INTRODUCTION:

Some of the problems of overcome by producing control drug delivery system which enhance the therapeutic efficacy of a given drug for obtain maximum therapeutic efficacy and minimum side effects it necessary to deliver the agent to the target tissue in the optimal amount. There are various approaches in delivering a therapeutic substance to the target site in a sustained controlled release fashion.¹ One such approach is using microspheress ascarriers for drugs. Microspheress can be described as small particles (in 1-1000 micrometer size range) for use as carriers of drugs and other therapeutic agents consisting of proteins or synthetic polymers which are biodegradable in nature.

The term microspheress describes a monolithic spherical structure with the drug or therapeutic agent distributed throughout the matrix either as a molecular dispersion or as a dispersion of particles. The behaviour of the drugs in vivo can be manipulated by combining the drug to a carrier particle. The clearance kinetics, tissue distribution, metabolism i.e. kinetics and cellular interaction of the drug are strongly influenced by the behaviour of the carrier. The exploitation of these changes in pharmaco dynamics behaviour may lead to enhanced therapeutic efficiency.^2-4 However, an intelligent approach to therapeutics employing drug carriers phenomenon requires a detailed understanding of the carrier interaction with cellular and organ systems and of the limitations of the systems with respect to the formulation procedures and stability issues.^3-6

Materials used in the preparation of Microsphere:

A number of different substances both biodegradable as well as non-biodegradable have been investigated for the preparation of microspheress. These materials include the polymers of natural and synthetic origin and also modified natural substances. Synthetic polymers employed as carrier materials are methyl methacrylate, acrolein, lactide, glycolide and their copolymers, ethylene vinyl acetate copolymer, polyanhydrides, etc. The natural polymers used for the purpose are albumin, gelatin, starch, collagen and carrageenan.^7-9

The material utilized for the preparation of micro particulates should have the following properties like Longer duration of action, Control of content release, Increase of therapeutic efficiency, Protection of drug, Reduction of toxicity, Biocompatibility, Sterilizability, Relative stability, Water solubility or dispersability, Bioresorbability, Target ability, Polyvalent.¹⁰

Types of Microspheres:

Magnetic Microspheres:

This kind of delivery system is very much important which localizes the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc.^11-14 The different type are Therapeutic magnetic microspheres are used to deliver chemotherapeutic agent to liver tumor. Drugs like proteins and peptides can also be targeted through this system.¹⁵

Diagnostic microspheres:

Magnetic drug transport technique is based on the fact that the drug can be either encapsulated into a magnetic microsphere or conjugated on the surface of the microsphere. The accumulation of the carrier at the target site allow them to deliver the drug locally.¹⁶

Floating microspheres:

In floating types the bulk density is less than the gastric fluid and so remains buoyant in stomach without affecting gastric emptying rate. The drug is released slowly at the desired rate, if the system is floating on gastric content, increases gastric residence and fluctuation in plasma concentration. It also reduces chances of striking and dose dumping and produces prolonged therapeutic effect.^17-20

Radioactive microspheres:

Radio immobilization therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they come across. They are injected to the arteries that lead to tumor of interest. So these radioactive microspheres deliver high radiation dose to the targeted areas without damaging the normal surrounding tissues. It differs from drug delivery system, as radio activity is not released from microspheres but acts from within a radioisotope typical distance and the different kinds of radioactive microspheres are α emitters, β emitters, γ emitters.^21-25

Mucoadhesive microspheres:

Mucoadhesive microspheres which are of 1-1000mm in diameter and consisting either entirely of a mucoadhesive polymer or having an outer coating of it and coupling of mucoadhesive properties to microspheres has additional advantages, e.g. efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio, a much more intimate Reposewith the mucus layer, specific targeting of drug to the absorption site achieved by anchoring plant lectins, bacterial adhesions and antibodies, etc. on the surface of the microspheres. Mucoadhesive microspheres can be tailored to adhere to any mucosal tissue including those found in eye, nasal cavity, urinary and gastrointestinal tract, thus offering the possibilities of localized as well as systemic controlled release of drugs.^26-28

Figure 1: Types of Microspheres

Method of Preparation

Double Emulsion Technique:

It is formation of multiple emulsions i.e. W/O/W is preparing by pouring the primary w/o emulsion into aqueous solution of poly vinyl alcohol. This w/o/w emulsion put at constant stirring for 30 min. Slowly add some water to the emulsion over a period of 30 min. collect Microcapsules by filtration and dry under vacuum.²⁹ It is best suited to water soluble drugs, peptides, proteins and the vaccines. Natural as well as synthetic polymer can use for this method. The aqueous protein solution is dispersed in a lipophilic organic continuous phase. This protein solution may contain the active constituents. Disperse in oil/organic phase homogenization/vigorous i.e. formation of first emulsion then addition to aqueous solution of PVA (Poly Vinyl Alcohol) i.e. multiple emulsion formed now by addition to large aqueous phase denaturation/hardening after this separation, washings’ and drying and collection of microspheres.³⁰

Single Emulsion Technique:

There are several Proteins and carbohydrates, which are prepared by this technique. The single emulsion method is primarily used for encapsulating hydrophobic drugs through an oil-in-water (o/w) emulsification process.^31-34 In which the natural polymers are dissolved in aqueous medium and the followed by dispersion in oil phase i.e. non-aqueous medium.

Coacervation Phase Separation Technique:

The principle of coacervation is decreasing the solubility of the polymer in organic phase to affect the formation of polymer rich phase called the coacervates.³⁵ The coacervation can be brought about by addition of the third component to the system which results in the formation of the two phases, one i.e. supernatant, depleted of the polymer. In this technique, the polymer is first dissolved in a suitable solvent and then drug is dispersed by making its aqueous solution, if hydrophilic or dissolved in the polymer solution itself, if hydrophobic. Phase separation is then accomplished by changing the solution conditions.

Spray Drying and Spray Congealing Technique:

Concept of spray drying technique depending upon the removal of solvent or the cooling of solution the two processes are spray drying and spray congealing Respectively. The polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, acetone, etc. The drug in the solid form is then dispersed in the polymer solution under high-speed homogenization. This dispersion is then atomized in a stream of hot air. The atomization leads to the formation of the small droplets or the fine mist from which the solvent evaporates instantaneously leading the formation of the microspheres in a size range 1- 100μm. Micro particles are separated from the hot air by means of the cyclone separator while the traces of solvent are removed by vacuum drying.³⁵

Solvent Extraction Technique:

In this method preparation of micro particles, involves removal of the organic phase by extraction of the organic solvent. Isopropanol can be use as water miscible organic solvents. By extraction with water, Organic phase is removed. Hardening time of microsphere can be decrease by this method. One variation of the process involves direct addition of the drug or protein to polymer organic solution. The rate of solvent removal by extraction method depends on the temperature of water, ratio of emulsion volume to the water and the solubility profile of the polymer.³⁶

Ionic Gelation Technique:

Ionotropic gelation (IG) is a technique that allows the production of nanoparticles and microparticles by electrostatic interactions between two ionic species under certain conditions. At least one of the species has to be a polymer.³⁶

Physicochemical Evaluation:

Particle Size and Shape:

The most widely used procedures to visualize micro particles are conventional light microscopy (LM) and scanning electron microscopy (SEM). Both can be used to determine the shape and outer structure of micro particles. LM provides a control over coating parameters in case of double walled microspheres. The microspheres structures can be visualized before and after coating and the change can be measured microscopically. SEM provides higher resolution in contrast to the LM.³⁷

Electron Spectroscopy for Chemical Analysis:

The surface chemistry of the microspheres can be determined using the electron spectroscopy for chemical analysis (ESCA). ESCA provides a means for the determination of the atomic composition of the surface. The spectra obtained using ECSA can be used to determine the surface degradation of the biodegradable microspheres.³⁸

Density Determination:

The density of the microspheress can be measured by using a multi volume pychnometer. Accurately weighed sample in a cup is placed into the multi volume pychnometer. Helium is introduced at a constant pressure in the chamber and allowed to expand. This expansion results in a decrease in pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressure are noted. From two pressure readings the volume and hence the density of the microspheres carrier is determined.³⁹

Angle of Repose:

The angle of Reposeis measured to determine the wetting property of a micro particulate carrier. It determines the nature of microspheress in terms of hydrophilicity or hydrophobicity. This thermodynamic property is specific to solid and affected by the presence of the adsorbed component. The angle of Reposeis measured at the solid/air/water interface. The advancing and receding angle of Reposeare measured by placing a droplet in a circular cell mounted above objective of inverted microscope. Reposeangle is measured at 20⁰C within a minute of deposition of microspheres.⁴⁰

Entrapment Efficiency:

The capture efficiency of the microspheres or the percent entrapment can be determined by allowing washed microspheress to lysate. The lysate is then subjected to the determination of active constituents as per monograph requirement. The percent encapsulation efficiency is calculated using following equation:⁴⁰

% Entrapment = Actual content/Theoretical content x 100

In Vitro Methods:

In vitro drug release studies have been employed as a quality control procedure in pharmaceutical production, in product development etc. Sensitive and reproducible release data derived from physic-chemically and hydro dynamically defined conditions are necessary, however no standard in vitro method has yet been developed. Different workers have used apparatus of varying designs and under varying conditions, depending on the shape and application of the dosage form developed.⁴¹

Interface Diffusion System:

This method is developed by Dearden and Tomlinson. It consists of four compartments. A represents the oral cavity, and initially contained an appropriate concentration of drug in a buffer. The compartment B representing the buccal membrane, contained 1-octanol, and compartment C representing body fluids, contained 0.2 M HCL. The compartment D representing protein binding also contained 1-octanol. Before use, the aqueous phase and 1- octanol were saturated with each other. Samples were withdrawn and returned to compartment A with a syringe.⁴¹

In vivo Methods:

Methods for studying the permeability of intact mucosa comprise of techniques that exploit the biological response of the organism locally or systemically and those that involve direct local measurement of uptake or accumulation of penetrate at the surface. The most widely used methods include in vivo studies using animal models, buccal absorption tests, and perfusion chambers for studying drug permeability.⁴²

Pharmaceutical Application of Microspheres ⁴³:

a. Vaccine delivery

b. Monoclonal antibodies

c. Imaging

d. Topical porous microsphere

e. Nasal drug delivery

f. Oral drug delivery

g. Targeting drug delivery

h. Gastroretentive controlled delivery system

i. Bio-medical application

Other applications:

Fluorescent microspheres can be used for membrane based technology for flow cytometry, cell biology, microbiology, Fluorescent Linked Immuno-Sorbent Assay. Yttrium can be used for primary treatment of hepatocellular carcinoma and also used for pre transplant management of HCC with promising results. Applications of microencapsulation in other industries are numerous. The best known microencapsulated products are carbonless copying paper, photosensitive paper, microencapsulated fragrances, such as ‘‘scent-strips’’ (also known as ‘‘snap-n-burst’’), and microencapsulated aromas (‘‘scratch-n-sniff’’). All of these products are usually prepared by gelatin–acacia complex coacervation. Scratch-n-sniff has been used in children’s books and food and cosmetic aroma advertising. Microcapsules are also extensively used as diagnostics, for example, temperature-sensitive microcapsules for thermo graphic detection of tumors. In the biotechnology industry microencapsulated microbial cells are being used for the production of recombinant proteins and peptides.^44-45

CONCLUSION:

Microspheres are better choice of drug delivery system than many other types of drug delivery system. In future by combining various other strategies, microspheres will find the central and significant place in novel drug delivery, particularly in diseased cell sorting, diagnostics, gene and genetic materials, safe, targeted, specific and effective in vitro delivery and supplements as miniature version of diseased organ and tissues in the body. Microspheres offer several improvements over existing technologies. These have emerged as an exciting new platform for biologists to adopt these techniques in the investigation of biomolecules interactions and cellular processes. In recent years there have been increasingnumbers of studies in which microspheres have been used in more diverse applications and it is evident that the range of potential applications is enormous. In addition, microspheres have been labeled with a variety of β and emitting radionuclide such as 131I, 99mTc, 113mIn or 51Cr. Such products have been used to scan the heart, brain, liver and gastro intestinal tracts and in a pulmonary perfusion and inhalation studies. Microsphere is a short term but it is having wide applications in drug delivery systems to get desire biological activity. By combining various strategies, microspheres will find central place in novel drug delivery system mainly particularly in cell sorting, diagnostics and Genetic engineering. From the study it is proved that Microspheres act as effective carriers for the novel drug delivery system.

REFERENCES:

1. Kawaguchi H. Functional polymer microspheres. Progress in polymer science. 2000 Oct 1;25(8):1171-210.

2. Freiberg S, Zhu XX. Polymer microspheres for controlled drug release. International journal of pharmaceutics. 2004 Sep 10;282(1-2):1-8.

3. O'Donnell PB, McGinity JW. Preparation of microspheres by the solvent evaporation technique. Advanced drug delivery reviews. 1997 Oct 13;28(1):25-42.

4. Sinha VR, Trehan A. Biodegradable microspheres for protein delivery. Journal of controlled release. 2003 Jul 31;90(3):261-80.

5. Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres. Advanced drug delivery reviews. 1997 Oct 13;28(1):5-24.

6. Mateus AY, Barrias CC, Ribeiro C, Ferraz MP, Monteiro FJ. Comparative study of nanohydroxyapatite microspheres for medical applications. Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials. 2008 Aug;86(2):483-93.

7. Sinha VR, Singla AK, Wadhawan S, Kaushik R, Kumria R, Bansal K, Dhawan S. Chitosan microspheres as a potential carrier for drugs. International journal of pharmaceutics. 2004 Apr 15;274(1-2):1-33.

8. Okada H, Toguchi H. Biodegradable microspheres in drug delivery. Critical Reviews™ in Therapeutic Drug Carrier Systems. 1995;12(1).

9. Scheffel U, Rhodes BA, Natarajan TK, Wagner HN. Albumin microspheres for study of the reticuloendothelial system. Journal of Nuclear Medicine. 1972 Jul 1;13(7):498-503.

10. Mathiowitz E, Jacob JS, Jong YS, Carino GP, Chickering DE, Chaturvedi P, Santos CA, Vijayaraghavan K, Montgomery S, Bassett M, Morrell C. Biologically erodable microspheres as potential oral drug delivery systems. Nature. 1997 Mar;386(6623):410-4.

11. Malviya VR, Tawar MG. Preparation and Evaluation of Oral Dispersible Strips of Teneligliptin Hydrobromide for Treatment of Diabetes Mellitus. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 Jan 31;13(1):4745-52.

12. Wei W, Wang LY, Yuan L, Wei Q, Yang XD, Su ZG, Ma GH. Preparation and application of novel microspheres possessing autofluorescent properties. Advanced Functional Materials. 2007 Nov 5;17(16):3153-8.

13. Senyei A, Widder K, Czerlinski G. Magnetic guidance of drug‐carrying microspheres. Journal of Applied Physics. 1978 Jun;49(6):3578-83.

14. Saralidze K, Koole LH, Knetsch ML. Polymeric microspheres for medical applications. Materials. 2010 Jun;3(6):3537-64.

15. Kim KK, Pack DW. Microspheres for drug delivery. InBioMEMS and biomedical nanotechnology 2006 (pp. 19-50). Springer, Boston, MA.

16. Benoit JP, Faisant N, Venier-Julienne MC, Menei P. Development of microspheres for neurological disorders: from basics to clinical applications. Journal of Controlled Release. 2000 Mar 1;65(1-2):285-96.

17. Buckberg GD, Luck JC, Payne DB, Hoffman JI, Archie JP, Fixler DE. Some sources of error in measuring regional blood flow with radioactive microspheres. Journal of applied physiology. 1971 Oct;31(4):598-604.

18. Denkbaş EB, Kilicay E, Birlikseven C, Öztürk E. Magnetic chitosan microspheres: preparation and characterization. Reactive and Functional Polymers. 2002 Feb 1;50(3):225-32.

19. Eldridge JH, Staas JK, Meulbroek JA, McGhee JR, Tice TR, Gilley RM. Biodegradable microspheres as a vaccine delivery system. Molecular immunology. 1991 Mar 1;28(3):287-94.

20. Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert opinion on biological therapy. 2004 Jan 1;4(1):35-51.

21. Malviya V, Thakur Y, Shrikhande S, Gudadhe K, Tawar M. Formulation and evaluation of natural gum based fast dissolving tablet of Meclizine hydrochloride by using 3 factorial design. Asian Journal of Pharmacy and Pharmacology. 2020;6(2):94-100.

22. Champion JA, Walker A, Mitragotri S. Role of particle size in phagocytosis of polymeric microspheres. Pharmaceutical research. 2008 Aug;25(8):1815-21..

23. Häfeli UO, Pauer GJ. In vitro and in vivo toxicity of magnetic microspheres. Journal of magnetism and magnetic materials. 1999 Apr 1;194(1-3):76-82.

24. Benner RE, Barber PW, Owen JF, Chang RK. Observation of structure resonances in the fluorescence spectra from microspheres. Physical Review Letters. 1980 Feb 18;44(7):475.

25. Vengadesh PK, Sundaramoorthi C, Selvaraju K, Karthick K, Beena KP. Preparation and Characterization of Chitosan Microspheres Containing a Model Antigen. Research Journal of Pharmacy and Technology. 2011;4(10):1630-2.

26. Venkateswaramurthy N, Sambathkumar R, Vijayabaskaran M, Perumal P. Preparation and Evaluation of Mucoadhesive Microspheres Containing Heparin for Antiulcer Therapy. Research Journal of Pharmacy and Technology. 2011;4(2):268-70.

27. Saravanakumar A, Minz S, Pradhan M, Sure P, Chandu AN, Mishra U, Kamalakannan K, Sivakumar T. Polylactic acid microspheres as a potential vaccine delivery system for the tetanus toxoid: Preparation and in vitro dissolution study. Research Journal of Pharmacy and Technology. 2008;1(4):453-9.

28. Malviya VR, Pande SD. Road CKN. Preparation ad Evaluation of Zolmitriptan Hydrochloride Lozenge. J Pharma Res. 2019;8(8):624-9.

29. Kalaivani M, Pulikottil MJ, Mary BM, Sakthivel R, Rajasekaran A. Preparation and Characterisation of Alginate Coated Chitosan Microspheres for Bacterial Vaccines. Research Journal of Pharmacy and Technology. 2010;3(2):503-6.

30. SP S, KL S. Preparation and In-Vitro evaluation of Abacavir Sulphate loaded microspheres cross-linked by different concentrations of glutaraldehyde. Research Journal of Pharmacy and Technology. 2010;3(4):1128-31.

31. Malviya V, Manekar S. Design, Development and Evaluation of Aceclofenac and Curcumin Agglomerates by Crystallo Co-Agglomeration Technique. Research Journal of Pharmacy and Technology. 2021 Mar 18;14(3):1535-41.

32. Mali SD, Khochage SR, Nitalikar MM, Magdum CS. Microencapsulation: a review. Research Journal of Pharmacy and Technology. 2013;6(9):954-61.

33. Malviya V. Preparation and Evaluation of Emulsomes as a Drug Delivery System for Bifonazole. INDIAN JOURNAL OF PHARMACEUTICAL EDUCATION AND RESEARCH. 2021 Jan 1;55(1):86-94.

34. Jain AA, Panigrahy RN, Mahale AM. Formulation and Evaluation of Extended Release Metformin Hydrochloride Microspheres by Ionotropic Gelation Technique. Research Journal of Pharmacy and Technology. 2011;4(7):1055-9.

35. Malviya V, Ladhake V, Gajbiye K, Satao J, Tawar M. Design and Characterization of Phase Transition System of Zolmitriptan Hydrochloride for Nasal Drug Delivery System. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 May 31;13(3):4942-51.

36. Shinde AD, Bhise SB. Development and Optimization of Mucoadhesive Microsphere of Bovine Insulin. Research Journal of Pharmacy and Technology. 2010;3(2):604-9.

37. Patil UK, Sahu R, Yadav SK. Formulation and Evaluation of Controlled Release Microspheres Containing Metformin Hydrochloride. Research Journal of Pharmacy and Technology. 2009 Mar 28;2(1):176-9.

38. Burange PJ, Tawar MG, Bairagi RA, Malviya VR, Sahu VK, Shewatkar SN, Sawarkar RA, Mamurkar RR. Synthesis of silver nanoparticles by using Aloe vera and Thuja orientalis leaves extract and their biological activity: a comprehensive review. Bulletin of the National Research Centre. 2021 Dec;45(1):1-3.

39. Gupta R, Prajapati SK, Bhardwaj P, Chaurasia H. In-Vivo Evaluation of Glipizide Floating Micropheres. Research Journal of Pharmacy and Technology. 2009;2(3):474-6.

40. Malviya VR, Pande SD, Bobade NN. Preparation and Evaluation of Sustained Release Beads of Zolmitriptan Hydrochloride. Research Journal of Pharmacy and Technology. 2019 Dec 30;12(12):5972-6.

41. Kulkarni AD, Bari DB, Surana SJ, Pardeshi CV. In vitro, ex vivo and in vivo performance of chitosan-based spray-dried nasal mucoadhesive microspheres of diltiazem hydrochloride. Journal of Drug Delivery Science and Technology. 2016 Feb 1;31:108-17.

42. Caruso F, Caruso RA, Möhwald H. Production of hollow microspheres from nanostructured composite particles. Chemistry of materials. 1999 Nov 15;11(11):3309-14.

43. Crotts G, Park TG. Preparation of porous and nonporous biodegradable polymeric hollow microspheres. Journal of Controlled Release. 1995 Aug 1;35(2-3):91-105.

44. Chang MW, Stride E, Edirisinghe M. A new method for the preparation of monoporous hollow microspheres. Langmuir. 2010 Apr 6;26(7):5115-21.

45. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y. Hollow microspheres for use as a floating controlled drug delivery system in the stomach. Journal of pharmaceutical sciences. 1992 Feb 1;81(2):135-40.

46. Arshady R. Microspheres for biomedical applications: preparation of reactive and labelled microspheres. Biomaterials. 1993 Jan 1;14(1):5-15.

Received on 24.06.2021 Modified on 16.12.2021

Asian J. Pharm. Tech. 2022; 12(2):136-140.

DOI: 10.52711/2231-5713.2022.00023