INTRODUCTION:

The most desired as well as effective method of providing medications to the circulatory system of the body is by oral administration.^1,2 An ideal medication administration system would provide a consistent dose of medication having regulated drug amount to the targeted area in a quantifiable and repeatable manner for prolong period of time.³ Some of the disadvantages of traditional therapy may be mitigated by a well-designed controlled drug delivery system and thus increasing the dosage form's therapeutic efficacy.⁴Gastro retentive types of dosages extend the duration for which a medicine can be released, allowing for longer dosage intervals and improved patient adherence or compliance.⁵Floating drug delivery systems, also known as hydro-dynamically balanced systems.

They can float in the stomach for extended periods of time without influencing the rate at which the stomach empties because they have a lower bulk density than gastric fluids.^6,7,8

Figure:1 Hollow Micro-Balloon

Micro-balloons are the spherical particles with size in the micrometric range (usually 1 to 1000µm) as shown in figure:1. Microspheres and micro-balloons are two terms for the same thing. Micro-balloons can be manufactured from both natural and man-made materials. Microspheres come in a variety of densities, both solid and hollow and having a variety of applications. To reduce density, hollow microspheres are often employed as fillers in materials.⁹

Using an emulsion solvent evaporation approach, Marbaniang D. et al.¹⁰created Extended release Floating Micro-balloons with Clerodendrum colebrookianum in 2019. This GI (gastro intestinal) transit-control formulation is designed to float in gastric fluid with a density of less than one. As a result of this attribute, the stomach transit is delayed. The medicine is slowly delivered at the desired rate, resulting in increased stomach retention and less changes in plasma drug concentration.¹¹

Advantages of floating microspheres^12,13,14,15

· As the dosage frequency is decreased, patient compliance improves.

· A drug with a short half-life can have its therapeutic effectiveness improved.

· The buoyancy of floating microspheres extends the duration that food is held in the stomach.

· Because the medicine is only soluble in the stomach, it has a higher absorption rate.

· Due to the sustained release action, gastric discomfort can be avoided.

Floating drug delivery system^16,17,18

Floating medication delivery systems are a relatively simple and reasonable method in the creation of Gastro retentive dosage forms (GRDFs) from a formulation and technology standpoint .Figure 2 depicts how they are classified.

Figure 2: Classification of FDDS (floating drug delivery system) ^22,23

Mechanism^24,25,26

Gel formers, polysaccharides, and polymers hydrate Containing microspheres come into contact with stomach juice, forming a barrier of colloidal gel that slows the penetration pace of the fluid into the device and the release of medication occurs. As the medicated dosage form's exterior surface dissolves, the hydration of the following hydrocolloid layer maintains the gel layer. The entrapped air reduces the density of the microspheres and gives them buoyancy. However, in order to achieve optimal buoyancy, a minimum stomach content is essential. Recent advances include acrylic resin hollow microspheres, floatable shells of Polystyrene, floating balloons of polycarbonate, and gelucire floating granules etc.

Method of Preparation:

Solvent evaporation method^27,28

Eudragit, HPMC KM4, and ethyl cellulose are among the polymers used to construct such systems. To make a homogeneous polymer solution, polymers and drugs are combined together and then dissolved in Ethanol, dichloromethane,acetone solutions, either in combination or alone. As indicated in figure 3, Pour the prepared solution in 100ml liquid paraffin and spin it at a speed of 1500rpm. Formation of emulsion takes place and then simmered for 3 hours at 35°C. Acetone or dichloromethane is entirely evaporated after the development of a stable emulsion, and the solidified micro-balloons are filtered using Whatman filter paper. Floating and sustained qualities are provided by this hollow micro-balloon.

Figure 3: Solvent Evaporation method²⁹

Emulsion solvent diffusion method^30,31

The drug polymer mixture is dissolved in an ethanol: dichloromethane solution and then added to the polyvinyl alcohol solution drop by drop. This solution is swirled for 1hour at 1500rpm and at various temperatures. The affinity between the drug and the organic solvent is stronger in the emulsion solvent diffusion method than between the aqueous solvent and organic solvent. The medication is then dispersed in an organic solvent, which is miscible, and In the aqueous solvent, the solution is disseminated, resulting in formation of emulsion droplets. As shown in Figure 4, The organic solvent diffuses into the aqueous phase around the emulsion droplets, and the aqueous phase diffuses into the droplets where the medication crystallises.

Figure 4 Emulsion solvent diffusion method^29,32

Ionotropic gelation method^33,34,35

The ability of a polyelectrolyte to cross link in the presence of counter ions which form beads is called ionotropic gelation. This method is widely used in the pharmaceutical industry. Despite their ability to coat the core of the medication and act as rate retardants, In their chemical makeup, natural polyelectrolytes contain particular anions. These anions, which are usually attached to anion blocks, form meshwork structures with cations having polyvalent structure and connect to them to encourage gelation.

Phase separation coacervation technique ^36,37,38,39

This approach works by lowering the solubility of the polymer in the organic phase, Coacervates, a polymer-rich phase, is formed as a result. A polymer having incompatiblity is introduced in the system after distributing the drug particles in a polymer solution, causing the firstly the polymer to phase separate and swallow the particles of drug. When a non-solvent is added to a polymer, it solidifies. To make poly lactic acid (PLA) microspheres, Butadiene is used as an incompatible polymer in this approach. Process variables such as the rate of producing coacervate have an impact on the dispersion of the polymeric film, agglomeration and particle size, of the generated particles. Using a high-speed stirrer to agitate the solution will help to prevent agglomeration, When the microsphere formation process begins, the generated polymerize globules begin to cling together and form agglomerates. The process factors are critical in determining the kinetics of the generated particles because there is no defined state of equilibrium achievement.

Spray drying technique^40,41,42

To dissolve the polymer, a suitable organic solvent(volatile), such as acetone or DCM, is utilised. Under high-speed homogenization, the medication is introduced to the polymer solution. Figure 5 shows how atomization of upward dispersion in a warm air stream results in the preparation of microscopic droplets or mist(fine). Microspheres with diameters ranging from 1 to 100m are formed when the solvent evaporates fast. The microspheres are then separated from the warm air using a cyclone separator and The ability to operate in aseptic circumstances, resulting in the creation of fast and porous micro particles that can be employed for poorly soluble medications, is a major benefit of this method.

Figure 5: Spray drawing technique ³⁹

Characterizations of floating microsphere:

For evaluating floating microspheres, the following parameters are used

1.) Particle size determination^43,44

The particle size was measured with the use of a calibrated oculometer under regular polarised light by an optical microscope, and By measuring 200-300 particles, the average particle size was calculated.

2.) Bulk density^45,46

The bulk density is calculated by dividing the Mass of powder divided by the Bulk volume. A 10gm sample of granules is accurately weighed and inserted into a 25 ml measuring cylinder. Bulk density is determined using the eq. (values must stated in gm/cm3) and Without disrupting the cylinder, the volume occupied by the granules was measured.

Bulk density = Weight of the sample/Volume of the sample

3.) Tapped density^47,48

It's the ratio of the blend's mass to the tapped volume. It was determined using a digital tap densitometer that assessed the amount of powder occupied after 100 standard tappings.

Tapped Density = Mass of microspheres / Volume of microspheres after tapping

4.)SEM (Scanning Electron Microscopy) ^49,50,51

The determination of surface morphology is done by using SEM. The microcapsule is fixed on the SEM sample slab. Before being analysed, a SEM sample slab was covered with gold film using double-sided sticking tape and applied at a low pressure.

5.) Entrapment efficiency^52,53

Microspheres containing the medication (5 mg) were crushed and dissolved in distilled water using an ultrasonic stirrer for 3 hours, then filtered and uv-vis spectroscopically determined. The ratio of real to theoretical drug content is used to calculate efficiency of entrapment.

% Entrapment = Actual content / Theoretical content x 100

6.) Angle of Repose.^54,55

Most commonly fixed funnel method was used to determine the micro-balloons' angle of repose, which quantifies particle flow resistance. The following formula was used to compute the angle of repose from the height and average radius

θ = tan^-1 ( h / r )

where, θ = The repose angle, h = Height of the pile, r = Average circle radius

7.) Swelling Studies^56,57,58

Swelling investigations are carried out to calculate the molecular characteristics of swollen polymers. To detect swelling, researchers use dissolution equipment, optical microscopy, and more advanced techniques like H₁NMR imaging, Cryogenic SEM, Confocal laser scanning microscopy (CLSM), and others are used. The swelling studies are determined by using the following method utilising a Dissolving equipment USP dissolution apparatus USP-24.

Amount of swelling = Wet formulation Weight / formulations Weight

8.) Floating or Buoyancy test^59,60,61

The time interval when the dosage form is introduced and when it floats in the simulated stomach fluid, as well as the interval of time of the dosage form remains floating, both are measured. Floating lag time (FLT) or buoyancy lag time (BLT) is the time that takes to emerge on the medium's surface , while the overall length of floatation, or how long the dosage form remains floating, is referred to as total floating time (TFT).

9.) In vitro release study^62,63,64,65

USP disso apparatus type-II will be used to perform the in vitro study for the formulations. The medium of dissolution (0.1 M HCl, 900 mL) is kept 37°C at constant rate of stirring. The pills should be inserted into the dissolving vessel. And sampling is carried out at regular periods and analysed by any sutable analytical method, such as UV spectroscopy.

CONCLUSION:

This article describes an overview of the floating microsphere preparation process and assessment parameter. Floating micro-balloons have shown to have a great potential for gastro-retention, and they can be used to improve bioavailability and control the release of numerous medications. Furthermore, current advancements in pharmaceutical research will undoubtedly pave the way for the creation of unique and effective methods for delivering these potential drug delivery systems.

REFERENCES:

1. Kaurav H. Hari SL. Kaur A. Mucoadhesive microspheres as carriers in drug delivery: a review, International journal of drug development & research. 2012 Apr ; 4(2): 21-34; 0975-9344

2. Kumar G. Anand J. Porous floating microsphere: a new dimension in controlled drug delivery, Research journal of pharmacy and technology 2011 sept ;4(9):1340-1357; 0974-3618

3. Rumpa B. Tanmay M. Sujit D. Recent advances in the development of floating microspheres for the treatment of hypertension, World journal of pharmacy and pharmaceutical sciences 2021 july; 10(8):1299-1313. DOI: 10.20959/wjpps20218-19667

4. Alagusundaram M. Chetty MS. Umashankari K. Microspheres as a novel drug delivery system-a review, International journal of chemtech research 2009 Jul;1(3):526-34; 0974-4290

5. Saxena A. Gaur K. Singh V. Singh RK. Floating microspheres as drug delivery system, American Journal of Pharmacy and Pharmaceutical Sciences. 2014;1(2):27-36. DOI: 10.12966/ajpps.06.02.2014.

6. 6.Prabhu S. Ali MA. Vijayalakshmi S. Sathali AH. Florulation and evaluation of ph sensitive Mucoadhesive microspheres of Fluvaststin sodium, Research journal of pharmacy and technology 2015 oct; 8(10): 1343-1352; 0974-3618

7. 7.Chintale AG. Kadam VS. Maske KS. Raut DB. Kale SV. Recent advances in microsphere drug delivery system: a review. Research journal of pharmacy and technology 2013 march;6(3) :307-312; 0974-3618

8. Arora S. Ali J. Ahuja A. Khar RK.Floating drug delivery systems: a review. Aaps PharmSciTech. 2005 Sep;6(3):372-390. http://www.aapspharmscitech.org.

9. Sahil K. Middha A. Sandhu P. Bilandi A. Microsphere: A review, International journal of chemtech research. 2011;1(4):1184-98, 2231-2781.

10. Marbaniang D. Das RJ. Pal P. Extended release floating micro balloons containing Clerodendrum colebrookianum extract: in vitro in vivo evaluation, Indian Journal of Pharmaceutical Education and Research. 2019 Jul 1;53(3):5246-54. DOI: 10.5530/ijper.53.3s.94.

11. 11.Sasidharan T. Nair SC. Magnetic microsphere: A review, Research journal of pharmacy and technology 2016 march ;9(3): 281-286; 0974-361

12. Hafeez A. Maurya A. Singh J. An overview on floating microsphere: gastro retention floating drug delivery system (FDDS), The Journal of Phytopharmacology. 2013;2(3):1-12, 2230-480X.

13. Srikar G. Dadi S. Ramesh J. Floating microspheres: A prevailing trend in the development of gastroretentive drug delivery system, Asian Journal of Pharmaceutics, 2018 oct 11;12(04).235-242.

14. Nithyashree RS. Kumar S. Gosh T. Floating Microballoon-A Novel Formulation For Gastrointestinal Diseases, Journal of Pharmaceutical Sciences and Research. 2020;12(1):74-78; 0975-1459.

15. Shinde TS. Barhate AN. A Review on floating microspheres, International Journal of Pharmaceutical and Biological Science Archive. 2019 Jun 14;7(3):87-92; 2349-2678.

16. Kumar L, Sharma A. Gastro Retentive Floating Microsphere: A Review, Journal of Pharmaceutical Science and Bioscientific Research. 2019;9(2):142-148; 2271-3681.

17. Bhardwaj L. Kumar PS. Malviya R. A short review on gastro retentive formulations for stomach specific drug delivery: special emphasis on floating in situ gel systems, African journal of basic and applied sciences. 2011;3(6):300-312; 2079-2034.

18. Grover I. Marwah M. Devgan M. Floating Drug Delivery System: A Novel Approach. Research journal of pharmacy and technology 2015 april; 8(4): 490-495; 0974-3618

19. Singh BN. Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention, Journal of Controlled release. 2000 Feb 3;63(3):235-259. PII: S0168-3659(99)00204-7.

20. Gholap SB. Banarjee SK. Gaikwad D. Jadhav L.Hollow microsphere: A review, International Journal of Pharmaceutical Sciences Review and Research. 2010 Mar;1(1):74-79.

21. Sharma G. Nautiyal U. Sayeed A. An Overview on Gastroretentive Drug Delivery System (GRDDS), International Journal of Health and Biological Sciences. 2019 Jun 30;2(2):01-08. DOI: https://doi.org/10.30750/ IJHBS.2.2.1.

22. Dhole AR. Gaikwad PD Bankar VH. A review on floating multiparticulate drug delivery system-A novel approach to gastric retention, International journal of pharmaceutical sciences review and research, 2011 Jan;6(2):205-211; 0976-044X.

23. Somwanshi SB. Dolas RT. Nikam VK. Floating multiparticulate oral sustained release drug delivery system. Journal of Chemical and Pharmaceutical Research, 2011;3(1):536-47; 0975-7384.

24. Taneja R. Kataria MK. Bilandi A. Floating microsphere: a potential gastroretentive drug delivery system, International journal of comprehensive pharmacy. 2013 Apr ;4(01):1-9; 0976-8157.

25. Mukund JY. Kantilal Br. Floating microspheres: a review, Brazilian Journal of Pharmaceutical Sciences. 2012;48(01):17-30,

26. Shivalingam MR. Kumaran KA. Reddy K. Reddy B. Formulation and evaluation of floating microballoons of ibuprofen for the enhanced enteric bioavailability, Research journal of pharmacy and technology 2010 june; 3(2) : 583-585; 0974-3618

27. Dehghan M. Khan FN. Gastroretentive drug delivery systems: A patent perspective, International Journal of Health Research. 2009March;2(1):23-44;e215p33-54.

28. Ichikawa M. Watanabe S. Miyake Y. A new multiple-unit oral floating dosage system. I: Preparation and in vitro evaluation of floating and sustained-release characteristics, Journal of pharmaceutical sciences. 1991 Nov ;80(11):1062-1066, 0022-3549/91/1100-1062.

29. Malleswari K. Reddy RB. Microballoons: A Review. International Journal of Advanced Research in Science, Engineering and Technology 2020, 7(1): 12370-12378; 2350-03228 .

30. Sharma N. Aggarwal D. Gupta ML. A comprehensive review on floating drug delivery system, International Journal of Research in Pharmaceutical and Biomedical Sciences. 2011 Apr;2(2):428-441; 2229-3701.

31. Varghese R. Nair NM. Lekshima L. Lekshmi MR. Floating Microspheres as Novel drug delivery system for Arthritis. Asian Journal of Pharmaceutical Research and Development. 2016 Jan;4(1):01-05; 2320-4850.

32. Patil JS. Kamalapur MV. Kadam DV. Ionotropic gelation and polyelectrolyte complexation: the novel techniques to design hydrogel particulate sustained, modulated drug delivery system: a review. Digest Journal of Nanomaterials and Biostructures. 2010 Mar ;5(1):241-248.

33. Prasad BS. Gupta VRM. Devanna N. Jayasurya K. Microspheres as drug delivery system-A review, Journal of Global Trends in Pharmaceutical Scinces. 2014;5(3):1961-1972; 2230-7346.

34. Chaurasia S. Rizawana K. Niranjan SK. A Review: Formulation and evaluation of floating microspheres, World Journal of Pharmacy and Pharmaceutical Sciences: 2018 Apr ;7(5):310-322. DOI: 10.20959/wjpps20185-11472.

35. Ali A. Pillai H. Mathew P. Das C. Formulation and evaluation of foating mucoadhesive microspheres loaded with antiulcer drug. Research journal of pharmacy and technology 2020 august ; 13(8) : 3759-3764; 0974-3618

36. Alagusundaram M. Chetty MS. Umashankari K. Microspheres as a novel drug delivery system-a review, International Journal of Chem Tech Research. 2009 Jul;1(3):526-534; 0974-4290.

37. Hire NN. Derle DV. Microsphere As Drug Carrier: A Review, International Journal of Advanced Research. 2014:2(3), 901-913, 2320-5407.

38. Pujara ND, Patel NV. Thacker AP. Doshi SM. Floating microspheres: A novel approach for gastro retention, World journal of pharmacy and pharmaceutical sciences. 2012 Aug ;1(3):872-895; 2278-4357.

39. Kumar A. Srivastava R. In Vitro In Vivo Studies On Floating Microspheres For Gastroretentive Drug Delivery System: A Review, Asian Journal of Pharmaceutical and Clinical Research. 2020 Nov ;14(01):13-26. DOI: http://dx.doi.org/10.22159/ajpcr.2021v14i1.39183.

40. Kumar L, Sharma A. Gastro Retentive Floating Microsphere: A Review, Journal of Pharmaceutical Science and Bioscientific Research. 2019 Apr;9(2):142-148; 2271-3681.

41. Thanoo BC. Sunny MC. Jayakrishan A. Oral Sustained‐release Drug Delivery Systems using Polycarbonate Microspheres Capable of Floating on the Gastric Fluid, Journal of pharmacy and pharmacology. 1993 Jan;45(1):21-24.

42. Varghese R. Nair NM. Aniyan N. Shajan A. Floating Microspheres as Novel Drug Delivery System For Arthritis, Asian Journal of Pharmaceutical Research and Development. 2016 Jan 4(1):1-5; 2320-4850.

43. Kumar V. Goel A. Floating / Hollow Microspheres: A Novel Approach For Gastroretention ; International Journal Of Pharma Professional’s Research ,2015 July 6(3),1275-1282; 0976-6723.

44. Kannan K. Karar PK. Manavalan R. Formulation and evaluation of sustained release microspheres of acetazolamide by solvent evaporation technique. Journal of Pharmaceutical Sciences and Research. 2009 Mar ;1(1):36-39; 0975-1459.

45. Miranda FC. Kamath KK. Shabaraya AR. Floating Microspheres: A Review; World Journal of Pharmacy And Pharmaceutical Sciences, 2019, 8(7) 379-403. DOI: 10.20959/wjpps20197-14081.

46. Solanki D. Patidar S. Motiwale M. Floating Drug Delivery System-Novel Tool for Delivering H2 Antagonist. International journal of pharmacy and pharmaceutical research,2017 jan;8(2):118-133; 2349-7203.

47. Pujara ND. Patel NV. Parmar RB. Floating microspheres: A novel approach for gastro retention, World journal of pharmacy and pharmaceutical sciences. 2012 Aug 1;1(3):872-95; 2278 – 4357l.

48. Trivedi P. Verma AML. Garud N. Preparation and characterization of aceclofenac microspheres, Asian Journal of Pharmaceutics, 2008 Aug ;2(2):110-115.

49. Midha K, Nagpal M, Arora S. Microspheres: A Recent Update. International of Recent Scientific Research, 6(8). 2015 Aug:5859-5867.

50. Chowdary KP, Babu JS. Permeability of ethylene vinyl acetate copolymer microcapsules: Effect of solvents, Indian journal of pharmaceutical sciences. 2003;65(1):62-66.

51. Patel A. Patil CC. Kulkarni RV. Kumar V. Jorapur P. Development and evaluation of sustained-release pioglitazone microsphere, Research journal of pharmacy and technology 2018 Dec ;11(12) : 5348-5354; 0974-3618

52. Gurung BD. Kakar S. An overview on microspheres. International Journal of Health and Clinical Research. 2020 Mar 30;3(1):11-24; 2590-3241.

53. Virmani T. Gupta G. Pharmaceutical application of microspheres: An approach for the treatment of various diseases, International Journal of Pharmaceutical Sciences and Research. 2017;8(8):3253-3260; 0975-8232.

54. Ayalasomayajula LU. Navya K. Earle RR. Review on non effervescent gastro retentive drug delivery systems-microballons, Asian Journal of Pharmaceutical Research. 2020 Oct;10(4):312-318. DOI: 10.5958/2231-5691.2020.00053.2.

55. Vidyadhara S. Sasidhar RL. Balakrishna T. Formulation and evaluation of controlled release floating Microballoons of stavudine. Scientia pharmaceutica. 2015 Dec;83(4):671-682. Doi:10.3797/scipharm.1501-07

56. Hajare PP, Rachh PR. Gastroretentive microballoons: a novel approach for drug delivery, International Journal of Pharmaceutical Sciences and Research. 2020;11(3):1075-1083; 0975-8232.

57. Awasthi R. Kulkarni GT. Development of novel gastroretentive floating particulate drug delivery system of gliclazide, Current drug delivery. 2012 Sep ;9(5):437-451; 1875-5704.

58. Vishnu p. Kishore VS. Design and development of mucoadhesive microspheres of propranolol hydrochloride. Research journal of pharmacy and technology 2011 jan;4(1): 92-97; 0974-3618

59. Pattan SR. Wani NP. Shelar MU. Chadhari PD. Scope and significance of floating drug delivery system, Indian drugs. 2012 oct;49(10):5-12.

60. Patil JM. Hirlekar RS. Hadam VJ. Trends in floating drug delivery systems, Journal of Scientific and industrial research.2006 jan;65(01):11-21.

61. Sonani NG. Hiremath SP. Sreenivas SA. Design and evaluation of gastroretentive mucoadhesive cephalexin tablets. Pharmaceutical development and technology. 2010 Apr 1;15(2):178-183. DOI: 10.3109/10837450903085426.

62. Shriwas K. Niranjan SK. A Brief Review on Mucoadhesive Microspheres in drug delivery system, World journal of pharmacy and pharmaceutical sciences, 2019 Aug;8(10):484-504. DOI: 10.20959/wjpr201910-15668.

63. Garg A. Upadhyay P. Mucoadhesive microspheres: A short review, Asian journal of pharmaceutical and clinical Research. 2012;5(3):24-27; 0974-2441.

64. Chakraborty S. Dhinda SC. Patra N. Fabrication and characterization of algino-carbopol microparticulate system of aceclofenac for oral sustained drug delivery. International Journal of Pharmaceutical Sciences Review and Research. 2010 Sep;4(2):192-199; 0976-044X.

65. Venkateswaramurty N. Kumar SB. Vijayabaskaran M. Perumal P. Preparation and evaluation of mucoadhesive microspheres containing heparin for antiulcer therapy. Research journal of pharmacy and technology 2011 feb; 4(2):268-270; 0974-3618.

Received on 15.03.2022 Modified on 13.05.2022

Research J. Pharm. and Tech 2023; 16(6):3025-3030.

DOI: 10.52711/0974-360X.2023.00499