Gastroretentive System Research Articles

FORMULATION AND CHARACTERIZATION OF GASTRORETENTIVE MUCOADHESIVE QUETIAPINE FUMARATE TABLETS

Background and the purpose of the study: Development of gastroretentive delivery system is one of novel approach in oral route of drug administration. Prolonging the gastric retention time is desirable for achieving greater therapeutic benefit of drug substance. The research was aimed to develop gastroretentive mucoadhesive tablets of quetiapine for prolonged residence time. Methods: The wet granulation method was used for the preparation of various formulations (F1-F12) using different mucoadhesive polymers viz. hydroxyl propyl methyl cellulose K4M, hydroxyl propyl cellulose, chitosan, carbopol 934P and sodium carboxy methyl cellulose in different combinations. The formulations were subjected to various evaluation parameters such as swelling index, mucoadhesive strength, in vitro drug release profile and physical properties. Results: The study showed that the formulation containing chitosan and carbopol 934P in combination (F7) exhibited good swelling index, high mucoadhesive strength of 192.66 g and maximum in vitro residence time (10.14 hrs) and in vitro cumulative drug release after 24 hrs (96.26%). The optimized formulation (F7) was further subjected to in vivo retention time determination in rabbit by X-ray technique and accelerated stability studies. Conclusion: The formulation (F7) had shown promising potential to achieve desired goal as depicted from the release studies, swelling studies & mucoadhesion studies.

In Situ Gel: A Novel Approach of Gastroretentive Drug Delivery

The oral delivery of drugs with a narrow absorption window in the gastrointestinal tract (GIT) is often limited by poor bioavailability with conventional dosage forms due to incomplete drug release and short residence time at the site of absorption. To overcome this drawback and to maximize the oral absorption of these drugs, novel drug delivery systems have been developed. Gastroretentive systems such as floating systems, mucoadhesive, high-density, expandable and have been developed, since they provide controlled delivery of drugs with prolonged gastric residence time. Among all oral dosage forms, liquid orals are more prone to low bioavailability as far as stomach specific drug deliveries are concerned, since they subjected to faster transit from the stomach/ duodenum. To produce sustained release formulation of an oral liquid formulation could be successfully augmented substantially through a strategy of liquid in-situ floating gel system. The formation of gel depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation, from which the drug gets released in a sustained and controlled manner. This comprehensive article contains approaches, polymers, marketed preparations, patents, herbal approaches and recent advances of in situ gel.

Statistical approach for assessing the influence of calcium silicate and HPMC on the formulation of novel alfuzosin hydrochloride mucoadhesive-floating beads as gastroretentive drug delivery systems.

Multiparticulate floating drug delivery systems have proven potential as controlled-release gastroretentive drug delivery systems that avoid the "all or none" gastric emptying nature of single-unit floating dosage forms. An objective of the presence investigation was to develop calcium silicate (CaSi)/calcium alginate (Ca-Alg)/hydroxypropyl methylcellulose (HPMC) mucoadhesive-floating beads that provide time- and site-specific drug release of alfuzosin hydrochloride (Alf). Beads were prepared by simultaneous internal and external gelation method utilizing 3(2) factorial design as an experimental design; with two main factors evaluated for their influence on the prepared beads; the concentration of CaSi as floating aid (X (1)) and the percentage of HPMC as viscosity enhancer and mucoadhesive polymer (X (2)), each of them was tested in three levels. Developed formulations were evaluated for yield, entrapment efficiency, particle size, surface topography, and buoyancy. Differential scanning calorimetry, Fourier transform infrared spectroscopy, in vitro drug release, as well as in vitro mucoadhesion using rat stomach mucosal membrane were also conducted. Percentage yield and entrapment efficiency ranged from 57.03% to 78.51% and from 49.78% to 83.26%, respectively. Statistical analysis using ANOVA proved that increasing the concentration of either CaSi or HPMC significantly increased the beads yield. Both CaSi and HPMC concentrations were found to significantly affect Alf release from the beads. Additionally, higher CaSi concentration significantly increased the beads diameter while HPMC concentration showed significant positive effect on the beads mucoadhesive properties. CaSi/Ca-Alg/HPMC beads represent simple floating-mucoadhesive gastroretentive system that could be useful in chronopharmacotherapy of benign prostatic hyperplasia.

FLOATING GASTRO-RETENTIVE DOSAGE FORMS – A NOVEL APPROACH FOR TARGETED AND CONTROLLED DRUG DELIVERY

Controlled (modified) release dosage forms are one of the key concepts in drug delivery, leading to enhanced drug bioavailability and increased patient’s compliance. However conventional modified release dosage forms encounter one big disadvantage- lack of site-specific drug delivery. Scientists developed different kinds of targeted oral controlled release forms. One of these are gastro-retentive systems- systems which can remain in the stomach region for prolonged period of time and thereby release the active compound in controlled fashion. Floating dosage forms are the most promising approach of all gastro-retentive systems. They are capable to float over the gastric content in longer time intervals. This article makes a review on floating dosage forms in general, different approaches for achieving floatation, advantages and disadvantages of this drug delivery concept. For better understanding the topic,an emphasis is made also on the anatomical and physiological features of the stomach and on the factors affecting gastric retention.

Development and evaluation of bromhexine hydrochloride floating microparticulates

The main objective of the present study is to prepare floating microsphere of the bromhexine hydrochloride in order to achieve gastro-retention which may result in the improvement of bioavailability and solubility as the bromhexine is soluble up to the pH range of 1–4. The microsphere is prepared by the non-aqueous solvent evaporation method using hydroxyl propyl methyl cellulose and ethyl cellulose in different drug polymer ratios.The in vitro release is studied in the USP dissolution apparatus type I.The percentage yield is more than 60% for the all the batches.The entrapment efficiency increased by increasing the polymer concentration and found to be maximum at 1:4 drug polymer ratios.The drug loading was found to be in the range of the 19.30–33.70%. All the batches show in vitro buoyancy percentage in the range of the 53.3% to 70.13% after 12 h. The in vitro dissolution and permeation studies revealed that the formulations followed zero order release pattern and ‘n’ values derived from the PEPPAs equation confirmed that the drug release from the floating system was the non-Fickian transport mechanism.The SEM studies revealed that the drug adsorbed on the surface of the microspheres can able to provide the burst effect in order to provide the immediate therapeutic effect. Therefore, the floating microspheres were able to be buoyant up to 12 h, having excellent flow properties, and met the required drug release kinetics for gastro-retentive systems.

Pharmaceutical Development and Clinical Pharmacokinetic Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin

The most common approach for achieving sustained drug release is by the use of hydrophilic polymeric excipients directly compressed with active ingredients into tablets. Hydrophilic polymers swell in the presence of water to form hydrogel structures from which drugs are released by slow diffusion. The purpose of this study was to prepare a floating drug delivery system of levofloxacin, a fluoroquinolone antibiotic. Levofloxacin is highly soluble in acidic media and precipitates in alkaline media, thereby losing its solubility. We designed a gastroretentive system of levofloxacin to enhance bioavailability by retaining them in the acidic environment of the stomach. Tablets were prepared by the direct compression technique using polymers such as hydroxypropyl- methylcellulose (HPMC K4M, HPMC K15M, and HPMC K100M). Sodium bicarbonate was utilized as a gas-generating agent. Tables were evaluated for their physical characteristics such as hardness, thickness, friability, weight variation, drug content, swelling studies, and floating properties. Tablet formulations were evaluated by in vitro dissolution studies. Formulations showed a floating lag time of 30 seconds and a floating time above 12 hours. Among these formulations F3, F7 and F11 exhibited controlled and prolonged drug release profiles while floating over the dissolution medium. The best formulation (F3) was selected based on in vitro characteristics and further tested in healthy volunteers by radiographic studies of tablets by incorporating BaSO4. These clinical studies revealed that the tablets remained in the stomach for 240 ± 30 minutes in fasting human volunteers, indicating gastric retention of the system.

Acyclovir-Loaded Chitosan Microspheres for Gastroretention: Development and Evaluation

Mucoadhesive chitosan microspheres of acyclovir were prepared to prolong the gastric residence time using simple emulsification phase separation technique. The particle morphology of drug-loaded formulations was measured by SEM and the particle size distribution was determined using an optical microscope. The release profile of acyclovir from microspheres was examined in simulated gastric fluid (SGF pH 1.2). The particles were found to be discreet and spherical with the maximum particles of an average size (31.62 ± 4.64). The entrapment efficiency was found to be in the range of 40.24 to 67.29%. The concentration of the glutaraldehyde (25%v/v) as a cross-linker 2 ml and drug polymer ratio of 1:2 caused an increase in the entrapment efficiency and the extent of drug release. The optimized chitosan microspheres were found to possess good bioadhesion (79.89 ± 1.01%). The gamma-scintigraphy study showed the gastric residence time of more than 6 hours which revealed that optimized formulation could be a good choice for gastroretentive systems.

Advances in gastro retentive drug-delivery systems

Introduction: In recent years, various technological improvements have been achieved and new concepts have been developed, in the area of controlled release solid oral dosage forms, especially for products where an extended time of release is associated with an extended gastric retention time. These Gastro Retentive Systems have been quite investigated because they can improve the in-vivo performance of many drugs.Areas covered: This paper summarizes current approaches in the research and development of gastro retentive dosage forms from recent literature. Apart from the numerous mechanisms of action involved, a short review of different key parameters is proposed, taking into account the stomach physiology. Most of the current technologies published, patented or marketed are presented. Promising drugs to develop in the near future are mentioned, and the importance of such systems in fixed Dose Combinations is also discussed. The importance of food effect is mentioned, and the impact of the multiple unit systems versus monolithic approach is discussed, especially regarding the dose intake.Expert opinion: In conclusion, numerous mechanisms like floating, sinking, effervescence, swelling, bioadhesion, magnetic, etc. have been proposed over the years. While most of the proposed systems show promising dissolution profiles and in-vitro retention, only few of them have also shown success in-vivo. Currently, the polymeric swelling monolithic systems are the most prominent marketed forms. The possibility to combine different mechanisms in order to ensure true gastric retention even in the fasted state should be further investigated.

Pharmaceutical Approaches for Optimizing Oral Anti-Inflammatory Delivery Systems

The purpose of the present review is to compile the recent literature in the field of anti-inflammatory treatments, with special focus to the state-of-the-art on pharmaceutical approaches for optimizing oral administration. Attending to the drawbacks associated with the use of these types of drugs, the development of oral modulated release formulations is highly desirable in order to achieve improved therapeutic efficacy and patient compliance. Several technological systems and their advantages in modulated and targeted drug releases (gastroretention or colonic release) have been described: matrix systems, coated dosage forms, osmotic pressure based formulations, prodrugs, colloidal carriers, microparticles and other carriers. These new approaches seem to be promising and have been considered by pharmaceutical companies. Keywords: Anti-inflammatory drugs, matrix systems, coated systems, osmotic systems, prodrugs, colloidal carriers, microparticles, gastroretentive systems, colon systems, coated dosage forms

Application of pectin in oral drug delivery

Introduction: Biopolymers have been used extensively in the pharmaceutical field. Pectin, a biopolymer, has several unique properties that enable it to be used as an excipient or carrier for oral drug delivery systems. Accordingly, several investigators have identified the benefits of pectin-based delivery systems for oral drug administration.Areas covered: This review first describes the chemical structure, source and production, degree of esterification and gel formation properties of pectin. The application of pectin in various oral drug delivery platforms is also discussed, that is, controlled release systems, gastro-retentive systems, colon-specific delivery systems and mucoadhesive delivery systems.Expert opinion: Pectin from different sources provides different gelling abilities, due to variations in molecular size and chemical composition. Like other natural polymers, a major problem with pectin is inconsistency in reproducibility between samples, which may result in poor reproducibility in delivery characteristics. Scintigraphic studies and in vivo studies, in both animals and human volunteers, demonstrate the successful development of a pectin-based colon-specific drug delivery system. Pectin-based controlled release systems, gastro-retentive systems and mucoadhesive systems present promising approaches for increasing the bioavailability of drugs, but are in their infancy. A lack of direct correlation between in vitro release and in vivo absorption studies is a major concern with these systems.

Development and Evaluation of a Floating Multiparticulate Gastroretentive System for Modified Release of AZT

The aim of this study was to develop and evaluate a floating multiparticulate gastroretentive system for the modified release of zidovudine (AZT). AZT was used as a model drug water-soluble at therapeutic doses. The floating gastroretentive system was obtained by co-precipitation, after solvent diffusion and evaporation. The proposed system was evaluated in vitro for particle morphology, lag time and floating time, loading rate, release profile, and the release kinetic of AZT release. AZT's physico-chemical characteristics were evaluated by differential scanning calorimetry (DSC), X-ray diffraction (XDR) and infrared spectroscopy (IR). The particles obtained were sphere-shaped, hollow, and had porous walls. The floating was immediate, and floating time was higher than 12 h. The loading rate was 34.0 ± 9.0%. The system obtained had an extended release. DSC and XDR results showed a modification in AZT's solid state. IR spectroscopy revealed that the chemical structure of the AZT was unchanged. The hollow microballoons presented gastroretentive, floating, and extended-release properties.

A comprehensive in vitro and in vivo evaluation of thiolated matrix tablets as a gastroretentive delivery system

The aim of this study was to investigate the potential of thiolated matrix tablets for gastroretentive delivery systems. Poly(acrylic acid)-cysteine (PAA-Cys) and chitosan-4-thiobuthylamidine (chitosan-TBA) were evaluated as anionic and cationic thiolated polymers and riboflavin was used as a model drug. Tablets were prepared by direct compression and each formulation was characterized in terms of disintegration, swelling, mucoadhesion, and drug release properties. Thereafter, the gastric residence times of tablets were determined with in vivo study in rats. The resulting PAA-Cys and chitosan-TBA conjugates displayed 172.80 ± 30.33 and 371.11 ± 72.74 µmol free thiol groups, respectively. Disintegration studies demonstrated the stability of thiolated tablets up to 24 h, whereas tablets prepared with unmodified PAA and chitosan disintegrated within a time period of 1 h. Mucoadhesion studies showed that mucoadhesion work of PAA-Cys and chitosan-TBA tablets were 1.341- and 2.139-times higher than unmodified ones. The mucoadhesion times of PAA, PAA-Cys, chitosan, and chitosan-TBA tablets were 1.5 ± 0.5, 21 ± 1, 1 ± 0.5, 17 ± 1 h, respectively. These results confirm the theory that thiol groups react with mucin glycoproteins and form covalent bonds to the mucus layer. Release studies indicated that a controlled release was provided with thiolated tablets up to 24 h. These promising in vitro results of thiolated tablets were proved with in vivo studies. The thiolated tablets showed a gastroretention time up to 6 h, whereas unmodified tablets completely disintegrated within 1 h in rat stomach. Consequently, the study suggests that thiolated matrix tablets might be promising formulations for gastroretentive delivery systems.

Development and evaluation of a gastro-retentive delivery system for improved antiulcer activity of ginger extract (Zingiber officinale)

Aim was to develop and optimize multiunit gastro-retentive floating beads (FBs) intended for localized and prolonged release of ginger for treating gastric ulcers. Protective effect of ginger extract (GE) against ulcer is well documented, but therapeutic use is compromised due to poor bioavailability and physicochemical properties. GE was only slightly soluble (3.19 ± 0.38 mg/ml) in simulated gastric fluid (SGF; pH 1.2). The solubility decreased in water to 0.69 ± 0.03 mg/ml and further by 26% in the presence of calcium carbonate (0.5% w/v). We prepared FBs of GE using calcium carbonate and sodium alginate in different proportions. Beads were evaluated for diameter, buoyancy, entrapment, and porosity. In vitro dissolution showed a Fickian release with a cumulative release of >80% at 24 h. Preclinical evaluation was done in cold-restraint stress induced gastric ulcers, in albino rats, in terms of (i) ulcer index, hemorrhagic streaks (l), mucus content, (ii) oxido-nitrosative stress, and (iii) histopathology. GE loaded FBs (200 mg/kg) were significantly better than free GE and better/equivalent to cimetidine (10 mg/kg). The system was evaluated for therapeutic effect (curative), i.e. after the induction of ulcers. Most of the natural phytochemical or antioxidants show pretreatment effectiveness. We, however, developed and established GE FBs for sustained curative effect.

Surface Characterisation of Bioadhesive PLGA/Chitosan Microparticles Produced by Supercritical Fluid Technology

Novel biodegradable and mucoadhesive PLGA/chitosan microparticles with the potential for use as a controlled release gastroretentive system were manufactured using supercritical CO(2) (scCO(2)) by the Particle Gas Saturated System (PGSS) technique (also called CriticalMix(TM)). Microparticles were produced from PLGA with the addition of mPEG and chitosan in the absence of organic solvents, surfactants and crosslinkers using the PGSS technique. Microparticle formulations were morphologically characterized by scanning electron microscope; particle size distribution was measured using laser diffraction. Microparticle surface was analyzed using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to evaluate the presence of chitosan on the surface. Mucoadhesiveness of the microparticles was evaluated in vitro using a mucin assay employing two different kinds of mucin (Mucin type III and I-S) with different degrees of sialic acid contents, 0.5-1.5% and 9-17%, respectively. The two analytical surface techniques (XPS and ToF-SIMS) demonstrated the presence of the chitosan on the surface of the particles (<100 μm), dependent on the polymer composition of the microparticles. The interaction between the mucin solutions and the PLGA/chitosan microparticles increased significantly with an increasing concentration of mucin and chitosan. The strong interaction of mucin with the chitosan present on the surface of the particles suggests a potential use of the mucoadhesive carriers for gastroretentive and oral controlled drug release.

Formulation and In Vitro evaluation of pH sensitive oil entrapped buoyant beads of amoxicillin.

A gastro retentive pH sensitive system has been a frontier approach to release the drug in controlled manner in stomach and duodenum. The aim of the study is to develop reliable formulation of amoxicillin which will release the drug in controlled way at specific site with acidic pH stimulus present in the gastric region. In the present investigation pectin based oil entrapped micro gel beads were prepared by ionic gelation technique using castor oil and mineral oil. The developed beads were evaluated in term of diameter, surface morphology, floating lag time, encapsulation efficiency, in vitro drug release.Prepared microbeads were regular and spherical in shape. The formulation exhibited sustained release profile and was best fitted in the Peppas model with n < 0.45. Subsequent coating of microbeads exhibited zero-order sustained pattern of amoxicillin release up to 8 hrs.The Results provides evidence that optimized gel bead may be used to incorporate antibiotics like amoxicillin and may be effective when administered locally in the stomach to cure microbial infection. Keywords: Amoxicillin (Am); Calcium pectinate bead; Residential time; pH Sensitive; Ethyl cellulose (EC)

Gastroretentive Floating Drug-Delivery Systems: A Critical Review

The oral delivery of drugs with a narrow absorption window in the gastrointestinal tract (GIT) is often limited by poor bioavailability with conventional dosage forms due to incomplete drug release and short residence time at the site of absorption. To overcome this drawback and to maximize the oral absorption of these drugs, gastroretentive systems such as mucoadhesive, high-density, expandable, and floating systems have been developed. These systems provide controlled delivery of drugs with prolonged gastric residence time. However, in humans, differences in various physiological and biological factors can affect the gastric residence time and drug-delivery behavior from gastroretentive systems. Some floating drug-delivery systems (FDDS) have shown the capability to accommodate these variations without affecting drug release. This review mainly focuses on various physiological considerations for development of FDDS, and highlights recent technological developments including new dosage forms and their production techniques (e.g., holt-melt extrusion, melt pelletization, and pulsed plasma-irradiation processes). Alternatives to the existing in vitro compendial methods for evaluating floating dosage forms will be discussed, and a critical analysis of the existing literature on FDDS, identifying the potential areas for future research, is provided.

Gastroretentive drug delivery system of acyclovir-loaded alginate mucoadhesive microspheres: Formulation and evaluation

In the present study, mucoadhesive alginate microspheres of acyclovir were prepared to prolong the gastric residence time using a simple emulsification phase separation technique. The particle size of drug-loaded formulations was measured by SEM and the particle size distribution was determined using an optical microscope and mastersizer. The release profile of acyclovir from microspheres was examined in simulated gastric fluid (SGF pH 1.2). The particles were found to be discreet and spherical with the maximum particles of an average size (70.60 ± 2.44 µm). The results indicated that the mean particle size of the microspheres increased with an increase in the concentration of polymer and decreased with increase in stirring speed. The entrapment efficiency was found to be in the range of 51.42−80.46%. The concentration of the calcium chloride (% w/v) of 10% and drug–polymer ratio of 1:4 resulted in an increase in the entrapment efficiency and the extent of drug release. The optimized alginate microspheres were found to possess good mucoadhesion (66.42 ± 1.01%). The best fit model with the highest regression coefficient values (R2) was predicted by Peppas model (0.9813). In Gamma scintigraphy analysis, the section of GIT was critically analyzed and much differentiation was present at each time point after oral administration, which revealed that the optimized formulation demonstrated gastroretention in vivo for more than 4 h, which revealed that optimized formulation could be a good choice for gastroretentive systems.

Floating Drug Delivery of Nevirapine as a Gastroretentive System

A multiple-unit floating drug delivery system based on gas formation technique was developed, in order to prolong the gastric residence time and to increase the overall bioavailability of the dosage form. The floating bead formulations were prepared by dispersing nevirapine together with calcium carbonate in a mixture of sodium alginate and hydroxypropyl methylcellulose solution and then dripping the dispersion into an acidified solution of calcium chloride. Calcium alginate beads were formed, as the alginate underwent ionotropic gelation by calcium ions, and carbon dioxide developed from the reaction of carbonate salts with acid. The obtained beads were able to float due to CO2-gas formation and the gas entrapment by the polymeric membrane. The prepared beads were evaluated for percent drug loading, drug entrapment efficiency, morphology, surface topography, buoyancy, in-vitro release, and release kinetics. The formulations were optimized for different weight ratios of the gas-forming agent and sodium alginate. The beads containing higher amounts of calcium carbonate demonstrated an instantaneous, complete, and excellent floating ability over a period of 24 hours. The increased amount of the gas forming agent did not affect the time to float, but increased the drug release from the floating beads, while increasing the coating level of the gas-entrapped membrane, increased the time to float, and slightly retarded the drug release. Good floating properties and sustained drug release were achieved. Finally, these floating beads seemed to be a promising gastroretentive drug delivery system.

Sustained delivery of propranolol by using multiparticulate gastroretentive drug delivery system

PURPOSE: Gastroretentive systems can significantly prolong the gastric residence time of drugs. If a drug is stable in gastric acid, prolonged gastric retention improves bioavailability. The objective of the present investigation was to develop an extended and controlled release composition and formulation of propranolol using expandable, gelling, swellable hydrocolloid polymer along with mineral oil. METHODS: A formulation was prepared without using mineral oil by conventional ionotropic gelation method. All other formulations of oil entrapped floating gel beads of propranolol hydrochloride were prepared by using emulsion gelation method in which sodium alginate was used as a gelling agent and mineral oil was used to impart buoyancy to the formulation Spherical gel beads were formed instantaneously. The prepared beads were evaluated for diameter, surface morphology, encapsulation efficiency and drug release. RESULTS: Low concentration of oil containing formulation exhibited greater release of drug. As the concentration of oil increases, drug release decreases to certain extent. Percentage buoyancy of floating propranolol hydrochloride gel beads was found satisfactory. The highest mean diameter was observed in the formulation with 30% of mineral oil. The formulation with 35% of mineral oil had the highest drug loading and scanning electron microscopy revealed that the beads were spherical in shape with rough surfaces. CONCLUSION: Oil entrapped gel beads can be used as floating drug delivery system for extended drug release for both local and systemic drug delivery. Keywords: Floating drug delivery system; Emulsion gelation; Sodium alginate; Mineral oil; Propranolol hydrochloride.

Evaluation of Anti-GERD Activity of Gastro Retentive Drug Delivery System of Itopride Hydrochloride

The present work describes the formulation and evaluation of the gastroretentive system of Itopride hydrochloride. In this research, we have formulated floating hydrogel-based microspheres employing calcium carbonate (CaCO(3)) as a gas forming agent dispersed in alginate matrix. In vitro characterizations such as drug content, particle size, and drug release were carried out. GI motility was determined by administration of charcoal meal to rats. Results demonstrated that prepared microspheres were spherical in shape with smooth surface, good loading efficiency, and excellent buoyancy. The gastro retentive dosage form of itiopride demonstrated significant antacid, anti-ulcer, and anti-GERD activity after 12 hours in comparison with the conventional dosage form.