Int J App Pharm, Vol 14, Issue 6, 2022, 28-33Review Article

IN VIVO MONITORING STRATEGIES FOR EVALUATION OF FLOATING DRUG DELIVERY SYSTEMS

SWATI SAINI1, BIGUL YOGESHVER BHARDWAJ2, JATIN CHHABRA1, MANISH KUMAR3, RAKESH PAHWA1*

1Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, Haryana, 136119, India, 2School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173229, India, 3M M College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala-133207, Haryana, India
Email: [email protected]

Received: 20 Jul 2022, Revised and Accepted: 21 Sep 2022


ABSTRACT

In recent years, various advancements have been introduced in the development of controlled drug release devices for resolving different physiological problems for example, gastric retention inconsistency along with erratic gastric emptying time. Gastroretentive delivery formulations receive considerable attention to overcome these drawbacks and in optimizing the absorption of different medicaments. Gastroretentive technologies considerably extend the stomach retention time of dosage forms with increased bioavailability as well as therapeutic efficacy. Gastroretention can be successfully achieved utilizing gastric floating system. The rationale of the present manuscript focuses on current advancements of gastric floating systems so as to accomplish appropriate drug bioavailability and, subsequently drug targeting to the stomach. In vivo evaluation parameters, especially pivotal imaging techniques including roentgenography, gamma scintigraphy, gastroscopy, magnetic marker monitoring, magnetic resonance imaging, ultrasonography, 13C octanoic acid breath test etc. have been emphasized in this manuscript for monitoring drug formulation behavior which extensively revolutionized thorough understanding in the avenue of improved bioavailability of gastroretentive systems.

Keywords: Gastroretentive technologies, Floating drug delivery systems, Gastric retention, In vivo imaging, Salient advantages


INTRODUCTION

In order to accomplish and sustain optimum drug concentration in the body, the rationale for developing any delivery system is to target active molecule to the site of action. Among diverse routes, oral route is generally the popular, potential and efficient route intended for administration of therapeutic agents [1-3]. According to recent research, there is growing curiosity in innovative delivery formulations that can be retained in stomach for sustained as well as consistent time period. Gastroretentive drug delivery systems are one of the novel strategy in this avenue [4-6]. Gastroretentive systems are configured for delivering therapeutic agents to the GIT in manner that disadvantages associated with conventional dosage types can be resolved [7-11]. Gastroretentive drug delivery system significantly improved patient compliance due to attributes like enhanced gastric retention time coupled with precise drug release for extended time period and ultimately increased bioavailability and decreased drug waste. Targeting of drug to the stomach and upper small intestine is also achievable in an efficient manner [1, 8, 12-16]. Successful designing of floating formulations is one of the thriving strategies in enhancing dosage residence in the stomach.

Floating systems are recognized as low density systems for floating over the gastric content and thus remains buoyant in gastric region for an extended time without disrupting gastric emptying process, thereby increasing the retention of dosage type at the drug absorption site, especially in the stomach region. The aim of formulating buoyant systems is to render the dosage forms less dense as compared to gastric fluids so as to allow it for floating in a successful manner [17-20]. To ensure advantageous bioavailability and superior therapeutic effectiveness of drugs, prolonged stomach retention of the delivery system is a significant process. Floating drug delivery systems are appropriate for therapeutic molecules with less stability and poor solubility in intestinal fluids. Floating drug delivery systems are categorized according to the usage of formulation variables such as effervescent and non-effervescent. Further, effervescent systems are classified as gas generating systems and osmotically controlled drug delivery systems and non-effervescent systems are classified as hollow microspheres, alginate beads, microporous compartment systems and colloidal gel barrier systems etc [2, 13, 21-25]. The pertinent literature was collected from comprehensive search on various databases like PubMed, ScienceDirect, Google Scholar and others utilizing several keywords, including “floating systems”, “in vivo imaging”, “gastroretentive technology” and many others. Referred publications in the English language accessed till June 2022 were chosen for this manuscript. Floating drug delivery systems are efficiently described in fig. 1.

Fig. 1: Classification of floating drug delivery systems [25]

Significant advantages

Following useful advantages of floating drug delivery systems are represented pictorially in the fig. 2 [20, 26, 27].

Fig. 2: Unique advantages of FDDS [18]

Numerous physiological and pharmaceutical factors affect the residence time of dosage form in the stomach. To ensure the effective release of drugs from gastroretentive systems, the dosage type needs comprehensive and meticulous assessment for optimum gastroretentive ability. This can be evaluated either explicitly by in vivo imaging technology or through measuring different crucial parameters. In vivo imaging assessment techniques are regarded as the most accurate and consistent methodologies. In vivo imaging evaluation result may also advances the prospect of obtaining a patent of any new gastroretentive drug delivery systems. Biorelevant approaches can also be implemented to reduce the probability of formulation failure in clinical trials [6, 28, 29].

In vivo evaluation techniques

Numerous in vivo imaging approaches are available to assess the gastroretentive performance of dosage types. These are roentgenography, gamma-scintigraphy, gastroscopy, 13C octanoic acid breath test, ultrasonography, magnetic resonance imaging, magnetic marker monitoring etc [28, 30-32]. Important in vivo imaging techniques are shown in fig. 3.

Fig. 3: In vivo imaging evaluation techniques [28]

Roentgenography

X-ray procedure is the most commonly employed tool for testing internal systems of human volunteers, beagle/mongrel dogs or albino rabbits. Compared with other approaches, it is one of the simplest and cheapest method. The study is conducted under fed and fasting conditions. Barium sulphate is a commonly employed radio-opaque marker inserted into the dosage form and X-ray imaging can be obtained at different intervals for illustrating positioning of in vivo environment of gastroretentive dosage type. Both floating time and gastro resident time of the systems are recorded. The chief disadvantage of this method is exposure to X-rays by volunteers which relies on the exposure period, frequency in addition to repetitions needed for verifying the effectiveness. High exposure condition to X-rays effect is considered as harmful risk to the human [4, 28].

Gamma-scintigraphy

Gamma-scintigraphy, a popular non-invasive technique utilizing gamma-emitting radioisotopes compounded into controlled release dosage forms has become a significant technique for gastrointestinal transit period evaluation. During preparation, a small amount of stable isotope i.e. 152Sm is compounded into dosage forms. In a neutron source, dosage form is irradiated for converting the isotope into a gamma-emitting material such as 153Sm [31, 33]. With images obtained from gamma camera, gastric emptying times can be revealed [34-36]. The gamma scintigraphic imaging is started just after dosing and then anterior images of the abdomen are performed after regular interval [30, 37]. High safety aspect owing to comparatively less radiation doses is the foremost and impressive benefit of this approach. However, some disadvantages of this approach include exposure to ionizing radiation, low sensitivity to several inserted markers, high cost etc. Also, drawbacks of gamma scintigraphy includes some ethical constraints that healthy subjects exposed to radiation without any personal benefit, low temporal and spatial resolution along with limited topographic information [32, 38, 39, 40-42].

Gastroscopy

Gastroscopy, a effective type of peroral endoscopy utilized for diagnosis and monitoring of gastroretentive systems. This approach comprises of optical fibre along with a video camera to assess dosage form position. This approach is appropriate and pivotal for different types of gastroretentive systems. For assessing the gastroretentive evaluation using peroral endoscopy, camera device should enter the volunteer body at regular time interval, concerning the gastroenterologist intervention for the whole assessment test. There are several challenging aspects of this process, such as invasiveness, the possibility of contamination and cross infection, expensive etc. which contributed to the restricted gastroscopy utilization [11, 29, 43].

Ultrasonography

Ultrasonic waves are utilized to provide images of some abdominal organs to determine the formulations intragastric position. Ultrasonic waves are reflected at significantly differing acoustic impedances across an interface in this approach, allowing imaging. An electronic equipment receives the reflected echoes and evaluates their intensity level. Findings can be viewed as either static photos or moving image of an interior body part. However, the disadvantage of this strategy is that some dosage forms may not reveal a satisfactory response. Also, this approach is less popular owing to lack of ultrasound traceability at the intestine and some dosage forms may not exhibit a sharp acoustic mismatch [6, 28, 31].

Magnetic marker monitoring

Formulation is magnetically labelled along with the addition of iron powder within dosage type and subsequently, images may be obtained using an extremely responsive bio-magnetic instrument of measurement. Method does not involve radiation and is thus not much hazardous than other reported methods. However, formulative improvements are still needed in this technique, such as iron powder incorporation which impact the performance and efficacy of gastroretentive drug delivery systems [28].

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is an imaging technology and is also non-invasive. In this technique, investigations can be carried out with a commercial 1.5 Tesla whole body imager. In order to generate accurate images of bone, soft tissues, organs, and nearly every inner body components, magnetic resonance imaging utilizes strong magnetic field, radio frequency signals along with computers. Images may be examined on a computer display during the investigational study [11, 40]. In gastrointestinal research, magnetic resonance imaging has been the most useful and attractive method of investigation of stomach emptying, motility as well as intragastric delivery of macronutrients along with active molecules. This particular magnetic resonance imaging technique consists of various useful advantageous features such as lack of ionizing irradiation, high temporal and spatial resolution, high soft tissue contrast, supra-magnetic and harmless paramagnetic, magnetic resonance imaging contrast agents etc. which may be used exclusively for improving or restraining the fluids and tissues signal and therefore allowing improved description and investigation of organs. However, temporal resolution of traditional magnetic resonance imaging measurements is reasonably low [6, 44-46].

13C Octanoic acid breath test

Octanoic acid, a medium-chain fatty acid which is absorbed by the upper portion of small intestine, transported rapidly to the liver and oxidised instantaneously to form CO2 and is exhaled out. 13C octanoic acid can be incorporated into gastro retentive systems. Octanoic acid produces CO2 owing to reaction in the stomach and emerges into the air. The “carbon atom” in octanoic acid, which essentially forms CO2 can be substituted with 13C isotope. Therefore, time until 13CO2 gas is detected in breath can be regarded as dosage form stomach retention period. No response will be obtained and without release of CO2 as dosage form transit to intestine. Major drawbacks of this test include lack of accuracy in comparison to scintigraphy, challenging mathematics for calculations, the requirement of multiple sampling, and extended sampling times etc. [47, 48].

Miscellaneous research efforts concerning with in vivo imaging characterization of floating dosage types have been reported. Some important results are meticulously depicted in table 1.

Table 1: In vivo characterization of floating dosage types

S. No. Drug Floating dosage form Method of preparation In vivo technique Authors Year Ref.(s)
1 Vildagliptin Floating microspheres - X-ray imaging Kumari et al. 2021 [49]
2 Moxifloxacin Floating matrix tablets - X-ray imaging Sheikh et al. 2020 [50]
3 Valsartan Floating matrix tablets Direct compression X-ray imaging Rahamathulla et al. 2019 [51]
4 Itraconazole Floating microspheres/beads

Ionotropic

gelation

Gamma scintigraphy Gokbulut et al. 2018 [52]
5 Calcium ion Floating tablets Direct compression Gamma scintigraphy Sharma et al. 2017 [53]
6 Metformin hydrochloride

Hydrodynamically

balanced matrix tablets

Wet granulation Gamma scintigraphy Razavi et al. 2015 [54]
7 Metformin hydrochloride Floating tablets Wet granulation Gamma scintigraphy Razavi et al. 2015 [55]
8 Ascaridole Floating tablets Direct compression Gamma scintigraphy Zhao et al. 2015 [56]
9 Bergenin and cetirizine dihydrochloride Floating tablets - Gamma scintigraphy He et al. 2012 [57]
10 Riboflavin Floating beads - Gamma scintigraphy Yao et al. 2012 [58]
11 Ciprofloxacin hydrochloride Floating matrix tablets Direct compression X-ray imaging Tadros et al. 2010 [59]
12 Atenolol and lovastatin Floating tablets Direct compression Roentgenography Kulkarni et al. 2009 [60]
13 Levodopa and carbidopa Floating minitablets Direct compression Gamma scintigraphy Goole et al. 2008 [61]
14 Diltiazem hydrochloride Floating microspheres Ionotropic gelation Gamma scintigraphy Ma et al. 2008 [62]
15 Propranolol hydrochloride Floating tablets Direct compression Magnetic resonance imaging Strubing et al. 2008 [63]
16 Clarithromycin Floating tablets Wet granulation Radiographic studies Nama et al. 2008 [64]
17 Metformin Floating capsules - Gamma scintigraphy Ali et al. 2007 [65]
18 Celecoxib Floating capsules Physical blending Gamma scintigraphy Ali et al. 2007 [66]
19 Verapamil hydrochloride Floating pulsatile capsule - Gamma scintigraphy Zou et al. 2007 [67]
20 Repaglinide Floating microspheres Solvent diffusion technique Gamma scintigraphy Jain et al. 2006 [68]
21 Orlistat Floating microspheres Solvent evaporation Gamma scintigraphy Jain et al. 2006 [69]
22 - Floating beads - Gamma scintigraphy Stops et al. 2006 [70]
23 Riboflavin Floating beads - Gamma scintigraphy Stops et al. 2006 [71]
24 Riboflavin Floating microballons Solvent diffusion Gamma scintigraphy Sato et al. 2004 [72]
25 Amoxicillin Polyionic complex gastroretentive hydrogels -

13C octanoic

acid breath test

Torrado et al. 2004 [73]
26 Riboflavin Floating hollow microballons Emulsion Solvent diffusion - Sato et al. 2003 [74]
27 - Floating tablets -

Magnetic resonance

imaging

Steingotter et al. 2003 [42]
28 - Floating beads Freeze-drying Gamma scintigraphy Whitehead et al. 1998 [75]
29 - Floating resin beads Ion exchange resin Gamma scintigraphy Atyabi et al. 1996 [76]
30 Theophylline Floating tablets - Gamma scintigraphy Desai et al. 1993 [77]
31 Propranolol hydrochloride Hydrodynamically balanced capsules - Gastroscopy Khattar et al. 1990 [78]
32 - Floating tablets, capsules and pellets - Gamma scintigraphy Davis et al. 1986 [79]

Therefore, significant and incessant research efforts have been done worldwide for in vivo imaging monitoring of innovative floating systems. Several in vivo strategies are available for the evaluation of gastro retentive floating dosage forms with site-specificity and unique drug release kinetics in the GIT region for achieving appropriate therapeutic needs.

FUTURE PERSPECTIVES

To assess in vivo gastric residence aspects, a variety of imaging methods frequently utilized involves gamma scintigraphy, roentgenography, ultrasonography, magnetic marker monitoring, magnetic resonance imaging etc. Different in vivo imaging monitoring approaches includes the use of radiation and exposure materials that need to be replaced with less hazardous materials in order to lessen the adverse impact of these substances. Improvements are also required so that more accurate in vivo imaging procedures should be risk-free, offer patient convenience and comfort, and get rid of various adverse effects. Additional sophisticated developments in dynamic scanning and imaging will improve the imaging technique more perfectly, particularly in the case of magnetic resonance imaging. New marker designs for magnetic resonance imaging should also be well exploited. Furthermore, ultrasound used in ultrasonosonography and gamma emitting radioisotopes in gamma scintigraphy need to be focused more precisely. Additionally, the utilization of advanced technologies which possesses all efficient characteristics for the successful imaging of gastroretentive delivery systems would be a suitable and promising futuristic endeavour in this vistas. It is also emphasized that further progress and technological advancements in the various in vivo imaging methodologies offers immense benefits to researchers in the avenue of gastroretentive floating systems.

CONCLUSION

Drugs having narrow absorption window in gastrointestinal tract is often restricted by reduced bioavailability, owing to inadequate drug release as well as less retention time at the absorption region. Gastroretentive systems revealed tremendous potential to enhance therapeutic efficacy and bioavailability of drugs to overcome constraints linked with conventional formulations. Among various promising approaches of gastroretentive technology, floating systems is one of the flourishing avenues for improving the drug residence into the stomach. This review provides insight into the significant characterization of floating drug delivery systems. Various in vivo imaging assessment techniques for comprehensive and effective analysis of gastroretentive drug delivery systems are summarized in this article along with their various salient advantages. Several research endeavours in the domain of in vivo imaging assessment methodologies for enhanced optimum efficacy of gastroretentive systems have also been distinctly presented.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All authors have equally contributed.

CONFLICT OF INTERESTS

No conflict of interest.

REFERENCES

  1. Kanupriya C, Nirmata S, Gill NS. Gastro retentive drug delivery system: a significant tool to increase the gastric residence time of drugs. Int J Curr Pharm Res. 2021;13(1):7-11.

  2. Adibkia K, Hamedeyazdan S, Javadzadeh Y. Drug release kinetics and physicochemical characteristics of floating drug delivery systems. Expert Opin Drug Deliv. 2011;8(7):891-903. doi: 10.1517/17425247.2011.574124, PMID 21506906.

  3. Wu Y, Zhang W, Huang J, Luo Z, Li J, Wang L. Mucoadhesive improvement of alginate microspheres as potential gastroretentive delivery carrier by blending with Bletilla striata polysaccharide. Int J Biol Macromol. 2020;156:1191-201. doi: 10.1016/j.ijbiomac.2019.11.156, PMID 31756485.

  4. Prajapati VD, Jani GK, Khutliwala TA, Zala BS. Raft forming system-an upcoming approach of gastroretentive drug delivery system. J Control Release. 2013;168(2):151-65. doi: 10.1016/j.jconrel.2013.02.028, PMID 23500062.

  5. Shashank C, Kumari P, Singh S, Agarwal VK. Approaches to increase the gastric residence time: floating drug delivery system-a review. Asian J Pharm Clin Res. 2013;6(3):1-9.

  6. Schneider F, Koziolek M, Weitschies W. In vitro and in vivo test methods for the evaluation of gastroretentive dosage forms. Pharmaceutics. 2019;11(8):416-45. doi: 10.3390/ pharmaceutics11080416, PMID 31426417.

  7. Kotreka UK, Adeyeye MC. Gastroretentive floating drug-delivery systems: A critical review. Crit Rev Ther Drug Carrier Syst. 2011;28(1):47-99. doi: 10.1615/critrevtherdrugcarriersyst.v28.i1.20. PMID 21395515.

  8. Mohapatra PK, Satayavani CH, Satajit S. Design and development of carvedil of gastroretentive floating drug delivery system using hydrophilic polymers and in vitro characterization. Int J Pharm Pharm Sci. 2020;12(7):66-73.

  9. Pahwa R, Bisht S, Kumar V, Kohli K. Recent advances in gastric floating drug delivery technology: a review. Curr Drug Deliv. 2013;10(3):286-98. doi: 10.2174/1567201811310030005, PMID 23808593.

  10. Pahwa R, Singh M, Kumar V, Kohli K. Recent advances and patent perspectives in gastroretentive technology. Recent Pat Drug Deliv Formul. 2012;6(3):278-90. doi: 10.2174/187221112802652660, PMID 22563754.

  11. Tripathi J, Thapa P, Maharjan R, Jeong SH. Current state and future perspectives on gastroretentive drug delivery systems. Pharmaceutics. 2019;11(4):1-22. doi: 10.3390/ pharmaceutics11040193, PMID 31010054.

  12. Adebisi AO, Conway BR. Modification of drug delivery to improve antibiotic targeting to the stomach. Ther Deliv. 2015;6(6):741-62. doi: 10.4155/tde.15.35, PMID 26149788.

  13. Arora S, Ali J, Ahuja A, Khar RK, Baboota S. Floating drug delivery systems: a review. AAPS PharmSciTech. 2005;6(3):E372-90. doi: 10.1208/pt060347, PMID 16353995.

  14. Streubel A, Siepmann J, Bodmeier R. Gastroretentive drug delivery systems. Expert Opin Drug Deliv. 2006;3(2):217-33. doi: 10.1517/17425247.3.2.217, PMID 16506949.

  15. Pahwa R, Bhardwaj BY, Sharma A, Piplani M, Kumar M. Gastroretentive floating technology for eradication of Helicobacter pylori: an insight view. Int J App Pharm. 2021;13(3):5-10. doi: 10.22159/ijap.2021v13i3.39369.

  16. Shah HP, Prajapati ST, Patel CN. Gastroretentive drug delivery systems: from conception to commercial success. J Crit Rev. 2017;4(2):10-21. doi: 10.22159/jcr.2017v4i2.16717.

  17. Awasthi R, Kulkarni GT. Decades of research in drug targeting to the upper gastrointestinal tract using gastro retention technologies: where do we stand? Drug Deliv. 2016;23(2):378-94. doi: 10.3109/10717544.2014.936535, PMID 25026414.

  18. Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J Control Release. 2000;63(3):235-59. doi: 10.1016/S0168-3659(99)00204-7, PMID 10601721.

  19. Nayak V, Somu K, Thomson SR, Bs S. Ceftriaxone-induced periorbital edema. Asian J Pharm Clin Res 2019;12(1). doi: 10.22159/ajpcr.2019.v12i1.25293.

  20. Naseem F, Shah SU, Rashid SA, Farid A, Almehmadi M, Alghamdi S. Metronidazole based floating bioadhesive drug delivery system for potential eradication of H. pylori: preparation and in vitro characterization. Polymers. 2022;14(3):519. doi: 10.3390/polym14030519, PMID 35160508.

  21. Hwang KM, Byun W, Cho CH, Park ES. Preparation and optimization of glyceryl behenate-based highly porous pellets containing cilostazol. Pharm Dev Technol. 2018;23(5):540-51. doi: 10.1080/10837450.2016.1245743, PMID 27718780.

  22. Chen R, Guo X, Liu X, Cui H, Wang R, Han J. Formulation and statistical optimization of gastric floating alginate/oil/chitosan capsules loading procyanidins: in vitro and in vivo evaluations. Int J Biol Macromol. 2018;108:1082-91. doi: 10.1016/j.ijbiomac.2017.11.032, PMID 29128589.

  23. Vasvari G, Haimhoffer A, Horvath L, Budai I, Trencsenyi G, Beresova M. Development and characterization of gastroretentive solid dosage form based on melt foaming. AAPS PharmSciTech. 2019;20(7):290. doi: 10.1208/s12249-019-1500-2, PMID 31428895.

  24. Simons FJ, Wagner KG. Modeling, design and manufacture of innovative floating gastroretentive drug delivery systems based on hot-melt extruded tubes. Eur J Pharm Biopharm. 2019;137:196-208. doi: 10.1016/j.ejpb.2019.02.022, PMID 30826475.

  25. Sopyan I, Sriwidodo, Wahyuningrum R, P NA. A review: floating drug delivery system as a tool to improve dissolution rate in gastric. Int J App Pharm 2020;12(4):51-4. doi: 10.22159/ ijap.2020v12i4.38415.

  26. Talukder R, Fassihi R. Gastroretentive delivery systems: A mini review. Drug Dev Ind Pharm. 2004;30(10):1019-28. doi: 10.1081/DDC-200040239, PMID 15595568.

  27. Sathish D, Himabindu S, Kumar YS, Shayeda MR Y, Rao YM. Floating drug delivery systems for prolonging gastric residence time: a review. Curr Drug Deliv. 2011;8(5):494-510. doi: 10.2174/156720111796642273, PMID 21696354.

  28. Parikh DC, Amin AF. In vitro and in vivo techniques to assess the performance of gastro-retentive drug delivery systems: a review. Expert Opin Drug Deliv. 2008;5(9):951-65. doi: 10.1517/17425247.5.9.951, PMID 18754747.

  29. Mandal UK, Chatterjee B, Senjoti FG. Gastro-retentive drug delivery systems and their in vivo success: A recent update. Asian J Pharm Sci. 2016;11(5):575-84. doi: 10.1016/j.ajps.2016.04.007.

  30. Ishak RAH. Buoyancy-generating agents for stomach-specific drug delivery: an overview with special emphasis on floating behavior. J Pharm Pharm Sci. 2015;18(1):77-100. doi: 10.18433/J3602K, PMID 25877444.

  31. Klausner EA, Lavy E, Friedman M, Hoffman A. Expandable gastroretentive dosage forms. J Control Release. 2003;90(2):143-62. doi: 10.1016/S0168-3659(03)00203-7, PMID 12810298.

  32. Pahwa R, Dutt H, Kumar V, Kohli K. Pharmacoscintigraphy: an emerging technique for evaluation of various drug delivery systems. Arch Appl Sci Res. 2010;2(5):92-105.

  33. Wilson CG. In vivo monitoring of dosage forms. J Pharm Pharmacol. 1998;50(4):383-6. doi: 10.1111/j.2042-7158.1998.tb06877.x. PMID 9625482.

  34. Billa N, Yuen KH, Khader MA, Omar A. Gamma-scintigraphic study of the gastrointestinal transit and in vivo dissolution of a controlled release diclofenac sodium formulation in xanthan gum matrices. Int J Pharm. 2000;201(1):109-20. doi: 10.1016/S0378-5173(00)00399-9, PMID 10867269.

  35. Feinle C, Kunz P, Boesiger P, Fried M, Schwizer W. Scintigraphic validation of a magnetic resonance imaging method to study gastric emptying of a solid meal in humans. Gut. 1999;44(1):106-11. doi: 10.1136/gut.44.1.106, PMID 9862835.

  36. Wilding IR, Coupe AJ, Davis SS. The role of γ-scintigraphy in oral drug delivery. Adv Drug Deliv Rev. 2001;46(1-3):103-24. doi: 10.1016/S0169-409X(00)00135-6, PMID 11259836.

  37. Kedzierewicz F, Thouvenot P, Lemut J, Etienne A, Hoffman M, Maincent P. Evaluation of peroral silicone dosage forms in humans by gamma-scintigraphy. J Control Release. 1999;58(2):195-205. doi: 10.1016/S0168-3659(98)00154-0, PMID 10053192.

  38. Davis SS, Hardy JG, Newman SP, Wilding IR. Gamma scintigraphy in the evaluation of pharmaceutical dosage forms. Eur J Nucl Med. 1992;19(11):971-86. doi: 10.1007/ BF00175865, PMID 1425786.

  39. Pahwa R, Dutt H, Kumar V, Sharma CP. In vivo evaluation using gamma scintigraphy. Pharm Technol. 2010;34(11).

  40. Khalaf A, Hoad CL, Blackshaw E, Alyami J, Spiller RC, Gowland PA. Simultaneous measurement of gastric emptying of a soup test meal using MRI and gamma scintigraphy. Diagnostics (Basel). 2020;10(3). doi: 10.3390/diagnostics10030170, PMID 32235742.

  41. Weitschies W, Blume H, Monnikes H. Magnetic marker monitoring: high-resolution real-time tracking of oral solid dosage forms in the gastrointestinal tract. Eur J Pharm Biopharm. 2010;74(1):93-101. doi: 10.1016/ j.ejpb.2009.07.007. PMID 19619649.

  42. Steingoetter A, Weishaupt D, Kunz P, Mader K, Lengsfeld H, Thumshirn M. Magnetic resonance imaging for the in vivo evaluation of gastric-retentive tablets. Pharm Res. 2003;20(12):2001-7. doi: 10.1023/b:pham.0000008049.40370.5a. PMID 14725366.

  43. Rauya E, Sha O, Darwazeh R, Zhang BQ. Efficacy and safety of magnetic guided capsule gastroscopy in gastric diseases. Acta Gastroenterol Belg. 2019;82(4):507-13. PMID 31950806.

  44. Pawar VK, Kansal S, Garg G, Awasthi R, Singodia D, Kulkarni GT. Gastroretentive dosage forms: a review with special emphasis on floating drug delivery systems. Drug Deliv. 2011;18(2):97-110. doi: 10.3109/10717544.2010.520354. PMID 20958237.

  45. Faas H, Schwizer W, Feinle C, Lengsfeld H, de Smidt C, Boesiger P. Monitoring the intragastric distribution of a colloidal drug carrier model by magnetic resonance imaging460. Pharm Res. 2001;18(4):460-6. doi: 10.1023/a:1011098125916. PMID 11451032.

  46. Schwizer W, Fraser R, Maecke H, Siebold K, Funck R, Fried M. Gd-DOTA as a gastrointestinal contrast agent for gastric emptying measurements with MRI. Magn Reson Med. 1994;31(4):388-93. doi: 10.1002/mrm.1910310407, PMID 8208114.

  47. Malpure PS, Chavan BR, Maru AD, Bhadhane JS, Thakare EB, Sonawane PS. Gastroretentive drug delivery system: a review. World J Pharm Pharm Sci. 2019;8(3):506-28.

  48. Lee J. Toward office-based measurement of gastric emptying in symptomatic diabetics using 13Coctanoic acid breath test. American Journal of Gastroenterology. 2000;95(10):2751-61. doi: 10.1016/S0002-9270(00)01976-6.

  49. Benna Kumari, Khansili A, Manish K. Development and optimization of vildagliptin loaded floating microspheres using central composite design: in vitro and in vivo evaluations. Ann Rom Soc Cell Biol. 2021;25(4):12742-55.

  50. Sheikh FA, Hussain MA, Ashraf MU, Haseeb MT, Farid-ul-Haq M. Linseed hydrogel based floating drug delivery system for fluoroquinolone antibiotics: design, in vitro drug release and in vivo real-time floating detection. Saudi Pharm J. 2020;28(5):538-49. doi: 10.1016/j.jsps.2020.03.005. PMID 32435134.

  51. Rahamathulla M, Saisivam S, Gangadharappa HV. Development of valsartan floating matrix tablets using low density polypropylene foam powder: in vitro and in vivo evaluation. AAPS PharmSciTech. 2019;20(1):35. doi: 10.1208/s12249-018-1265-z, PMID 30604045.

  52. Gokbulut E, Vural I, Aşıkoglu M, Ozdemir N. Floating drug delivery system of itraconazole: formulation, in vitro and in vivo studies. J Drug Deliv Sci Technol. 2019;49:491-501. doi: 10.1016/j.jddst.2018.12.019.

  53. Sharma BG, Khanna K, Kumar N, Nishad DK, Basu M, Bhatnagar A. Development and gamma scintigraphy evaluation of gastro retentive calcium ion-based oral formulation: an innovative approach for the management of gastro-esophageal reflux disease (GERD). Drug Dev Ind Pharm. 2017;43(11):1759-69. doi: 10.1080/03639045.2017.1339080, PMID 28581835.

  54. Razavi M, Karimian H, Yeong CH, Sarji SA, Chung LY, Nyamathulla S. Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits. Drug Des Devel Ther. 2015;9:3125-39. doi: 10.2147/DDDT.S82935. PMID 26124637.

  55. Razavi M, Karimian H, Yeong CH, Chung LY, Nyamathulla S, Noordin MI. Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits. Drug Des Devel Ther. 2015;9:4373-86. doi: 10.2147/DDDT.S86263. PMID 26273196.

  56. Zhao Q, Gao B, Ma L, Lian J, Deng L, Chen J. Innovative intragastric ascaridole floating tablets: development, optimization, and in vitro-in vivo evaluation. Int J Pharm. 2015;496(2):432-9. doi: 10.1016/j.ijpharm.2015.10.007. PMID 26453784.

  57. He S, Li F, Zhou D, Du J, Huang Y. Formulation and evaluation of novel coated floating tablets of bergenin and cetirizine dihydrochloride for gastric delivery. Drug Dev Ind Pharm. 2012;38(10):1280-8. doi: 10.3109/03639045.2011.645836. PMID 22206469.

  58. Yao H, Yao H, Zhu J, Yu J, Zhang L. Preparation and evaluation of a novel gastric floating alginate/poloxamer inner-porous beads using foam solution. Int J Pharm. 2012;422(1-2):211-9. doi: 10.1016/j.ijpharm.2011.10.054, PMID 22093955.

  59. Tadros MI. Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride: development, optimization and in vitro-in vivo evaluation in healthy human volunteers. Eur J Pharm Biopharm. 2010;74(2):332-9. doi: 10.1016/j.ejpb.2009.11.010, PMID 19932750.

  60. Kulkarni A, Bhatia M. Development and evaluation of regioselective bilayer floating tablets of atenolol and lovastatin for biphasic release profile. Iran J Pharm Res. 2009;8(1):15-25.

  61. Goole J, Van Gansbeke BV, Pilcer G, Deleuze P, Blocklet D, Goldman S. Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa. Int J Pharm. 2008;364(1):54-63. doi: 10.1016/ j.ijpharm.2008.08.016, PMID 18778758.

  62. Ma N, Xu L, Wang Q, Zhang X, Zhang W, Li Y. Development and evaluation of new sustained-release floating microspheres. Int J Pharm. 2008;358(1-2):82-90. doi: 10.1016/ j.ijpharm.2008.02.024, PMID 18407442.

  63. Strubing S, Abboud T, Contri RV, Metz H, Mader K. New insights on poly(vinyl acetate)-based coated floating tablets: characterization of hydration and CO2 generation by benchtop MRI and its relation to drug release and floating strength. Eur J Pharm Biopharm. 2008;69(2):708-17. doi: 10.1016/j.ejpb.2007.12.009. PMID 18249530.

  64. Nama M, Gonugunta CSR, Reddy Veerareddy PR. Formulation and evaluation of gastroretentive dosage forms of clarithromycin. AAPS PharmSciTech. 2008;9(1):231-7. doi: 10.1208/s12249-008-9038-8, PMID 18446486.

  65. Ali J, Arora S, Ahuja A, Babbar AK, Sharma RK, Khar RK. Formulation and development of hydrodynamically balanced system for metformin: in vitro and in vivo evaluation. Eur J Pharm Biopharm. 2007;67(1):196-201. doi: 10.1016/j.ejpb.2006.12.015, PMID 17270409.

  66. Ali J, Arora S, Ahuja A, Babbar AK, Sharma RK, Khar RK. Formulation and development of floating capsules of celecoxib: in vitro and in vivo evaluation. AAPS PharmSciTech. 2007;8(4):E119. doi: 10.1208/pt0804119, PMID 18181540.

  67. Zou H, Jiang X, Kong L, Gao S. Design and gamma-scintigraphic evaluation of a floating and pulsatile drug delivery system based on an impermeable cylinder. Chem Pharm Bull (Tokyo). 2007;55(4):580-5. doi: 10.1248/cpb.55.580, PMID 17409552.

  68. Jain SK, Agrawal GP, Jain NK. A novel calcium silicate-based microspheres of repaglinide: in vivo investigations. Journal of Controlled Release. 2006;113(2):111-6. doi: 10.1016/ j.jconrel.2006.04.005.

  69. Jain SK, Agrawal GP, Jain NK. Evaluation of porous carrier-based floating orlistat microspheres for gastric delivery. AAPS PharmSciTech. 2006;7(4):90. doi: 10.1208/pt070490, PMID 17233542.

  70. Stops F, Fell JT, Collett JH, Martini LG, Sharma HL, Smith AM. The use of citric acid to prolong the in vivo gastro-retention of a floating dosage form in the fasted state. Int J Pharm. 2006;308(1-2):8-13. doi: 10.1016/j.ijpharm.2005.09.036, PMID 16338108.

  71. Stops F, Fell JT, Collett JH, Martini LG, Sharma HL, Smith AM. Citric acid prolongs the gastro-retention of a floating dosage form and increases the bioavailability of riboflavin in the fasted state. Int J Pharm. 2006;308(1-2):14-24. doi: 10.1016/j.ijpharm.2005.09.039, PMID 16343829.

  72. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H, Fujibayashi Y. Pharmacoscintigraphic evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans. J Control Release. 2004;98(1):75-85. doi: 10.1016/j.jconrel.2004.04.021, PMID 15245891.

  73. Torrado S, Prada P, de la Torre PM, Torrado S. Chitosan-poly (acrylic) acid polyionic complex: in vivo study to demonstrate prolonged gastric retention. Biomaterials. 2004;25(5):917-23. doi: 10.1016/S0142-9612(03)00579-9, PMID 14609680.

  74. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H. In vivo evaluation of riboflavin-containing microballoons for floating controlled drug delivery system in healthy human volunteers. J Control Release. 2003;93(1):39-47. doi: 10.1016/S0168-3659(03)00370-5, PMID 14602420.

  75. Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating dosage forms: an in vivo study demonstrating prolonged gastric retention. J Control Release. 1998;55(1):3-12. doi: 10.1016/S0168-3659(97)00266-6, PMID 9795000.

  76. Atyabi F, Sharma HL, Mohammad HAH, Fell JT. In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins. J Control Release. 1996;42(2):105-13. doi: 10.1016/0168-3659(96)01344-2.

  77. Desai S, Bolton S. A floating controlled-release drug delivery system: in vitro-in vivo evaluation. Pharm Res. 1993;10(9):1321-5. doi: 10.1023/a:1018921830385. PMID 8234170.

  78. Khattar D, Ahuja A, Khar RK. Hydrodynamically balanced systems as sustained release dosage forms for propranolol hydrochloride. Pharmazie. 1990;45(5):356-8. PMID 2395898.

  79. Davis SS, Stockwell AF, Taylor MJ, Hardy JG, Bechgaard H, Christensen FN. The effect of density on gastric emptying time of single and multiple unit dosage form. Pharm Res 1986;3(4):208-13.https://doi.org/10.1023/A:1016334629169.