Microspheres as Novel Drug Delivery Advantages and Application: A Review

Abstract

Microspheres are innovative drug delivery systems that have gained significant attention in pharmaceutical and biomedical applications due to their ability to deliver therapeutic substances in a controlled and sustained manner. These microscopic, spherical particles, typically composed of biodegradable polymers and drugs, offer a variety of benefits, including improved drug solubility, extended release, and enhanced bioavailability. Microspheres are versatile, used in various fields such as vaccine delivery, controlled drug release, and diagnostic purposes. Their small particle size, ranging from 1 ?m to 1000 ?m, allows for precise delivery to target sites, minimizing side effects and enhancing therapeutic efficacy. Several methods of microsphere preparation, such as solvent evaporation, spray drying, and double emulsion techniques, are employed to achieve the desired drug release characteristics. The characterization of microspheres is crucial to assess parameters such as particle size, drug encapsulation efficiency, release behavior, and stability. This paper also explores various in vitro and in vivo methods for evaluating microsphere performance and their potential applications in drug delivery, particularly in controlled and sustained release systems.

Keywords

Introduction

Novel drug delivery system delivers a therapeutic substance to the target site in a well-controlled and sustained model (Rajput et al., 2012). Microspheres or microparticles are defined as a free-flowing spherical particles consisting of polymer matrix and drug. They consist of proteins or synthetic polymers which are biodegradable in nature having a particle size less than 200µm (Saini et al., 2018). Microspheres are small spherical particles, with diameters in the micrometer range (typically 1 μm to 1000 μm). Microspheres are sometimes referred to as microparticles. Microspheres can be manufactured from various natural and synthetic materials. Glass microspheres, polymer microspheres and ceramic microspheres are commercially available. Solid and hollow microspheres vary widely in density and, therefore, are used for different applications. Hollow microspheres are typically used as additives to lower the density of a material. Solid microspheres have numerous applications depending on what material they are constructed of and what size they are.  Polyethylene and polystyrene microspheres are two most common types of polymer microspheres. Polystyrene microspheres are typically used in biomedical applications due to their ability to facilitate procedures such as cell sorting and immuno precipitation. Proteins and ligands adsorb onto polystyrene readily and permanently, which makes polystyrene microspheres suitable for medical research and biological laboratory experiments. Polyethylene microspheres are commonly used as permanent or temporary filler. Lower melting temperature enables polyethylene microspheres to create porous structures in ceramics and other materials. High sphericity of polyethylene microspheres, as well as availability of colored and fluorescent microspheres, makes them highly desirable for flow visualization and fluid flow analysis, microscopy techniques, health sciences, process troubleshooting and numerous research applications. Charged polyethylene microspheres are also used in electronic paper digital displays Glass microspheres are primarily used as filler for weight reduction, retro-reflector for highway safety, additive for cosmetics and adhesives, with limited applications in medical technology. Ceramic microspheres are used primarily as grinding media. Microspheres vary widely in quality, sphericity, uniformity of particle and particle size distribution. The appropriate microsphere needs to be chosen for each unique application (Thanoo et al., 1992). The range of techniques for the preparation of microspheres offers a variety of opportunities to control aspects of drug administration. This approach facilitates the accurate delivery of small quantity of the potent drugs, reduced drug concentration at the site other than the target site and the protection of the labile compound before and after the administration and prior to appearance at the site of action. The behavior of the drugs in vivo can be manipulated by coupling the drug to a carrier particle. The clearance kinetics, tissue distribution, metabolism and cellular interaction of the drug are strongly influenced by the behavior of the carrier. The exploitation of these changes in pharmacodynamics behavior may lead to enhanced therapeutic effect. However, an intelligent approach to therapeutics employing drug carrier’s technology requires a detailed understanding of the carrier interaction drugs in vivo can be manipulated by coupling the drug to a carrier particle. The clearance kinetics, tissue distribution, metabolism and cellular interaction of the drug are strongly influenced by the behavior of the carrier. The exploitation of these changes in pharmacodynamics behavior may lead to enhanced therapeutic effect. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration the most convenient and commonly employed route of drug delivery has historically been by oral ingestion Drugs that are easily absorbed from the GIT and having a short half-life are eliminated quickly from the blood circulation. To avoid these problems oral controlled drug delivery systems have been developed as they release the drug slowly into the GIT and maintain a constant drug concentration in the serum for longer period of time. However, incomplete release of the drug and a shorter residence time of dosage forms in the upper gastrointestinal tract, a prominent site for absorption of many drugs, will lead to lower bioavailability. Efforts to improve oral drug bioavailability have grown in parallel with the pharmaceutical industry. As the number and chemical diversity of drugs has increased, new strategies are required to develop orally active therapeutics. Thus, gastro retentive dosage forms, which prolong the residence time of the drugs in the stomach and improve their bioavailability, have been developed (Gholap et al., 2010). A well-designed controlled drug delivery system can overcome some of the problems of conventional therapy and enhance the therapeutic efficacy of a given drug. To obtain maximum therapeutic efficacy, it becomes necessary to deliver the agent to the target tissue in the optimal amount in the right period of time there by causing little toxicity and minimal side effects. There are various approaches in delivering a therapeutic substance to the target site in a sustained controlled release fashion. One such approach is using microspheres as carriers for drugs. Microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers which are biodegradable in nature and ideally having a particle size less than 200 µm (Agusundaram et al., 2009). Microspheres offer several advantages as drug delivery systems. One of the primary benefits is the continuous and lasting therapeutic action they provide, which enhances the duration of the drug’s effectiveness. This extended release also decreases the frequency of doses, improving patient compliance (Herfarth et al., 2002). Additionally, microspheres are large enough to be inserted into the body and possess a spherical form, which is conducive to easy administration and targeted delivery. Their configuration enables predictable fluctuations in drug release and breakdown, allowing for controlled and consistent therapeutic outcomes (Kavita et al., 2010). The reduced size of microspheres increases their surface area, which can significantly enhance the solubility of poorly soluble drugs, thereby improving their bioavailability. When microspheres are coated with polymers, they can protect the drug from enzymatic cleavage, ensuring more effective drug distribution (Gullotti and Yeo, 2009). Furthermore, the polymer coating allows the microspheres to become less reactive to the external environment, providing stability to the core drug (Alagusundaram et al., 2009). Overall, the increased surface area resulting from the reduced size can further enhance the effectiveness of poorly soluble ingredients, leading to better therapeutic outcomes (Rathore et al., 2012).

METHOD OF PREPARATION

The solvent evaporation method

In vehicle phase of liquid manufacturing this process is carried out. In the volatile solvent the microcapsule coating is dispersed which is immiscible with the vehicle phase of the liquid manufacturing. In the coating polymer solution the core material which is microencapsulated is dissolved (Anandeaet al., 2008). To obtain the appropriate size microcapsule the agitation with the core material mixture is dissolved in the liquid manufacturing vehicle phase (Guojun et al., 2005). If necessary, the mixture is heated to evaporate & the solvent for the polymer of a core material is dissolved in the polymer solution around a core polymer shrinks. The matrix type microcapsules are formed if the core material is dissolve in the coating polymer solution. The core materials are either soluble materials or water soluble (Dutta et al., 2011; Ahmad et al., 2016).

The spray drying method

In this technique, in the volatile organic solvent such as acetone, dichloromethane etc, the polymer is dissolved first. A drug in the solid form is then dispersed in to the polymeric solution with a highspeed homogenization. In the hot air stream this dispersion is then atomized. The atomization leads to the form the small droplets from which the solvent evaporates instantly which leads the formation of microspheres in the size range 1 to 100μm. From hot air by the cyclone separator the micro particles are separated while by vacuum drying the trace of solvent is removed. The major advantages of this process is under aseptic conditions there is feasibility of operation (Suvarna, 2015).

The double emulsion technique

This method involves the formation of multiple emulsions or double emulsion of the type w/o/w & is best suited to the water-soluble drugs, proteins, vaccines, peptides. This method can be used with the both synthetic & natural polymers. In the lipophilic organic continuous phase the aqueous protein solution is dispersed. This protein solution may contain the active constituents (Prasanth et al., 2011).

The single emulsion technique

By the single emulsion technique, the micro particulate carriers of the natural polymers i.e. carbohydrates & proteins are prepared. The natural polymers are dissolved in the aqueous medium which is followed by a dispersion in the non-aqueous medium like oil. The cross linking of the dispersed globule is carried out in the next step. By the heat or by using the chemical cross linkers the cross linking can be achieved. Formaldehyde, glutaraldehyde, acid chloride are the chemical cross linking agents that are used. For the thermo labile substance the heat denaturation is not suitable. The chemical cross linking having the drawback of excessive exposure of the active ingredient to the chemicals if added at the time of preparation & then subjected to the centrifugation, separation, washing, nature of the surfactants used to stabilize the emulsion phases can be influenced greatly by the size distribution, size, loading drug release, surface morphology & bio performance of the final multiparticulate product (Suvarna, 2015).

The Spray drying & spray congealing

On the drying of the mist of polymer and drug in the air, these methods are based. These two processes are named spray drying and spray congealing depending upon the removal of the solvent or cooling of the solution (Kawashima et al., 1991).

The phase separation coacervation technique

This technique is based on the principle of the decreasing the solubility of the polymer in the organic phase which affect the formation of the polymer rich phase called as the coacervates. In this technique the drug particles are dispersed in the solution of the polymer & an incompatible polymer is added to the system which makes the first polymer for the separation of phase (Suvarna, 2015).

The quassi emulsion solvent diffusion

The novel quasi-emulsion solvent diffusion method is used for the manufacturing of a controlled release microspheres of the drugs with acrylic polymers, in the literature has been reported. By using external phase which contains distilled water and polyvinyl alcohol the microsponges can be manufactured by the quassi emulsion solvent diffusion method. The internal phase consists of the polymers, drug & ethanol. The internal phase is manufactured first at 60oC & after then it is added to the external phase at the room temperature. Then emulsification the mixture is stirred continuously for two hours. Then for the separation of the microsponges the mixture can be filtered (Kawashima et al., 1991; Yadav et al., 2019).

The solvent extraction

For the manufacturing of microparticles the solvent evaporation method is used & it involves the removal of the organic phase by extraction of the non-aqueous solvent. This method involves the water miscible organic solvent which is the isopropanol (Suvarna, 2015).

Characterization of Microsphere

The characterization of the microspheres is an important phenomenon which helps to design a suitable carrier for the delivery of proteins, drugs or antigens. These microspheres have different microstructures. These microstructures determine the release and the stability of the microspheres (Barkai et al., 1990).

Particle size and shape: The most used procedures to visualize microspheres are conventional Light Microscopy (LM) and Scanning Electron Microscopy (SEM). Both techniques can be used to determine the shape and outer structure of these microspheres. Light Microscopy (LM) provides control over coating parameters in the case of double-walled microspheres. The microsphere structures may be visualized before and after coating and the change can be measured by microscope. SEM provides higher resolution in comparison to the LM (Jain, 2004). Scanning Electron Microscopy (SEM) allows investigations of the surface of the microsphere and after particles are cross-sectioned, it can also be used for the investigation of double-walled systems. Confocal fluorescence microscopy is used for the structure characterization of multiple-walled microspheres (Bodmeier and Chen, 1989). Laser light scattering and multi-size coulter counter other than instrumental methods can be used for the characterization of the size, shape and morphology of the microspheres.

Density determination: The density of the microspheres can be measured by using a device called a multi-volume pychnometer. An accurately weighed sample in a cup is then placed into the multi-volume pychnometer. Helium is introduced at a constant pressure in the chamber and it is allowed to expand. This expansion leads to a decrease in pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressures are noted down. From two pressure readings, the volume and thus the density of the microsphere carrier is determined (Sinha et al., 2005).

Isoelectric point: The microelectrophoresis is an apparatus that is used to measure the electrophoretic mobility of microspheres from which the isoelectric point can be determined. The average velocity at different pH values ranging from 3 to10 is calculated by measuring the time of movement of particles over a distance of 1 mm. By using this data, the electrical mobility of the particle can also be determined. The electrophoretic mobility may be related to the surface-contained charge, ionisablebehaviour or ion absorption nature of the microspheres.

Angle of contact: The wetting property of a microparticulate carrier is ascertained by measuring the angle of contact. this findsout the nature of microspheres in terms of hydrophilicity or hydrophobicity. This thermodynamic property is specific to solids and it gets affected by the presence of the adsorbed component. A solid/air/water interface is used to measure the Angle of contact. The advancing and receding angle of contact is measured by placing a droplet in a circular cell mounted above the objective of the inverted microscope. The contact angle is measured at 20°C within a minute of deposition of microspheres (Kawashima et al., 1991).

Electron spectroscopy for chemical analysis: The surface chemistry of the microspheres can be determined using Electron Spectroscopy for Chemical Analysis (ESCA). The technique of Electron Spectroscopy for Chemical Analysis (ESCA) makes it possible to ascertain the surface's atomic composition. The spectra obtained by using ECSA can be used to determine the surface degradation of the biodegradable microspheres.

Fourier transform-infrared spectroscopy: the degradation of the polymeric matrix of the carrier system is determined by using the FT-IR. The surface of the microspheres is investigated by measuring Alternated Total Reflectance (ATR). The IR beam that passes through the ATR cell gets reflected many times through the sample to provide IR spectra mainly of surface material. The ATR-FTIR provides information about the surface composition of the microspheres depending on manufacturing procedures and conditions (Tanaka et al., 1977).

Swelling Index: To calculate the swelling index, measure the extent to which microspheres expand when placed in a specific solvent. Assess the equilibrium swelling degree by allowing 5 mg of dried microspheres to swell overnight in a measuring cylinder containing 5 ml of buffer solution (Ingle et al., 2023).

 Use the provided formula to compute the swelling index.

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Entrapment efficiency: The capture efficiency of the microspheres or the per cent entrapment can be determined by allowing washed microspheres to lysate. The lysate is then subjected to the determination of active constituents as per the monograph requirement (Ingle et al., 2023). The per cent encapsulation efficiency is calculated using the following equation:

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The percentage yield: The percentage yield is calculated by dividing the total weight of the medication and polymer used to prepare each batch by the weight of the microspheres obtained from that batch, and then multiplying the result by 100 (Ingle et al., 2023).

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Drug Loading Efficiency: Drug loading is the amount of drug loaded per unit nanoparticle weight, indicating the percentage of nanoparticle weight which is attached to the encapsulated product. Drug loading (%) can be determined by the total amount of drug entrapped, divided by the total weight of nanoparticles. In the delivery of drugs, yield is given as a percentage which represents the amount of drug delivered per quantity (Ingle et al., 2023).

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In Vivo Methods

In vivo methods are utilized to study the permeability of intact mucosa, taking advantage of the biological responses of the organism, either locally or systemically. Historically, the simplest studies of mucosal layer permeability involved observing the systemic pharmacological effects after drug ingestion or absorption through the oral mucosa. Currently, the most common techniques involve the use of animal models, buccal absorption tests, and corneal perfusion chambers to study drug permeability (Prasad et al., 2014). 

Animal Models: Animal models are used to screen a series of compounds to explore the mechanisms and effectiveness of permeation enhancers or to evaluate different formulations. Various animals such as dogs, rats, rabbits, cats, hamsters, pigs, and sheep are commonly used. The procedure includes anaesthetizing the animal and administering the dosage form to be studied. For example, in rats, the esophagus is ligated to prevent absorption pathways other than the oral mucosal layer. The absorption rate is then determined by withdrawing blood samples at different intervals and analyzing them (Prasad et al., 2014). 

Buccal Absorption: Test Known for its simplicity and reliability, the buccal absorption test measures the extent of drug loss in the oral cavity using single or multi-component drug mixtures. This method determines the structure, contact time, pH, and initial drug concentration of the solution when the drug is held in the oral cavity (Rathbone, 1991).

Corneal Perfusion Chambers: The corneal perfusion chamber method is very useful in developing and accessing ophthalmic drugs. This method involves designing and testing a modified perfusion chamber suitable for the topical application of drugs isolated to corneoscleral preparations, allowing continuous monitoring of endothelial cell function. The chamber, made from polycarbonate and stainless steel, clamps corneas in a horizontal plane, making it suitable for topical drug delivery. Endothelial cell function is assessed using ultrasonic pachymetry and specular microscopy during perfusion, while epithelial barrier function is evaluated by measuring fluorescein penetration. Leakage is assessed by measuring the penetration of large proteins, and tissue architecture is examined using conventional histology after perfusion (Thiel et al., 2001).

In Vitro Methods

Beaker Method: In this method, the dosage form is adhered to the bottom of a beaker containing the medium, which is uniformly stirred using an overhead stirrer. The medium volume ranges from 50 to 500 ml, and the stirrer speed varies from 60 to 300 rpm. Samples are withdrawn at intervals to determine the amount of drug dissolved in the medium (Tejash et al., 2016).

Interface Diffusion System: Dearden and Tomlinson developed the interface diffusion system with four compartments. Compartment A represents the oral cavity and contains the drug in a buffer. Compartment B, representing the buccal membrane, contains 1- octanol. Compartment C, representing body fluids, contains 0.2 M HCl. Compartment D, representing protein binding, also contains 1-octanol. Before use, the aqueous phase and 1-octanol are saturated with each other. Samples are withdrawn and returned to compartment A with a syringe. This system allows the determination of drug dissolution in different body compartments by analyzing samples from all four compartments (Prasad et al., 2014).  

Modified KesharyChien cell method: It utilizes equipment specifically designed for laboratory use. This setup includes a KesharyChien cell containing 50 cc of distilled water and a dissolving medium maintained at 37 °C. Within a glass tube, which has a #10 sieve at the bottom and moves back and forth in the medium at a rate of 30 strokes per minute, a TMDDS (Trans Membrane Drug Delivery System) is placed (Kushwaha et al., 2022).

Dissolution apparatus method: The paddle and basket, both rotating components, have been employed in standard USP or BP dissolution apparatuses to assess in vitro release characteristics. The dissolution medium used in the study varies between 100 to 500 ml, with a rotational speed ranging from 50 to 100 rpm (Kushwaha et al., 2022).

Application of Microsphere

Microspheres in vaccine delivery: The condition for vaccinesare immunity to microorganisms and their toxic components. This same need for efficacy, protection, and cost-effectiveness in application and charge should be met by an ideal vaccination. It is difficult to protect yourself and prevent negative consequences. Application mode is closely related to the element of safety and the volume of antibody response manufacturing. The shortcomings of this same biodegradable intravenous vaccine delivery technology may be used to address traditional vaccinations (Sailaja and Begum, 2018).

Microsphere in chemotherapy: The most potential use of microspheres is as delivery systems for anti-tumor medications. Microspheres injected into leaky vasculature resulted in increased endocytic activity. The process of making stealth microspheres involves covering them with soluble polyoxy ethylene. Cancer chemotherapy may potentially benefit from non-stealth microsphere accumulation in the RETiculo Endothelial System (RES) (Singh et al., 2013; Kreuter et al., 1983 & Costa and Lobo, 2001).

Ophthalmic drug delivery: The favourable biological characteristics that microspheres made of polymers exhibit, such as bioadhesion, permeation-enhancing properties, and intriguing physicochemical properties, make them exceptional materials for the creation of ophthalmic drug delivery agents, including gelatin, chitosan, and alginate (Jain, 2004; Jadhav et al., 2013).

Gene delivery: Microspheres may serve as an effective oral gene carrierdue to their GI tract adhesion and transport characteristics. For instance, gene therapy with the administration of insulin, cationic liposomes, chitosan, gelatin DNA plasmid complexes, viral vectors, and polycations. Additionally, since immunity to the bacterium or virus is a requirement for receiving a vaccine, it is helpful in vaccine administration. Itsdangerous by product. Biodegradable delivery technologies for intravenous vaccines may be able to compensate for the drawbacks of conventional vaccinations. Biodegradable microspheres made of polymers have used to encapsulate a number of parenteral vaccines, containing the diphtheria and tetanus vaccination (Hafeli, 2002).

Oral delivery: Microspheres containing polymers are able to form films, allowing for their usage in the creationdose of film shapes alternatively to drug tablet forms. Due to their pH sensitivity and the categories of primary amines reactivity, microspheres are better suited for use in oral drug delivery applications such as chitosan and gelatin (Hafeli, 2002).

Nasal drug delivery: Microspheres, liposomes, and gels are examples of polymer-based drug delivery methods that have been shown to have effective microspheres. As soon as they come into contact with the nasal mucosa, their bioadhesive capabilities and ability to spread quickly are increased. The length of a drug's nasal route of administration and its bioavailability. For instance, starch, dextran, and albumin Gelatin and chitosan (Khan and Doharey, 2014).

7. Buccal drug delivery: Chitosan and sodium alginate are two examples of polymers that are effective for buccal administration because they have mucosal /bioadhesive qualities and can improve absorption (Jain, 2004; Jadhav et al., 2013).

CONCLUSION

Microspheres represent a promising and versatile approach in modern drug delivery systems, offering multiple advantages for both therapeutic and diagnostic applications. Their ability to provide continuous and sustained drug release makes them ideal for enhancing drug efficacy, reducing the frequency of doses, and improving patient compliance. The controlled release of drugs from microspheres can also improve the bioavailability of poorly soluble drugs and offer protection against enzymatic degradation. The various preparation methods, including solvent evaporation, spray drying, and emulsion techniques, provide flexibility in optimizing the drug release profiles to suit specific therapeutic needs. Additionally, the advanced characterization techniques for microspheres, such as particle size analysis, encapsulation efficiency, and surface chemistry evaluation, ensure the quality and effectiveness of these systems. The in vitro and in vivo testing methods further help to refine the application of microspheres, ensuring their optimal performance in drug delivery. With ongoing advancements, microspheres hold significant promise in revolutionizing drug delivery, offering tailored solutions for controlled and sustained release therapies in a range of medical fields, including vaccine delivery and the treatment of chronic diseases.

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