high temperatures because it doesn't require heat or moisture.
6) EVALUATION:
6.1) In-vitro evaluation:
6.1.1) Floating capacities:
The floating capacities were tested using the following procedure: in a dissolution vessel containing 900 mL of either deionized water (DIW) or simulated gastric fluid (SGF) without pepsin (pH 1.2) at a temperature of 37 0.5 C with no stirring, the time it took the tablets to reach the water's surface (floating lag time) and the amount of time they remained there continuously (designated as floating duration) were measured. Each formulation that was studied underwent three measurements (n = 3).12
6.1.2) Specific Gravity (Density):
The displacement method, which uses benzene as the displacement medium, can be used to calculate density.13
6.1.3) Determination of swelling index:
The three-dimensional swelling of the tablet can be measured by either the percentage of weight gain of the enlarged tablet or the percentage of volume increase estimated by
× (diameter/2)2 × thickness with the
assumption that the tablet swelled as a cylindrical form.
Dissolution equipment was used for the swelling studies. There were no rotational speeds used. The tablets were submerged in either 900 mL of DIW or SGF at a temperature of 37.+-0.5 °C. The swelled tablets were taken out of the solution at predetermined intervals (0.5, 1, 2, 4, 6, 8, 12, 16, and 24 h), immediately wiped with a paper towel to remove any surface droplets, and measured to determine the diameters. The following equation was used to compute the swelling index (Sw)
Swelling index (Sw) = Wt – W0 /W0
Where , Wt and W0 represent the initial weight of the dry tablet and that of the swollen tablet at time t, respectively. The data represent mean±SD from at least three samples per formulation. 14
6.1.4) Water uptake:
It is a direct measurement of a matrix's ability to swell. In this case, the dosage form is taken out at regular intervals, and weight changes are calculated over time.This is why it is also known as weight gain.
Water uptake =
(weight of dosage form at time t) - (initial weight of dosage form)
initial weight of dosage form
6.1.5) Release studies:
Based on the apparatus II method, drug release from GRDDS tablets was tested in 900 mL of either DIW or SGF during a 24-hour period at 37 0.5 °C and 50 rpm. At predefined intervals (0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 h), the medium (5 mL) was sampled and replaced with a new medium of the same volume. A suitable wavelength ultraviolet/visible spectrophotometer was used to measure the medication concentration. After accounting for the accumulated amount in earlier samples, the average percentage of the drug dissolved at each sampling period was computed. Additionally, three duplicates of each in vitro dissolution test were carried out.2
6.2) In-vivo studies:
6.2.1) Radiology:
X-rays are frequently utilised to examine internal body systems. Radio opaque marker made of barium sulphate is frequently used. Therefore, BaSO4 is added to the dosage form, and x-ray images are collected at regular intervals to monitor dosage form gastro-retention.15
6.2.2) Scintigraphy
Emitting elements are put into dose form, similar to x-ray, and images are captured using scintigraphy. A major advantage of this technique is its high safety profile, as it accompanied by relatively low doses of radiation.16
6.2.3) Gastroscopy:
Peroral endoscopy using fibre optics or a video system is known as gastroscopy. The use of gastroscopy allows for a visual examination of the effects of stomach extension. It can also provide a comprehensive analysis of GRDDS.17
6.2.4) Magnetic Marker Monitoring:
This method uses an iron powder-filled dosage form that is magnetically tagged so that images can be captured by highly sensitive biomagnetic measurement equipment. This method's advantage is that it uses less radiation and is hence safe.18
6.2.5) Ultrasonography:
Used sometimes, not used generally because it is not traceable at intestine. Ultrasonic waves reflected at substantially different acoustic impedance across an interface enable the imaging of some abdominal organs .ultrasound is not routinely used in oral biopharmaceutics because it does not delineate the intestine.19
7) Application of floating drug delivery system:
7.1)Enhanced Bioavailability:
When compared to the administration of CR polymeric formulations without GRDF, the bioavailability of riboflavin CR-GRDF is dramatically increased. The amount of medication absorption is influenced by a number of simultaneous mechanisms related to drug absorption and transit in the gastrointestinal system.20
7.2) Sustained Drug Delivery:
Problems with oral CR formulations include gastric residence duration in the GIT. The HBS systems, which can stay in the stomach for extended periods of time and have a bulk density of 1, can solve these issues by allowing them to float on the contents of the stomach. These systems aren't allowed to pass via the pyloric aperture because they are significantly larger in size.21
7.3) Site-Specific Drug Delivery:
These systems are especially useful for medications like riboflavin and furosemide that are primarily absorbed from the stomach or the proximal small intestine.E.g. The stomach absorbs furosemide the most, followed by the duodenum. According to reports, a monolithic floating dosage form with an extended stomach residence duration was created, increasing the bioavailability. The floating tablets' AUC was around 1.8 times greater than that of regular furosemide tablets.22
7.4) Absorption or Bioavailability Enhancement:
Potential possibilities for formulation as floating drug delivery systems include medications with low bioavailability due to site-specific absorption from the upper gastrointestinal tract, which would maximise their absorption. Comparing the bioavailability of floating dosage forms (42.9%) to enteric-coated LASIX-long product (29.5%) and commercially available LASIX tablets (33.4%) reveals a considerable improvement.23
7.5) Reduced fluctuations of drug concentration:
Compared to immediate release dosage forms, continuous input of the drug after CRGRDF administration results in blood drug concentrations within a tighter range. As a result, variations in medication effects are reduced, and undesirable effects that are concentration dependent and linked to peak concentrations can be avoided. This characteristic is especially crucial for medications with a limited therapeutic index.
8) CONCLUSION:
Drug absorption in the gastrointestinal tract is a highly variable procedure, and increasing stomach retention of the dosage form prolongs drug absorption time. Gastroretentive floating and swelling drug delivery systems have evolved as effective methods of increasing the bioavailability and controlling the distribution of various medicines. The rising sophistication of delivery technology will result in the development of an increasing variety of gastroretentive drug delivery strategies to optimise the delivery of molecules with a narrow absorption window, low bioavailability, and substantial first pass metabolism. SFDDS appears to be a promising treatment for gastric retention. Although there are a lot of challenges to overcome in order to achieve prolonged gastric retention, a huge number of companies are working to commercialise this technology.
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Received on 21.09.2023 Modified on 15.11.2023
Accepted on 26.12.2023 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2024; 14(1):56-62.
DOI: 10.52711/2231-5659.2024.00009