floating drug delivery system research articles

Research article
Open access
Published: 09 October 2021

To control floating drug delivery system in a simulated gastric environment by adjusting the Shell layer formulation

Yu-Tung Hsu 1 ,
Chen-Yu Kao 2 , 3 ,
Ming-Hua Ho ORCID: orcid.org/0000-0001-6620-4207 1 , 4 &
Shiao-Pieng Lee 5 , 6

Biomaterials Research volume 25 , Article number: 31 ( 2021 ) Cite this article

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Gastroretentive drug delivery system (GDDS) are novel systems that have been recently developed for treating stomach diseases. The key function of all GDDS systems is to control the retention time in the stomach. However, research into the bulk density or entanglement of polymers, especially regarding their effects on drug float and release times, is scarce.

In this research, we prepared the floating core-shell beads carrying tetracycline. The ratio of chitosan and xanthan gum in the shell layer was changed to modify polymer compactness. Tetracycline was encapsulated in the alginate core.

Using scanning electron microscopy (SEM) techniques, we observed that the shell formulation did not change the bead morphology. The cross-sectional images showed that the beads were highly porous. The interaction between anionic xanthan gum and cationic chitosan made the shell layer dense, resisting to the mass transfer in the shell layer. Due to the high mass transfer resistance to water penetration, the longer float and delivery time were caused by the dense surface of the beads. The cell culture demonstrated that floating core-shell beads were biocompatible. Importantly, the beads with tetracycline showed a significant prolonged anti-bacterial effect.

Research results proved that the floating and releasing progress of core-shell beads can be well controlled by adjusting the shell layer formulation that could promote the function of gastroretentive drugs.

Introduction

Oral administration is the most common drug delivery method as it is multifunctional and convenient [ 1 ]. The size of drug carriers is usually adjusted to 1–2 mm, allowing the medicine in the stomach to pass through the pylorus and enter into the small intestine [ 2 ]. Advances in pharmaceutical techniques have enabled to release drugs in a specific position in vivo to lower toxicity, decrease side effects, and promote efficiency. Thus, the gastroretentive drug delivery system (GDDS) has been developed for treating stomach cancer, ulcer and infection. GDDS could keep drugs in stomach for a prolonged period to achieve a specific release, including several types: floating, mucoadhesive, expandable and rafting forming drug delivery systems.

The floating drug delivery system (FDDS) is also called a hydrodynamically balanced system (HBS). In FDDS, the drugs carriers float in gastric juice to ensure that drugs do not leave stomach shortly. It efficiently increases drug bioavailability by prolonging the release period. The variation of drug concentrations in blood is also decreased [ 3 ]. FDDS is a potential treatment for stomach and duodenum diseases. The density of FDDS carriers must be lower than those of the gastric juice and chymus. Therefore, medicines float and are slowly released in the stomach, compared with the convectional drug delivery methods. Most antibacterial agents have low minimum inhibitory concentration (MIC) to Helicobacter Pylori in vitro, but are not very effective for the eradication of infection caused by Helicobacter Pylori in vivo . The short residence time is the key problem [ 4 ]. Better stability and prolonged residence time allow more effective antibiotic penetration through the gastric mucus layer to suppress or eradicate Helicobacter Pylori in stomach [ 5 , 6 ], which would be achieved by FDDS.

Currently, most FDDS would not float for 2–8 h; however, the drug float and release periods need to be prolonged. To obtain improved drug float and release times, previous research studies have widely investigated control of the drug carrier materials. Kawashima, Sato, Thanoo [ 7 , 8 , 9 , 10 ] et al. prepared hollow spheres for FDDS by using the emulsion-solvent diffusion method. These studies focused on controlling the carrier density by solvent diffusion. In particular, polymer porosity dominates the solvent diffusion rates that determining the carrier floating behaviors. Xu, Choi and El-Kamel et al. added gas-forming/generating agents in polymers to increase the porosity, and therefore, the floating properties [ 11 , 12 , 13 ]. Indeed, the porosity was influenced by the amount of gas-generating agents. According to prior researches, the gas generating agents and solvent diffusion would significantly affect the porosity in FDDS. In contrast, research into the bulk density or entanglement of polymers, especially regarding their effects on drug float and release times, is scarce.

In this research, we prepared the core-shell floating particles for GDDS. We used two polymers, chitosan and xanthan gum, as the shell layer, which are cationic and anionic, respectively. Chitosan and xanthan gum were widely used in previous researches for the drug delivery, so their biocompatibility and biodegradability have been well approved. Manca et al. controlled the ratios of chitosan and xanthan gum to adjust the surface potential of liposome with coating layer, which influenced the rheological properties of microparticles in aerosol performance [ 14 ]. In the study of Kulkarni et al., chitosan and xanthan gum were blended to produce dense particles. Their results supported that the chitosan/xanthan gum ratio influenced the mucoadhesive properties [ 15 ]. Fareez et al. prepared chitosan-coated alginate/xanthan gum beads. The surface properties of beads were determined by chitosan shell layer [ 16 ]. Although chitosan and xanthan gum were used in these studies, the core-shell and porous particles with shell layer controlled by chitosan and xanthan gum interactions have been never applied for the FDDS and GDDS system.

Adjusting the chitosan/xanthan gum (C/X) ratio enabled us to adjust the polymeric entanglement, and allowed us to control the shell layer properties and structures in floating beads. We studied how the shell layer affects the float, release and biocompatibility properties. Moreover, the efficient drug carriers with better duration in GDDS would be developed by controlling the shell layer properties.

Materials and methods

Alginic acid sodium salt (medium viscosity), xanthan gum (from Xanthomonas campestris ), NaHCO 3 (sodium bicarbonate powder), chitosan (low molecular weight), tetracycline (> 98.0%) were purchased from Sigma-Aldrich (St. Louis, MO). CaCl 2 (calcium chloride) and HCl and acetic acid were purchased from J.T. Baker, Japan. Dulbecco’s modified eagle medium (DMEM), fetal bovine serum (FBS), penicillin, trypsin was purchased from Gibco Life Technologies (Thermo Fisher Scientific - TW). Kaighn’s modification of Ham’s F-12 medium was purchased from Manassas, VA, USA. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) kit was purchased from Carlsbad, CA, USA. Distilled deionized (DI) water was used throughout the experiment.

Preparation of floating beads containing tetracycline

Two solutions were prepared respectively for core-shell beads. One was the tetracycline-alginate aqueous solution for core, and the other was the chitosan/xanthan-gum (C/X) solution for shell. First, 50 mg tetracycline and 200 mg alginate were mixed in 10 ml DI water, and stirred for 2 h to obtain the tetracycline-alginate solution. 200 mg NaHCO3 was then added into alginate solution, and stirred at 500 rpm for 1 h.

On the other hand, the C/X solution was prepared by mixing chitosan solution and xanthan gum solution. The chitosan solution was fabricated by dissolving chitosan powders in 1 v/v% acetic acid aqueous solution, and xanthan gum solution was prepared by dissolving xanthan gum in DI water. After that, chitosan and xanthan gum solutions were mixed with different C/X ratios of 4:1, 4:2, 4:3, 4:4 and 1:4, where CaCl2 was also added as the concentration of 1 w/v%.

After finishing tetracycline-alginate solution for core and C/X solution for shell respectively, we extruded the tetracycline-alginate solution through a 26-gauge needle into the continuously stirred C/X solution. The C/X shell layer was then formed outside the alginate core, and the solution with floating beads was stabilized after continuously stirred for 15 min. After the beads were collected and washed with DI water, they were vacuum dried for 48 h and then stored in 4 °C until used. The exact formulations of core and shell layer were described in Table 1 .

FE-SEM (field emission scanning electron microscope) analysis

SEM (JEOL JSM-6390LV, Japan) images were taken to analyze the morphology of floating beads. The beads were dried at 4 °C. After that, the bead samples were spread and fixed on the metal plate with double-sided carbon tape, and a gold layer was then coated on the sample surface under vacuum using an auto-sputter coater for 1 min under argon atmosphere. The beads morphologies were then observed with SEM. With SEM images, the bead diameters were measured by Image J software.

Swelling and floating test

The swelling percentage of beads was determined by measuring the extent of swelling of the polymer matrix in pH 2 aqueous solution. The weight of dried beads was recorded. After the immersion in pH 2 buffer for 1, 2, 4, 6, 8, 12 and 24 h, water on bead surfaces was removed by filter paper and the weight beads were measured again. The swelling percentage was calculated by using the following equation.

For the floating analysis, twenty dried beads were kept in pH 2 buffer for 24 h with continuous shaking. After 1, 2, 4, 6, 8, 12 and 24 h, the floating percentage was calculated according to following equation:

N f : number of floating beads; Ns: number of settled beads

In vitro release and encapsulation efficiency of tetracycline

The dry beads were immersed in pH 2 buffer in the dynamic gastric simulator [ 17 ]. After 2, 4, 6, 8, 12 and 24 h, 10 ml solution was taken out and analyzed by UV/VIS spectrophotometer at 266 nm, followed by refilling fresh 10 ml buffer.

In the analysis of encapsulation efficiency, beads were suspended in pH 2 buffer with continuous shaking at 37 °C for 24 h, where a part of encapsulated tetracycline was released. Then, the beads were completely broken by using ultrasonic shaker for 30 min, and the residual tetracycline would be completely released. After the solution was filtrated, UV/VIS spectrophotometer was applied to quantify tetracycline in buffer by deducting the absorbance at 266 nm, allowing the determination of encapsulation efficiency as following equation.

Cytotoxicity test

MTT assay was applied to evaluate the cytotoxicity of core-shell beads. In this experiment, a stomach cell line, AGS, was seeded on a 24-well plate with the density of 5 × 10 3 cells per well. AGS has been applied in the cytotoxicity of biomaterials for stomach in previous researches [ 18 ]. As the cell monolayer were cultured to confluence, they were exposed to fluid extracts. The extracts were obtained by placing the core-shell beads in culture medium (0.2 g core-shell particles in 1 ml medium) for 24 h at 37 °C. The C/X = 4:3 core-shell beads were applied in this research. Each fluid extract obtained was then applied to AGS monolayer, replacing the medium that had nourished the cells. The cells were then cultured with extracts for 1 day. After the cell culture, the metabolic activity of AGS was determined by MTT assay. The cells were incubated with 1 mg/mL of MTT for 4 h. Then, the MTT was removed and the formazan crystals were dissolved with dimethyl sulfoxide for 30 min. Finally, absorbance values were read at 570 nm by using an automatic microplate reader (ELx800; Bio-Tek Instruments, Winooski, VT, USA).

Antibacterial testing

LB medium (from Creative Life Science Co., Ltd.) was applied for the culture of E. coli which was from Bioresources Conservation and Research Center (BCRC), Taiwan. The medium with cultured bacterial was added onto agar plate evenly, followed by an overnight culture. After that, core-shell beads were added onto the agar plate, and the antibacterial effects were observed at various time points.

Statistical analysis

The one-way ANOVA was used to analyze the statistical significance of particle diameters, encapsulation efficiency, floating percentage, and cell viability. The two-way ANOVA was used to analyze the statistical significance of swell percentage.

Table 1 demonstrates the floating bead formulations. In this research, the mass ratio of chitosan to xanthan gum (C/X) in the shell layer was adjusted to 4:1, 4:2, 4:3, 4:4 and 1:4, where the amounts of salts (CaCl 2 and NaHCO 3 ) and alginate in core were fixed.

The morphologies of core-shell particles were analyzed by using SEM as shown in Fig. 1 (a). The beads were roughly spherical, with a diameter ranging from 1.5 to 2 mm. The particle diameters were analyzed using Image J and presented in Fig. 1 (b). The formulation of the shell layer had a weak impact on the particle morphologies and diameters. The ANOVA analysis indicated p > 0.1 for the formulation effects on particle diameters, revealing the ratios of chitosan and xanthan gum did not change particle size significantly. The cross-sectional images of core-shell beads are presented in Fig. 2 . Results show that the particles prepared in this research were highly porous. On the other hand, the surfaces of floating beads were highly dense. The whole particle was highly dense when only alginate was applied to prepare dense bead.

Morphologies of core-shell floating beads with various formulation in chitosan/xanthan-gum shell layer ( n = 20). (a) SEM images of floating beads. The C/X ratios are 4:1 (A), 4:2 (B), 4:3 (C), 4:4. (D) and 1:4 (E). (b) Diameters of beads with various formulations in chitosan/xanthan-gum (C/X) shell layer ( p > 0.1 form ANOVA test, n ≥ 10)

The cross-sectional SEM images of floating beads with various formulation in chitosan and xanthan gum shell layer. The C/X ratios are 4:1 (A), 4:2 (B), 4:3 (C), 4:4 (D) and 1:4 (E). The magnified images of alginate dense bead (F) and floating beads with C/X = 4:3 (G) were presented to identify the dense and porous structures in beads

Figure 3 revealed the swelling ratios of core-shell particles with different immersion periods at pH 2. As shown in Fig. 3 (a), all kinds of particles were gradually swelled during first 6 h ( p < 0.05 from ANOVA test) and reached a steady state over the next 2 h. The highest swelling ratios at steady state were 150–250%.

The swelling ratios of core-shell beads with various in chitosan/xanthan-gum (C/X) formulation in pH = 2 buffer ( n ≥ 4). The times for immersion were 1, 2, 4, 6, 8, 12 and 24 h. The results were pooled in accordance with formulation (a) and with immersion period (b). In (a), the significance from ANOVA test from 1 h to 6 h with fixed formulation was marked by * ( p < 0.05), ** ( p < 0.01) and *** ( p < 0.005) for indicated groups. In (b), the significance from ANOVA test for C/X ratio with fixed immersion time was marked by *** ( p < 0.005)

Figure 3 (b) shows that the particles are swelled faster and steady-state swelling ratios increased when the amounts of chitosan were much higher or much lower than the amounts of xanthan gum, such as C/X = 4:1 and 1:4. In contrast, the swelling ratios were relatively low with C/X = 4:3 and 4:4. At all the given time point, C/X = 4/1 and 1/4 showed the highest swelling ratio, and the second high were C/X = 4/2. The lowest swelling ratio appeared in C/X = 4/3 and C/X = 4/4. All differences mentioned in this paragraph were significant according to t-test ( p < 0.05).

Figure 4 presents the floating percentages of core-shell beads in the aqueous solution with pH 2 after immersion for different periods. Figure 4 shows that the floating percentage of chitosan and alginate beads respectively decreased to 55 and 11.6% after 24 h when there is no core-shell structure. Results in Fig. 4 also show that about 90 and 88% of core-shell particles would still keep their floating conditions after 8 and 24 h. The differences between core-shell beads and non-core-shell beads (dense chitosan and alginate beads) were statistically significant after the immersion for 6 h. On the contrary, the ANOVA test indicated that there is no significant difference caused by the ratios of chitosan and xanthan gum ( p > 0.15).

The floating percentage of core-shell beads with various chitosan/xanthan gum ratios, chitosan beads and alginate beads ( n ≥ 3). The significant difference between core-shell beads with all the formulations and dense chitosan beads was indicated by * ( p < 0.05) and ** ( p < 0.01) from t-test at the same immersion time. The significant difference between core-shell beads with all the formulations and dense alginate beads was indicated by # ( p < 0.05), ## ( p < 0.01) and ### ( p < 0.005) from t-test at the same immersion time ( n ≥ 3). Chitosan and alginate beads were dense particles without core-shell structure. There is not significant differences between floating beads with different C/X ( p > 0.15) from ANOVA test

The encapsulation efficiency and releasing rate of tetracycline of floating beads are described in Fig. 5 . There was significant difference in the formulation C/X = 4/1 and C/X = 4/4, as revealed in Fig. 5 (a). The release profile in Fig. 5 (b) was evaluated in dynamic conditions. The results support that the formulation of shell layer actually influence the releases of tetracycline ( p < 0.1 and p < 0.05 from ANOVA test) at 2nd, 4th and 6th hr. That is, the particles released tetracycline faster when the amounts of chitosan are much higher or much lower than the amounts of xanthan gum, such as C/X = 4:1 and 1:4.

Encapsulation efficiency (a) and releasing profile (b) of tetracycline-alginate floating beads in pH = 2 buffer. In (a), the significant differences were indicated by ### ( p < 0.005) from t-test ( n ≥ 3). In (b), the significant differences were indicated by * ( p < 0.1) and ** ( p < 0.05) from ANOVA test with the same release time ( n ≥ 4)

The biocompatibility of floating particles was analyzed by culturing AGS cell line. The C/X = 4:3 core-shell beads were applied because they showed the best floating and long-term release properties in this research. The results in Fig. 6 identify the good biocompatibility of floating beads when the bead concentration was as high as 1.5 mg/ml, which contained 149.03 μg/ml tetracycline, 112.9 times higher than the effective concentration of tetracycline for a 60-kg person [ 17 ].

Biocompatibility of floating beads. The bead amounts in culture medium were 0.5, 1 and 1.5 mg/ml, respectively. Floating beads are core-shell beads with C/X = 4/3. TCPS was tissue culture polystyrene which was used as the controlled group. The culture period was 24 h. From ANOVA test, there was no statistical difference ( p > 0.05 and n ≥ 4). From t test, all the core-shell bead groups were not significantly different from TCPS ( p > 0.05 and n ≥ 4)

The anti-bacterial effects of floating beads are proved in Fig. 7 . The obvious anti-bacterial rings are formed by applying beads with encapsulated tetracycline onto cultured E. coli. It was caused by the released tetracycline, and the core-shell beads without tetracycline did not result in any anti-bacterial ring (Fig. 7 (a), (b), and (c)). To identify the duration of the floating particles, we immersed the particles in a pH 2-buffer for 2 and 4 h before conducting the anti-bacterial experiments. The results in Fig. 7 (e) and (f) proved that the beads can efficiently suppress E. coli though there was a pre-release for 2 and 4 h. Compared with the beads without prerelease in Fig. 7 (d), the anti-bacterial effect did not decay, as shown in in Fig. 7 (e) and (f). Figure 7 (g) presented the anti-bacterial effects of alginate beads without tetracycline. The alginate beads were immersed in a pH 2-buffer for 4 h before the test. The result shows that the alginate bead is not effective on E. coli .

Antibacterial effects of floating beads with/without tetracycline for different immersion periods. (a), (b) and (c) are core-shell beads (C/X=4/3) without tetracycline, and (d), (e) and (f) are core-shell beads (C/X=4/3) with tetracycline. (g) is non-core-shell alginate beads without tetracycline. The immersion time before antibacterial test is 0 hour for (a) (d), 2 hours for (b) (e), and 4 hours for (c) (f) and (g). The beads in (d), (e) and (f) encapsulate 69.9 μg tetracycline in total

The densities of chitosan and xanthan gum used in this research were approximately 0.3 and 1.5 g/cm 3 , respectively. The bulk densities of blended chitosan and xanthan gum were approximately 1.47 g/cm 3 when the ratio was 1:1. After get mixed, chitosan and xanthan gum demonstrated high density compared with their original values. Thus, we assume that interactions between chitosan and xanthan gum increase the density of the two components. The anionic polymer chains of xanthan gum and protonated chitosan exert high intermolecular forces because of the electro-affinity. Polymer interactions make the shell layer dense. In previous researches, polyelectrolyte complexes (PECs) were prepared by blending chitosan and polyanions, such as carrageenan [ 19 ], alginate [ 20 ], poly (acrylic acid) (PAA) and poly (vinylpyrrolidone) (PVP) [ 21 ]. By varying the amounts of positive chitosan and negative polymers, the charge density would be changed, causing differences in the diffusion through PECs. The mass transfer properties were highly related to the polymeric electrostatic interactions, corresponded to our finding in this research.

According to SEM images, the bead surfaces are dense, which would prolong floating periods due to the resistance of mass transfer in water penetration. The dense skin layer could be help prolong the release time of encapsulated drugs. The C/X ratios did not significantly affect the porosity of core-shell beads.

The positive charges of chitosan and negative charges of xanthan gum would result in a strong polymer interaction. These interactions make the shell layer dense, forming a resistance of mass transfer in the shell layer. This hinders water penetration into particles, and therefore, the swelling ratio is low. This result in Fig. 3 revealed that the particle swelling can be tuned by controlling the electro-statistical properties of the shell layer. Besides, the high swelling ratios of core-shell beads show that all the beads developed in this research are very hydrophilic. The hydrophilic particles can provide good encapsulation efficiency and release profile due to the high affinity between the drugs and particles.

The retention periods of FDDS in the stomach reported in previous studies were about 2–4 h [ 22 ]. The floating time of core-shell particles was about 24 h, which was much longer than the above residual periods. It indicates that the dense shell layer developed in this research can prolong the floating time of drugs in the stomach.

When the amounts of chitosan are much higher or much lower than xanthan gum (C/X = 4:1 and 1:4), the release of tetracycline is also higher than those from C/X = 4:3 and 4:4. This is due to the strong interactions between positive chitosan and negative xanthan gum, which results in a dense shell layer. With the dense shell layer, the particle swelling is slow, and the tetracycline release is delayed due to the high resistance in mass transfer. The results supported that the prolonged release can be achieved by controlling the formulation of the dense layer in the core-shell floating beads.

Many researches supported that the ionic crosslinking, which was achieved by mixing chitosan and polyanions, was effective on the control release [ 23 , 24 , 25 ]. In this research, we adjusted the ratio between positive chitosan and negative xanthan gum, and the diffusion properties were thus controlled. The differences between this study and previous researches lies in the components diffusing through polycation/polyanion layer. The water diffusion through shell layer was influenced in this work to prolong the swelling and floating periods of core-shell porous beads. On the other hand, most previous researches focused on the controlled release of encapsulated drugs but not on the floating behaviors.

The floating beads are proved to be biocompatible, and can carry effective antibiotics when they were applied. The released tetracycline from core-shell beads present clear antibacterial effects. According to the statistical analysis, the C/X ratio significantly prolonged the swelling ( p < 0.005 from ANOVA test) and drug release ( p < 0.1 and p < 0.05 from ANOVA test). This supports that the core-shell beads developed in this research can continuously delivery antibiotics for a long period for a certain period.

In this research, we developed core-shell floating beads for GDDS with porous alginate core and a dense chitosan/xanthan-gum shell layer. The compactness of the shell layer in floating beads was controlled by adjusting the ratios of anionic xanthan gum and cationic chitosan. When the C/X ratio was 4:3 and 4:4, the shell layer would be dense and would cause high resistance of mass transfer under the water penetration. Thus, a low swelling rate and a prolonged release was achieved. The experimental results proved the high biocompatibility of the floating beads, and the anti-bacterial effects of beads were also significant after the release for 4 h. This study proposed the method to modify the properties of shell layer, allowing the control of the swelling and release behaviors of floating beads.

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Abbreviations

Gastroretentive drug delivery system

Scanning electron microscopy

Floating drug delivery system

Hydrodynamically balanced system

Minimum inhibitory concentration

Chitosan/xanthan-gum ratio

Dulbecco’s modified eagle medium

Fetal bovine serum

Analysis of variance

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Acknowledgements

The authors would like to thank Precious Instrumentation Center of NTUST for the assistances in SEM set up.

This work was financially supported by National Science Council, Taiwan (NSC, No. 108–2221-E-011-107-) and by National Taiwan University of Science and Technology (NTUST), Tri-Service General Hospital and National Defense Medical Center.

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Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 10617, Taiwan

Yu-Tung Hsu & Ming-Hua Ho

Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan

Chen-Yu Kao

Biomedical Engineering Research Center, National Defense Medical Center, Taipei, 11490, Taiwan

R&D Center for Membrane Technology, National Taiwan University of Science and Technology, Taipei, 10617, Taiwan

Ming-Hua Ho

Division of Oral and Maxillofacial Surgery, Department of Dentistry, Tri-Service General Hospital, Taipei, 11490, Taiwan

Shiao-Pieng Lee

Department of Biomedical Engineering, National Defense Medical Center, Taipei, 11490, Taiwan

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Ming-Hua Ho, Shiao-Pieng Lee and Chen-Yu Kao designed this research. Yu-Tung Hsu performed the experiments. Shiao-Pieng Lee supported the culture and analysis of AGS cells. Ming-Hua Ho, Yu-Tung Hsu, Shiao-Pieng Lee and Chen-Yu Kao wrote the manuscript. Ming-Hua Ho supervised the project and reviewed the manuscript. All authors contributed to the article and approved the submitted version.

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Hsu, YT., Kao, CY., Ho, MH. et al. To control floating drug delivery system in a simulated gastric environment by adjusting the Shell layer formulation. Biomater Res 25 , 31 (2021). https://doi.org/10.1186/s40824-021-00234-6

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DOI : https://doi.org/10.1186/s40824-021-00234-6

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Floating drug delivery systems: a review

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1 Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University, New Delhi 110062, India. [email protected]
PMID: 16353995
PMCID: PMC2750381
DOI: 10.1208/pt060347

The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their classification and formulation aspects are covered in detail. This review also summarizes the in vitro techniques, in vivo studies to evaluate the performance and application of floating systems, and applications of these systems. These systems are useful to several problems encountered during the development of a pharmaceutical dosage form.

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Modern Approaches to Obtaining Floating Drug Dosage Forms (A Review)

Published: 08 December 2022
Volume 56 , pages 1277–1284, ( 2022 )

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E. V. Blynskaya 1 , 2 ,
V. P. Vinogradov 1 ,
S. V. Tishkov 2 ,
S. N. Suslina 1 &
K. V. Alekseev 2

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Floating dosage forms (FDFs) represent widely used types of gastroretentive drug delivery systems that provide targeted delivery to the upper gastrointestinal tract. This article proposes a classification of FDFs according to which approaches to achieving drug flotation are reviewed based on published works. FDFs present on the market and the concepts used to create them are described. Various parameters and factors affecting the efficacy of this type of dosage form that must be taken into account in the drug development process and the problems that this approach to gastroretention solves are described. FDF development directions utilizing existing progress and promising for the future are highlighted.

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Risk-based approach for systematic development of gastroretentive drug delivery system

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Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 56, No. 9, pp. 51 – 58, September, 2022.

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Blynskaya, E.V., Vinogradov, V.P., Tishkov, S.V. et al. Modern Approaches to Obtaining Floating Drug Dosage Forms (A Review). Pharm Chem J 56 , 1277–1284 (2022). https://doi.org/10.1007/s11094-022-02786-w

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Floating Drug Delivery Systems: A Comprehensive Review of Formulation Strategies and Applications

K. Jaganathan Department of Pharmaceutics, JKKMMRF’S Annai JKK Sampoorani Ammal College of Pharmacy, Ethirmedu, Komarapalayam – 638183, Namakkal (DT), Tamil Nadu, India
D. Devanandh Department of Pharmaceutics, JKKMMRF’S Annai JKK Sampoorani Ammal College of Pharmacy, Ethirmedu, Komarapalayam – 638183, Namakkal (DT), Tamil Nadu, India
S. Chandra Department of Pharmaceutics, JKKMMRF’S Annai JKK Sampoorani Ammal College of Pharmacy, Ethirmedu, Komarapalayam – 638183, Namakkal (DT), Tamil Nadu, India
N. Senthilkumar Department of Pharmaceutics, JKKMMRF’S Annai JKK Sampoorani Ammal College of Pharmacy, Ethirmedu, Komarapalayam – 638183, Namakkal (DT), Tamil Nadu, India

Floating drug delivery systems (FDDS) have garnered significant attention in pharmaceutical research due to their ability to improve drug bioavailability and therapeutic efficacy. This comprehensive review aims to provide an in-depth analysis of the formulation strategies and applications of floating drug delivery systems.The review commences by discussing the physiological basis of gastric retention, highlighting the importance of FDDS in achieving prolonged residence time within the stomach. It explores the factors affecting gastric emptying and their impact on FDDS performance. Various approaches for formulating buoyant drug delivery systems, including single-unit and multiple-unit systems, are elucidated along with their respective advantages and limitations.Furthermore, the review delves into the diverse range of polymers, gelling agents, and gas-generating agents employed in FDDS formulation. Special emphasis is placed on recent advancements in material science and their contribution to enhancing the floating properties, drug release kinetics, and overall performance of these systems. Additionally, the integration of innovative technologies such as microbubbles, magnetic particles, and mucoadhesive polymers is explored for their potential to further optimize FDDS functionality.The applications of FDDS go beyond improving drug delivery to include therapeutic areas such as gastroesophageal reflux disease, peptic ulcers, motion sickness, and local gastric treatment. The review highlights the clinical significance of FDDS in these contexts, shedding light on recent clinical trials and outcomes.In conclusion, this review underscores the profound impact of floating drug delivery systems on pharmaceutical research and patient care. It provides a comprehensive understanding of the formulation strategies, materials, and applications associated with FDDS, paving the way for continued innovation in drug delivery and therapeutic effectiveness.

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Floating drug delivery system: an outlook

Ananta Choudhury Department of Pharmacy, Assam Down Town University, Panikhaiti, Guwahati, Assam, India Pin- 781026
Lalmalsawmi Renthlei Department of Pharmacy, Assam Down Town University, Panikhaiti, Guwahati, Assam, India Pin- 781026
Manjima Dewan Department of Pharmacy, Assam Down Town University, Panikhaiti, Guwahati, Assam, India Pin- 781026
Raju Ahmed Department of Pharmacy, Assam Down Town University, Panikhaiti, Guwahati, Assam, India Pin- 781026
Himal Barakoti Department of Pharmacy, Assam Down Town University, Panikhaiti, Guwahati, Assam, India Pin- 781026
Biplab Kumar Dey Department of Pharmacy, Assam Down Town University, Panikhaiti, Guwahati, Assam, India Pin- 781026

Floating drug delivery is considered as the most effective amongst the several approaches of gastro retentive drug delivery systems. The short gastric residence times (GRT) and unpredictable gastric emptying times (GET) are the two most important parameters that play a vital role in improving the bioavailability of drugs those are having an absorption window at the stomach. The floating drug delivery approach is a low-density system that may be effervescent or Non-Effervescent type with sufficient buoyancy to flow over the gastric contents and remain buoyant in the stomach without affecting the stomachic emptying rate for a prolonged duration. Floating dosage forms include tablets, granules, capsules, microspheres, microparticle, etc. are few formulations available commercially. A comprehensive summary of different floating drug delivery and its present status has been highlighted in this review.

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Review Article
Published: 25 June 2024

Precision drug delivery to the central nervous system using engineered nanoparticles

Jingjing Gao 1 ,
Ziting (Judy) Xia 2 ,
Swetharajan Gunasekar 2 ,
Christopher Jiang 2 ,
Jeffrey M. Karp 2 , 3 , 4 , 5 , 6 &
Nitin Joshi ORCID: orcid.org/0000-0001-8138-7611 2 , 3

Nature Reviews Materials ( 2024 ) Cite this article

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Drug delivery
Neuroscience

Development of novel therapies for central nervous system (CNS) disorders has experienced a high failure rate in clinical trials owing to unsatisfactory efficacy and adverse effects. One of the major reasons for limited therapeutic efficacy is the poor penetration of drugs across the blood–brain barrier. Despite the development of multiple drug delivery platforms, the overall drug accumulation in the brain remains sub-optimal. Another critical but overlooked factor is achieving precision delivery to a specific region and cell type in the brain. This specificity is crucial because most neurological disorders exhibit region-specific vulnerabilities. Multiple trials have failed owing to adverse CNS effects induced by nonspecific drug targeting. In this Review, we highlight the key regions and cell types that should be targeted in different CNS diseases. We discuss how physiological barriers and disease-mediated changes in the blood–brain barrier and the overall brain can impact the precision delivery of therapeutics via the systemic route. We then perform a systematic analysis of the current state-of-the-art approaches developed to overcome these barriers and achieve precision targeting at different levels. Finally, we discuss potential approaches to accelerate the development of precision delivery systems and outline the challenges and future research directions.

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Strategies for delivering therapeutics across the blood–brain barrier

Drug delivery to the central nervous system

Nanomedicine-based immunotherapy for central nervous system disorders

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Acknowledgements

The authors thank all authors whose work in CNS drug delivery and related areas contributed to this Review. The authors also thank the reviewers for their constructive suggestions, which helped them to improve this Review.

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Department of Biomedical Engineering, Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, USA

Jingjing Gao

Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Ziting (Judy) Xia, Swetharajan Gunasekar, Christopher Jiang, Jeffrey M. Karp & Nitin Joshi

Harvard Medical School, Boston, MA, USA

Jeffrey M. Karp & Nitin Joshi

Harvard-MIT Program in Health Sciences and Technology, MIT, Cambridge, MA, USA

Jeffrey M. Karp

Harvard Stem Cell Institute, Cambridge, MA, USA

Broad Institute of MIT and Harvard, Cambridge, MA, USA

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All authors researched data for the article. J.G., Z.J.X., S.G., J.M.K. and N.J. contributed substantially to the discussion of the content. J.G., Z.J.X., S.G. and C.J. wrote the article. C.J. crafted all the figures. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Jingjing Gao , Jeffrey M. Karp or Nitin Joshi .

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N.J. and J.M.K. have one pending patent on nanoparticles for gene delivery in the brain. The other authors declare no competing interests.

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Gao, J., Xia, Z.(., Gunasekar, S. et al. Precision drug delivery to the central nervous system using engineered nanoparticles. Nat Rev Mater (2024). https://doi.org/10.1038/s41578-024-00695-w

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Published : 25 June 2024

DOI : https://doi.org/10.1038/s41578-024-00695-w

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Turk J Pharm Sci
v.19(4); 2022 Aug

Features and Facts of a Gastroretentive Drug Delivery System-A Review

Kuldeep vinchurkar.

1 Indore Institute of Pharmacy, Department of Pharmaceutics, Indore, India

2 Devi Ahilya Vishwavidyalaya University, School of Pharmacy, Department of Pharmaceutics, Indore, India

Jitendra SAINY

Masheer ahmed khan, sheetal mane, dinesh k mishra, pankaj dixit.

English oral delivery of drug was the commonly used modality because of patient compliance and ease of administration. After oral administration of any drug, its bioavailability is affected by its residence time in stomach. Recently, gastroretentive drug delivery systems (GRDDS) have gained wide acceptance for drugs with a narrow absorption window, decreased stability at high alkaline pH, and increased solubility at low pH. This approach develops a drug delivery system, which gets retained within gastric fluid, thereby releasing its active principles in the stomach. Some methods used to achieve gastric retention of drugs include the use of effervescence agents, mucoadhesive polymers, magnetic material, bouncy enhancing excipient, and techniques that form plug-like devices that resist gastric emptying. This review provides a concise account of various attributes of recently developed approaches for GRDDS.

INTRODUCTION

Oral administration is popular despite continuous improvement in drug delivery approaches owing to patient comfort and ease of administration. Controlled release drug delivery systems are designed for oral administration. These drug delivery systems release the medication in a predetermined, predictable, and controlled way. They are not suitable for drugs with low bioavailability due to stability or absorption issues. 1 These problems can get better through modern approaches, which are designed to increase the residence of such drugs in the stomach for an extended time. Such drug delivery systems are called gastroretentive drug delivery systems (GRDDS). GRDDS are suitable for those drugs, which are absorbed from the stomach ( e.g. albuterol), 2 labile at alkaline pH ( e.g. ranitidine and metformin), 3 poorly soluble at alkaline pH ( e.g. furosemide and diazepam), 4 and having a narrow window of absorption ( e.g. riboflavin and levodopa). 5

Some of the common advantages associated with use of GRDDS include improved patient compliance by reducing the frequency of dosing; improved therapeutic efficacy of drugs with a short half-life; site-specific delivery of medications; sustained and controlled release of drugs in the stomach; enhanced residence time of drugs at the absorption site; improved bioavailability from the gastrointestinal tract; avoiding dose dumping of medicines. 6

To develop GRDDS, different materials like ion-exchange resins, mucoadhesives, high-density materials, raft forming substances, magnetic substances, and super porous hydrogels are used. 7 , 8

This review provides a concise account of various attributes of recently developed approaches for GRDDS.

Anatomy and physiology of the stomach

Knowledge about the anatomy and physiology of the stomach is essential for the successful formulation of gastroretentive dosage forms. Anatomically, the stomach is divided into three areas: the proximal portion toward the esophagus is fundus, followed by the body, which serves as a storage site for engulfed food, and the antrum, last part that connects the body to the small intestine. Antrum helps in churning action and in gastric emptying. 9 In fasting state, a sequence of contractions occurs cyclically through the stomach and intestine every 120-180 min, called the migrating myoelectric cycle. It is further divided into four phases. The pattern of contraction changes in a fed state is termed as the digestive motility pattern. 10 This pattern comprises phase 1- (basal phase); phase 2- (preburst phase); phase 3- (burst phase); and phase 4. 11 Figure 1 depicts the motility pattern in the gastrointestinal tract.

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Motility pattern in gastrointestinal tract

Physicochemical properties of GRDDS

Physicochemical properties of GRDDS include density, size, and shape of the dosage form, which play major roles in the formulation of GRDDS. The dosage forms having a density lower than the gastric contents can float to the surface, while high-density systems sink to the bottom of the stomach. For an ideal formulation, the density should be in the range of 1.0-2.5 g/cm 3 . Dosage forms having a diameter of more than 7.5 mm show better gastric residence time (GRT). Circular, spherical or tetrahedron-shaped devices show excellent gastroretentive properties. 12

Physiological factors affecting retention of GRDDS in the stomach

The most important factors controlling the gastric retention time of dosage forms include fed or unfed state, nature of the meal, caloric content, and frequency of feeding. In the case of a fasting environment, gastric retention time is less due to the increase in GI motility. Emptying of gastric content occurs due to peristalsis. If peristalsis coincides with dosage form administration, the gastric residence is short. However, after meals, peristalsis is delayed and may help increase the gastric residence of the formulation. A high-calorie meal containing proteins, fats, and fibrous compounds increases gastric retention time. In the case of multiple meals, the gastric retention is more than a single meal due to persistent inhibition of peristalsis.

Also, some other factors, such as sex and age, affect gastric retention. Compared with males, females have a slower gastric emptying time irrespective of height, weight, and body surface. A person at the age of more than 70 exhibits longer GRT. In comparison, neonates show less GRT compared with geriatric patients. 13 , 14 , 15

Gastroretentive dosage form approaches

Continuous research and advancements in various approaches to gastroretentive dosage forms over the last few years are as presented in Figure 2 . These approaches to GRDDS help in delivering the medicament in a sustained and restrained way through the gastrointestinal tract.

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Approaches of gastroretentive drug delivery system

Classification of GRDDS

GRDDS are classified into mainly two types: floating and non-floating systems. Floating systems are further classified into effervescent system and non-effervescent systems based on the mechanism of floating, while non-floating systems classified into four different classes based on the mechanism used for gastroretention. Figure 3 depicts the classification of the GRDDS.

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Classification of gastroretentive drug delivery system

I- High-density system

The density of dosage form plays an important factor in the formulation of the GRDDS. A high-density system uses its weight as a retention mechanism. To enhance the gastric residence of a drug in the stomach, its density must exceed the normal stomach content (1.004 g/mL). 16 Figure 4A depicts the principle of a high-density system. Clarke et al. 17 compared gastrointestinal transit of placebo pellet systems of varying densities using gamma scintigraphy. They reported that GRT of such a formulation can be extended from an average of 5.8 h to 25 h, depending more on density than on the diameter of the pellets.

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Different types of gastroretentive drug delivery system. A) High density system, B) floating/low density system, C) inflatable system, D) mucoadhesive system, E) magnetic system (i- stomach, ii- gastric fluid, iii- dosage form)

II- Floating or low-density system

Another approach to increase gastric residence is to lower the density of dosage form than the normal gastric content. These systems remain buoyant due to lower density and provide continuous drug release. In this way, they increase GRT of the drug and improve its bioavailability. 18 Figure 4B depicts the principle of floating or low-density systems.

(A) Effervescent system

This system uses carbonates ( e.g. sodium bicarbonate) to generate in situ carbon dioxide (CO 2 ). 19 , 20 Organic acids ( e.g. citric and tartaric acids) are added to speed up the reaction, thus reducing the density of dosage form and remaining buoyant in the stomach. 20 It is categorized into two classes:

a) Volatile liquid/vacuum type: These are further classified into three types.

i) Inflatable system

It consists of a pullout system having a space filled with volatile liquids that evaporate at body temperature. Thus, when these systems are introduced into the stomach, the chamber inflates, and the system floats. The inflatable chamber comprises a bioerodible polymer filament that is made from polymers like polyvinyl alcohol and polyethylene. When the inflatable chamber floats in the gastrointestinal fluid, the polymer gradually dissolves and releases the drug. After some time, due to polymer dissolution, the inflatable section collapses. 19 , 20 Figure 4C depicts a floating effervescent type of inflatable system.

ii) Intragastric floating system

It contains a chamber filled with a vacuum and includes a microporous compartment serving as a drug reservoir. 20 Figure 5 depicts a floating type of intragastric system. Patel et al. 21 developed intragastric floating tablets of verapamil HCl using hydroxypropyl methylcellulose (HPMC), carbopol, and xanthan gum as gel-forming agents. Buoyancy was achieved by adding an effervescent mixture of sodium bicarbonate and anhydrous citric acid. Optimized formulation exhibited satisfactory results with a short buoyancy lag time of 36 sec, a total buoyancy time of more than 24 h, and controlled drug release for up to 24 h.

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Intragastric floating gastrointestinal drug delivery system.

iii) Intragastric-osmotically controlled system

Osmotic control can be achieved using a biodegradable capsule comprising inflatable floating support congestion with an osmotic pressure-controlled drug delivery device. 22 , 23 Zhao et al. 24 used fenofibrate-loaded mesoporous silica nanoparticles to prepare an oral push-pull osmotic pump. Polyethylene oxide (100,000) and polyethylene oxide (6,000,000) were selected as suspending agents and expanding agents, respectively. Cellulose acetate was used as a semipermeable membrane along with polyethylene glycol 6,000 to increase flexibility and control the membrane permeability. The prepared system is reported to stay in the stomach for a period of 21.72 h rather than 12.48 h of the reference tablet and delivers the drug in an approximately zero-order manner for 24 h.

b) Matrix tablets: They are of two types, i.e. single-layer and bilayer matrix tablets. The single-layer matrix tablets are prepared using a drug and a hydrocolloid forming gel, while the bilayer matrix tablet contains one immediate-release layer and another sustained release layer. Saisivam et al. 25 developed single-layer floating matrix tablets of losartan potassium using different proportions of HPMC-K4M and karaya gum as retarding polymer and sodium bicarbonate as an effervescent agent by direct compression method. Results of an in vivo study of optimized formulation displayed the floatability of tablet in gastric content and prolonged the GRT to approximately 12 h. X-ray imaging study in albino rabbits indicated the residence of tablet in the stomach even after a period of 12 h.

c) Gas generating systems: Gas-generating systems are prepared using effervescent compounds along with hydrophilic polymers.

i) Floating capsules

These dosage forms involve encapsulation of drugs in hydrophilic polymers like ethyl cellulose and eudragit RS-100 with effervescent agents such as sodium bicarbonate, calcium carbonate, etc. Moursy et al. 26 developed a hydrodynamically balanced capsule containing a mixture of nicardipine hydrochloride and hydrocolloids. Upon contact with gastric fluid, the capsule shell dissolves with subsequent swelling, forming a gelatinous barrier, which remains buoyant in the gastric juice for an extended period.

ii) Floating pills

Multiple unit types of oral floating dosage forms have been developed using a hydrophilic polymer in the outer layer and an effervescent agent in the inner layer. When it comes in contact with the gastric fluid, the outer layer of hydrophilic polymer starts to swell and then sinks, but as the effervescent agent meets gastric content, it releases CO 2 , and the system starts to float. 27 , 28 Meka et al. 29 prepared multiple-unit minitab of captopril based on a gas formation technique to prolong the GRT and to increase the overall bioavailability of the drug. They developed drug-containing core units using the direct compression process, which were coated with three successive layers of an inner seal coat, effervescent layer (sodium bicarbonate), and an outer gas-entrapped polymeric membrane of polymethacrylates (eudragit RL30D, RS30D, and combinations of them). They found that increasing the coating level of gas-entrapped polymeric membrane decreased the drug release.

iii) Floating systems with ion exchange resins

These floating systems are mainly developed to prolong the GRT of dosage forms using ion exchange resin. They consist of drug resin complex beads loaded with bicarbonate ions, and they are coated with hydrophilic polymers. 30 It results in the generation of CO 2 gas when it comes in contact with the gastric fluid and causes the beads to float. Atyabi et al. 31 developed a floating system based on an ion exchange resin, which consists of resin beads, loaded with bicarbonate and a negatively charged drug that was bound to the resin. Two resins, i.e. Amberlite IRA-400 and Dowex 2 x 10, were investigated and both exhibited in vitro floating times of over 24 h using a standardized procedure. The coated dosage form remained for over 3 h in the stomach with the non-coated system and demonstrated a marked increase in retention over conventional formulation.

(B) Non-effervescent systems

In non-effervescent floating systems, the drug comes in contact with gastric fluid and it swells. It maintains its shape, and its density remains less than one, hence it floats in gastric juice. 32 Matrix forming polymer, gel-forming, or swellable type hydrocolloids are used for these types of floating systems. They are further classified as follows:

i. Hydrodynamically balanced systems (HBS)

These systems mainly consist of a mixture of drugs and hydrocolloids that forms a gelatinous barrier, when it comes in contact with gastric fluid due to swelling of the combination. It remains buoyant in the stomach for an extended period as its bulk density is less than one in gastric fluid. Nayak and Malakar 33 developed gastroretentive theophylline HBS capsules using HPMC, polyethylene oxide, polyvinylpyrrolidone, ethylcellulose, liquid paraffin, and lactose to control the delivery of theophylline for a longer period in the stomach with a minimum floating time of 6 h.

ii. Microballoons

Microballoons are described by the gradual addition of drug-containing emulsion into a volatile solvent. On evaporation of the solvent, gas is generated in a dispersed polymer droplet, which results in the formation of an interior orifice in the microsphere of the drug with polymer. It is also called emulsion solvent diffusion method. 22 The floating time of microspheres depends upon the type and amount of polymer used in the formulation. Gupta et al. 34 developed pantoprazole sodium-loaded microspheres using eudragit L100 by adopting an emulsion solvent diffusion method with a non-effervescent approach. The results of in vitro and in vivo studies exhibited a suitable drug-release pattern in terms of increased bioavailability and efficient ulcer healing effect. Figure 6 depicts the steps involved in the preparation of microballoons by solvent diffusion method.

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Preparation technique and mechanism of microballoons formation

iii. Alginate beads

These systems are prepared using a hydrocolloid gel-forming agent and sodium alginate as the interlocking agents. In the presence of gastric fluid, the hydrocolloid absorbs water and forms a barrier that results in entrapment of air in the polymer, which causes swelling of the polymer, and hence the dosage form starts to float, and results in releasing the drug for a prolonged period. Ghareeb and Radhi 35 developed trimetazidine calcium alginate floating beads using sodium alginate solution (2, 3, and 4% w/v), HPMC, and peppermint oil (15, 20, and 25% v/v) using emulsion gelation method. They found that oil entrapped floating beads gave promising results for sustaining the release of the drug over 10 h.

iv. Layered tablets

Layered tablets are more popular due to ease of their preparation, low cost, and high stability.

a. Single-layered floating tablets: These tablets were developed by mixing drug and gas generating agents within the matrix tablet. These formulations have lower bulk density than gastric fluid, and thus they remain buoyant in the stomach by increasing GRT. 36 Kim et al. 37 developed non-effervescent gastroretentive tablets of pregabalin once a day using wet granulation and compaction. They found that the amounts of HPMC and crospovidone were found be critical factors affecting in vitro dissolution and floating properties of the prepared tablets. Figure 7 depicts a schematic of single-layered floating tablets.

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Mechanism of single layer tablet

b. Double-layered floating tablets: It comprises of two formulations separated by layering, one on top of the other, having two different release profiles. 3 , 38 Kuldeep et al. 39 developed a bilayer floating tablet of metoprolol succinate (sustained-release layer) and rosuvastatin calcium (immediate-release layer) by direct compression method. HPMC K100, K4M, and K15M were used as gel-forming agents, while cross carmellose sodium, sodium starch glycolate, and crospovidone were used as super disintegrant. Sodium bicarbonate is used as an effervescent agent. From the in vitro buoyancy study, it was observed that as the concentration of gas-generating agents increases, floating lag time decreases. Also, the polymer gas generating agent ratio was found to influence the floating lag time and the total duration of floating.

III- Mucoadhesive and bioadhesive systems

A mucoadhesive and bioadhesive system uses its adhesive properties to target a drug to a specific region of the body for an extended period. Figure 4D displays a mucoadhesive system of GRDDS. For this, bioadhesive or mucoadhesive polymers are mainly used. 40 Natural polymers such as sodium alginate, gelatin, guar gum, etc. , and semisynthetic polymers such as HPMC, lectins, carbopol, and sodium carboxymethyl cellulose are widely used for mucoadhesion. The adhesion is mediated by hydration, bonding, or receptor interactions. 41 , 42 Madgulkar et al. 43 developed sustained-release tablets of itraconazole using mucoadhesive polymer carbopol 934P and HPMC K4M. They confirmed sustained drug release and gastric retention for six hours in albino rats. Figure 8 depicts the principle of mucoadhesive drug delivery systems.

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Principle of mucoadhesive drug delivery system

IV- Swelling system

These systems, when come in contact with gastric fluid, their size increases significantly than that of the pyloric sphincter and thus, after swelling, remain logged in the stomach. These are also called a “plug type system”. 44 Controlled and sustained drug release is achieved using an appropriate excipient. The swelling ability of polymer mainly depends upon the degree of cross-linking of hydrophilic polymer network. The high degree of cross-linking maintains the integrity of the system, while a low degree of cross-linking causes extensive swelling resulting in rapid dissolution of the polymer. 45

V- Superporous hydrogels

Superporous hydrogels are a three-dimensional network of hydrophilic polymers that have numerous super-size pores inside them. The swelling of superporous hydrogels occurs by the mechanism of capillary wetting through interconnected open pores. To develop superporous hydrogels, certain ingredients like initiators and cross-linkers are used to initiate the cross-linking. 46 Other ingredients were foam stabilizers, foaming aids, and foaming agents. Desu et al. 47 developed a superporous hydrogel system using N’ , N’ -methylene bisacrylamide as the cross-linking operator and polyvinyl alcohol as a composite specialist, ammonium persulfate and N , N -tetramethylenediamine as an initiator pair and Span 80 as a surfactant. They are used as a froth stabilizer to make a permeable structure using the gas-forming method.

VI- Magnetic system

In this system, by using a strong magnet with a powerful magnetic field onto the body surface, the movement of gastroretentive formulation with a small internal magnet is controlled. Several reports tell about the positive results of this system, but the success of this system depends upon the selection of the magnet position with very high precision. 48 Gröning et al. 49 developed peroral acyclovir depot tablets with an internal magnet. An extracorporeal magnet was used to prolong the GRT of the dosage form and to influence the duration of absorption of acyclovir. They performed an in vivo study with five healthy male subjects and determined the plasma concentration-time profiles of acyclovir. Computer simulations were carried out to display the influence of GRT of acyclovir depot preparations on the plasma concentration-time profiles of acyclovir. Figure 4E displays a magnetic system of GRDDS.

In vitro assessment

For GRDDS, in vitro assessment is very essential to predict gastric transit behavior. Following are the parameters, which should be considered for designing novel gastroretentive formulations.

i. Buoyancy lag time

It is the time taken for gastroretentive formulations to move onto the surface of the dissolution medium. It is determined using a USP dissolution apparatus containing 900 mL of 0.1 N HCl solution as a testing medium maintained at 37°C. The time required to float different dosage forms noted as floating lag time. 50

ii. Floating time

This determines the buoyancy of dosage form. In this test, a specific dissolution apparatus is used depending upon the type of dosage form with 900 mL of dissolution medium kept at 37°C. The floating time or floating duration of the dosage form is determined by visual observation. 51 , 52

iii. Specific gravity/density

Specific gravity estimates are essential for both low-density and high-density GRDDS. Specific gravity is determined using the displacement method. 53

iv. Swelling index

Swelling index is determined by immersing the tablets in 0.1 N HCl at 37°C and their periodic removal at regular intervals. 54

v. Water uptake

In this study, the dosage form is removed from the dissolution medium after the regular interval and a weight change is determined. 55

Water uptake (WU) = (W t - W o ) * 100/W o

where W t = weight of the dosage form at time t, W o = initial weight of the dosage form

vi. Weight variation

Various official methods are recommended by pharmacopeias to calculate the weight variation. Usually, the individual and average weight of 20 tablets are recorded. From these data, average weight and weight variation is calculated. 56 , 57

iii. Hardness and friability

Hardness or crushing strength is determined using a Monsanto tester, Strong cobb tester, Pfizer tester, etc. Friability (strength) of tablets is determined using a Roche friabilator. 58 , 59

viii. In vitro dissolution tests

This test is performed to determine drug release from GRDDS in gastric fluid and intestinal fluid maintained at 37°C at a definite time using USP dissolution type II apparatus (paddle). 59 , 60

Here, after in vitro assesment, Table 1 represents the recent trends in GRDDS, while Table 2 represents the names of drug candidates for GRDDS.

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Evaluation of microsphere and beads

An optical microscope was used to measure the particle size of beads and microspheres. Surface morphology and cross-sectional morphology are evaluated with the help of a scanning electron microscope.

In vivo assessment

A. radiology.

This technique is mainly used to determine the position of gastroretentive dosage form filled with barium sulfate (radio-opaque marker) inside the body system concerning time using X-ray. X-ray pictures are taken at different intervals to record the correct position of the dosage form. 61 , 62

b. Scintigraphy

Similar to radiology, it is used to determine in vivo floating behavior of the gastroretentive dosage form. In scintigraphy, 99mTc pertechnetate is used as an emitting material instead of an X-ray to engulf the formulation to record the image. 63 , 64

c. Gastroscopy

Gastroscopy is widely used for visual examinations of gastroretentive dosage forms. In this technique, an illuminate optical, tubular, and slender instrument called “endoscope” is used to look deep inside the body parts such as the stomach, esophagus, and small intestine. 65 , 66

d. Ultrasonography

It is a diagnostic imaging technique, in which ultrasound is used for imaging internal body structures. The main disadvantage of this test is non-detectability at entrails. 1 , 66 , 67

e. 13 C octanoic acid breath test

Radioactive 13 C octanoic acid is used to assess the extent of absorption of drugs from GRDDS. This compound gets absorbed from the duodenum, and, when it is radiolabelled, then after its metabolism, the CO 2 exhaled in breath can be correlated with the amount of octanoic acid absorbed. The radiolabelled CO 2 was measured by isotope ratio mass spectroscopy. 65 , 66

f. Magnetic marker monitoring

Compared with radiology and scintigraphy, this method is radiation-less, and thus is non-hazardous. 67 , 68 It involves real-time tracking of the dosage form in the gastrointestinal tract. 69 , 70 This technique is mainly used for the determination of the gastrointestinal motility and dissolution behavior of pharmaceuticals. In this technique, the dosage form is labeled as a magnetic dipole by incorporating a trace of ferromagnetic particles and recording the magnetic dipole field by an apparatus responsive to bio-magnetic measurement. 71 , 72 , 73

Advantages and applications of gastroretentive delivery systems

Gastroretentive dosage forms release the drug in a controlled manner to their specific site of action. 74 These systems help increase the bioavailability of drugs that get metabolized in the upper part of the gastrointestinal tract, such as riboflavin and levodopa, etc . 75 , 76 For drugs that have a short half-life, gastroretentive dosage forms help reduce the dosing frequency and improve patient compliance by enhancing GRT. Also, they provide a sustained and prolonged release of drugs in the stomach and intestine, which are helpful in local therapy. 77 , 78 , 79 Lastly, Table 3 depicts the gastroretentive technologies adopted by various pharmaceutical companies, and Table 4 represents the list of commonly used drugs for various floating systems.

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GRDDS are unique systems and have become important in the last three decades. It offers various advantages, viz ., site-specific, slow, and controlled release of drugs from different types of gastroretentive dosage forms, thus improving patient compliance and reducing the side effects by minimizing dosing frequency. Therefore, it is expected that in the future, various pharmaceutical companies will come forward to initialize gastroretentive drug delivery technology to create excellent advantages, prolonging patents, and a better outcome for their marketed formulations.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

IMAGES

(PDF) Floating Drug Delivery System: A Brief Review
(PDF) Floating Drug Delivery Systems: A Review
(PDF) An Update on Floating Drug Delivery System: A Review
(PDF) Floating Drug Delivery System: Applications based on in situ gel
(PDF) A REVIEW ON FLOATING DRUG DELIVERY SYSTEM
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(PDF) Floating Drug Delivery Systems: A Review
A floating dosage type is a commonly accepted method especially for drugs with. restricted absorption sites in the small upper intestine. Disadvantages of the delivery mechanism for floati ng ...
Formulation and Evaluation of Floating Drug Delivery System of
A multiple unit oral floating drug delivery system of famotidine was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. Drug and polymer compatibility was studied by subjecting physical mixtures of drug and polymers to differential scanning calorimetry. Cod liver oil entrapped calcium alginate ...
(PDF) FLOATING DRUG DELIVERY SYSTEM: A REVIEW
This review summarizes the design of the FDDS systems, factors that affect floating system, advantages, limitations, evaluation parameters and applications. Available via license: CC BY 4.0 ...
Floating drug delivery systems: A review
Abstract. The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to ...
To control floating drug delivery system in a simulated gastric
Background Gastroretentive drug delivery system (GDDS) are novel systems that have been recently developed for treating stomach diseases. The key function of all GDDS systems is to control the retention time in the stomach. However, research into the bulk density or entanglement of polymers, especially regarding their effects on drug float and release times, is scarce. Methods In this research ...
Floating Drug Delivery Systems: An Emerging Trend for the ...
Floating drug delivery system (FDDS) is the main approach to prolonging the gastric residence time in the stomach in which the bilayer floating tablet has the main role. It is more suitable for the treatment of local infections such as peptic ulcer, gastritis, Zollinger-Ellision syndrome, indigestion, and other local infections related to the ...
To control floating drug delivery system in a simulated gastric
The floating drug delivery system (FDDS) is also called a hydrodynamically balanced system (HBS). In FDDS, the drugs carriers float in gastric juice to ensure that drugs do not leave stomach shortly. ... It indicates that the dense shell layer developed in this research can prolong the floating time of drugs in the stomach. When the amounts of ...
Floating drug delivery systems: A review
The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their ...
Floating Drug Delivery System: A Brief Review
Floating. Drug Delivery Systems (FDDS) is one of the gastro-retentive dosage for ms used to achieve. extended duration of gastric residency. The aim of writing this review on floating drug ...
Floating drug delivery systems: a review
Abstract. The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to ...
Modern Approaches to Obtaining Floating Drug Dosage Forms (A ...
Floating dosage forms (FDFs) represent widely used types of gastroretentive drug delivery systems that provide targeted delivery to the upper gastrointestinal tract. This article proposes a classification of FDFs according to which approaches to achieving drug flotation are reviewed based on published works. FDFs present on the market and the concepts used to create them are described. Various ...
Floating drug delivery systems: an approach to oral controlled drug
Finally, with an increasing understanding of polymer behavior and the role of the biological factors mentioned above, it is suggested that future research work in the floating drug delivery systems should be aimed at discovering means to accurately control the drug input rate into the GI tract for the optimization of the pharmacokinetic and ...
PDF Floating drug delivery system: an outlook
The floating drug delivery approach is a low-density system that may be effervescent or. Non-Effervescent type with sufficient buoyancy to flow over the gastric contents and remain. buoyant in the stomach without affecting the stomachic emptying rate for a prolonged duration.
Development and Optimization of a Floating Multiparticulate Drug
INTRODUCTION. The oral route plays an important role in therapy as it is the most preferred and convenient route for drug delivery systems. 1 Gastroretentive drug delivery systems (GRDDSs) are an advanced approach for the novel drug-delivery systems in which the drug is retained in the stomach for a prolonged period. 2,3 GRDDSs are particularly suitable for drugs having a narrow absorption ...
(PDF) Floating Drug Delivery Systems: A Review
Abstract and Figures. The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation ...
Floating Drug Delivery Systems: A Comprehensive Review of Formulation
Floating drug delivery systems (FDDS) have garnered significant attention in pharmaceutical research due to their ability to improve drug bioavailability and therapeutic efficacy. This comprehensive review aims to provide an in-depth analysis of the formulation strategies and applications of floating drug delivery systems.The review commences by discussing the physiological basis of gastric ...
Floating drug delivery system: an outlook
A review of floating drug delivery system. Asian journal of biomedical and pharmaceutical science, 3(24): 1-6,(2013) Gupta P, Gnanarajan, Kothiyal P., Floating drug delivery system: a review. International Journal of Pharma Research & Review, 4(8):37-44,(2015) Tripathi P, Ubaidulla U, Khar RK, Vishwavibhuti., Floating drug delivery system.
PDF Floating Drug Delivery System: a Review
FLOATING DRUG DELIVERY SYSTEM: A REVIEW ¹Rohit D. Jondhale, ²*Pallavi S. Gadhave, ²Ashish A. Mahajan, ²Mohini S. Bodhane ... Nasik. ABSTRACT 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 ...
Polymeric Excipients in the Technology of Floating Drug Delivery Systems
2. Floating Drug Delivery Systems. Floating drug delivery systems, DF, the value of the bulk density of which is initially lower than the density of gastric juice (1.004 g/cm 3) or decreases to the required value after ingestion for a certain period of time [1,2,3,6,7].This property allows the drug to remain on the surface of the contents of the stomach, thereby avoiding evacuation to the ...
PDF Floating Drug Delivery System (Fdds): Types, Advantages, Disadvantages
Nivas et al. European Journal of Pharmaceutical and Medical Research www.ejpmr.com │ 321Vol 9, Issue 3, 2022.│ ISO 9001:2015 Certified Journal │ FLOATING DRUG DELIVERY SYSTEM (FDDS): TYPES, ADVANTAGES, DISADVANTAGES & APPROACHES Ram Nivas*1, Suraj Mandal2, Himani Gururani3, Pragati Saxena4, Sanjeev Kumar5 and Dr. Navneet Verma6
(PDF) Floating Drug Delivery System
Abstract. Floating drug delivery system (FDDS) helps to improve the buoyancy property of the drug over the gastric fluids and hence maintain the longer duration of action. It is helpful in ...
Precision drug delivery to the central nervous system using ...
The development of therapeutics for central nervous system disorders suffers from high failure rates owing to poor blood-brain barrier penetration and lack of targeted delivery. This Review ...
How A.I. Is Revolutionizing Drug Development
Terray is developing new drugs for inflammatory diseases including lupus, psoriasis and rheumatoid arthritis. The company, Dr. Berlin said, expects to have drugs in clinical trials by early 2026 ...
Formulation and in vitro evaluation of floating tablets of
INTRODUCTION. Gastroretentive drug 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 tract.[] A modified release drug delivery system with prolonged residence time in the stomach is of particular interest for drugs- acting ...
Features and Facts of a Gastroretentive Drug Delivery System-A Review
After oral administration of any drug, its bioavailability is affected by its residence time in stomach. Recently, gastroretentive drug delivery systems (GRDDS) have gained wide acceptance for drugs with a narrow absorption window, decreased stability at high alkaline pH, and increased solubility at low pH.

To control floating drug delivery system in a simulated gastric environment by adjusting the Shell layer formulation

Introduction

Materials and methods

Preparation of floating beads containing tetracycline

FE-SEM (field emission scanning electron microscope) analysis

Swelling and floating test

In vitro release and encapsulation efficiency of tetracycline

Cytotoxicity test

Antibacterial testing

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Availability of data and materials

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Features and Facts of a Gastroretentive Drug Delivery System-A Review

Jitendra SAINY