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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright   © 2024 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                                         Review Article

A Review on Microspheres as a Promising Drug Carrier 

Mohini Yadav ¹*, Trushali A. Mandhare ², Vaishnavi Jadhav ¹, Dr. Kishor Otari ³

¹ Department of Pharmaceutics, Navshyadri Institute of Pharmacy, Pune 412213, Maharashtra, India. 

² Assistant Professor, Department of Pharmaceutics, Navshyadri Institute of Pharmacy, Pune 412213, Maharashtra, India.

³ Principle, Department of Pharmacology, Navshyadri Institute of Pharmacy, Pune 412213, Maharashtra, India. 

 

 

1. Introduction:

Microspheres are spherical particles that range in diameter from 10 μm to 1000 μm. Microspheres are essential for improving the way conventional drugs are absorbed and lessening their side effects. The controlled release of the medicinal content is the primary benefit of using microspheres as a drug delivery mechanism. By postponing the medication's release from dose forms, microencapsulation reduces adverse effects and enhances patient adherence. This method uses emulsion solvent diffusion evaporation to coat an aqueous insoluble coat (polymer) over an aqueous insoluble core (drugs) to create a sustained release drug delivery system. There are various methods for making microspheres, such as phase separation, spray-dry, and emulsification using single or double solvent evaporation systems. 

One method for creating microspheres is to dissolve the precursor components in volatile solvents and then disperse them in a different solvent that isn't miscible with the first one. A fine powder known as microspheres that is soluble in water will be produced when the last solvent has completely evaporated. Medication with a brief half-life that is merely transferred from the gastrointestinal tract (GIT) is instantly eliminated from the bloodstream¹.

In order to circumvent this issue, oral sustained or controlled release (CR) has also been created. This method will gradually release the drug into the gastrointestinal tract and maintain a constant level of medicine intensity in the plasma for an extended amount of time. A dose formulation that achieves the necessary plasma therapeutic drug concentration and stays stable over the course of the treatment is considered appropriate. This can be accomplished by administering a conventional dosage form at a predetermined frequency and dose. They have the advantage of not being microcarriers since nanoparticles act locally by migrating into the interstitium within the lymphatic system's 100 nm range.

Most certainly, dangerous materials can be transported. Dried microparticles can be considered solids rather than liquids once encapsulated. The intake dose is administered as a series of discrete, small multiarticulate particles, each of which retains and releases a portion of the dosage; hence, the failure of one subunit has no effect on the overall dosage failure. In order to facilitate the release of medication into the skin, microparticles are employed in skin applications. This helps to ensure that the drug stays localized at the application site and does not unnecessarily reach the systemic circulation. They serve as a reservoir that releases an active ingredient gradually over time to keep medication items at an appropriate concentration in the skin while minimizing unwanted side effects. As a result, there are fewer cycles of over- and under-medication. In the treatment of infectious diseases, it is particularly pertinent to the decrease of antibiotic resistance. Additionally, by integrating the product into the proper vehicle, these distribution methods can improve product safety² .

1.1 Polymer used for formulation of microspheres:

Polymers are typically utilized as microspheres. They fall into two categories.

• Synthetic polymers
• Natural polymers

Synthetic polymers are divided into two types.

Non-biodegradable polymers

• Poly methyl methacrylate (PMMA)
• Acrolein
• Glycidyl methacrylate
• Epoxy polymers

Biodegradable polymers

• Lactides, Glycosides & their co polymers
• Poly alkyl cyano Acrylates
• Poly anhydrides^3,4.

Natural polymers obtained from different sources like Proteins, carbohydrates and chemically modified Carbohydrates

Proteins

• Albumin 
• Gelatin
• Collagen

Carbohydrates

• Agarose
• Carrageenan
• Chitosan
• Starch

Chemically modified carbohydrates

• Poly dextran
• Poly starch^5,6.

1.2 Advantages of Microspheres:

• Reduction in size leads to an increase in surface area and can boost the strength of the poorly soluble substance.
• Reducing dose and risk. 
• Maintaining a constant level of medication in the body to enhance patent compliance.
• Polymer-based drug packaging keeps the medication from undergoing enzymatic cleavage while allowing it to be used with a drug delivery system.
• Shorter dosage intervals increase patient compliance⁷.

1.3 Disadvantages of Microspheres:

• The modified formulation-based releases.
• The controlled dosage process's release rate, which varies depending on a number of variables including nutrition and levels of transfer via the intestines.
• Differences in the rate of discharge between doses.
• Chewing or breaking these dosage forms is not permitted.
• There is less reproducibility⁸. 

1.4 Pre-requisites for ideal micro particulate carriers:

Pre-requisites for optimal micro particle carriers include meeting the following requirements.

• Extended duration of effect 
• Control of content release 
• Increase in therapeutic efficacy 
• Drug protection
• toxicity reduction
• Biocompatibility 
• Sterilizability 
• Relative stability
• Water solubility or dispersibility 
• Target ability 
• Polyvalent⁹

2. Type of Microspheres:

Microspheres are classified into different types. They are of following

2.1 Bioadhesive microspheres 

2.2 Magnetic microspheres 

2.3 Floating microspheres 

2.4 Radioactive microspheres

2.5 Polymeric microspheres 

    2.5.1 Biodegradable polymeric microspheres

    2.5.2 Synthetic polymeric microspheres

2.1 Bioadhesive microspheres:

Adhesion refers to how a drug adheres to a membrane using a water-soluble polymer. Bio adhesion is the phrase used to describe the adherence of a medication delivery device to a mucosal membrane, such as the nasal, rectal, ophthalmic, or buccal. These microspheres produce superior therapeutic activity because they stay longer at the application site, form close contact with the absorption site, and have a longer residence time. To have a way to give the drug delivery system and the absorbent membranes close contact, it would be beneficial to manufacture bioadhesive microspheres. Because of its superior bioadhesive qualities, Polycarbophil was choosen as the polymer for the creation of bioadhesive microspheres¹⁰.

2.2 Magnetic microspheres:

A targeted medicine delivery system is essential for treating illnesses. Magnetic targeting allows for a lower amount of treatment to replace more freely circulating drugs. Incorporated materials used to create magnetic microspheres respond magnetically to a magnetic field through magnetic carriers. medicines that dissolve in water (lipophilic medicines also require the dispersing agents) and 10 nm magnetite (Fe₃O₄) particles are combined in an aqueous solvent of the matrix material to create magnetic microspheres. After that, the oil is used to emulsify this combination. To create particles in the appropriate size range, ultrasonication or shearing are used. The matrix is then heated or chemically cross-linked to stabilize it. 

 I] Therapeutic magnetic microspheres

II] Diagnostic microspheres¹¹

2.3 Floating microspheres:

Because the bulk density of floating kinds is lower than that of gastric fluid, they float in the stomach without slowing down the pace at which the stomach empties. The medication is released gradually at the desired pace if the stomach material is floating in the system, lengthening the duration of gastric residency and causing more variations in plasma concentration. By producing a sustained therapeutic impact, this approach lowers the frequency of dose. Sink particles will disperse over a wide region of absorption sites with each consecutive gastric emptying, improving the likelihood of a more or less predictable drug release profile and absorption. Furthermore, there is less chance of dosage dumping because each dose is made up of several subunits¹².

2.4 Radioactive microspheres:

Radioembolization treatment involves inserting 10-30 nm microspheres, which are larger than capillaries, into the first capillary bed they encounter. They are injected into the arteries that supply the targeted tumor. Radioactive microspheres provide targeted radiation doses without harming neighbouring healthy tissues. There are three different types of radioactive microspheres: those that emit α, β, and γ. The subset of microspheres that interact radioactively is usually treated similarly to non-radioactive microspheres. Radioactive microspheres contain radio-nuclides in addition to matrix material, allowing for targeted delivery to certain tissues or organs. Radioactive microspheres can provide significant radiation doses to specific areas in small numbers without injuring surrounding tissue^13,14. 

2.5 Polymeric microspheres:

Polymeric microspheres can be classed as biodegradable or non-biodegradable.

 

 

2.5.1 Biodegradable polymeric microspheres:

Starch is used because of its biodegradability, biocompatibility, and bioadhesive properties. When biodegradable polymers come into touch with mucous membranes, they stay longer because of their high degree of swelling property with aqueous medium, which causes gel to form. The polymer concentration and the sustained release pattern regulate the drug's release rate and extent. The primary disadvantage is the complexity and difficulty in controlling drug release associated with the drug loading efficiency of biodegradable microspheres in clinical settings. On the other hand, they offer a broad range of applications in microsphere-based therapy¹⁵ 

2.5.2 Synthetic polymeric microspheres:

Synthetic polymeric microspheres are commonly employed in therapeutic applications. However, their tendency to migrate away from the injection site poses a danger of embolism and organ injury¹⁶.

3. Methods of Preparation:

Certain requirements should be met when preparing microspheres.

• The ability to incorporate drug at reasonable concentrations
• Stability of the preparation following synthesis with a clinically acceptable shelf-life
• Controllable particle size and dispensability in aqueous vehicles for injection
• Good control over the release of the active agent over an extended period of time 
• Biocompatibility with controlled biodegradability, and susceptibility to chemical modification are the six factors that need to be considered¹⁷.

 

 

 

Figure 1: Technique for Microspheres preparation¹⁰

 

3.1 Single emulsion technique:

Natural polymers, such as ex-carbohydrates and proteins, can serve as microparticulate carriers when created using a single emulsion process. Natural polymers are dissolved or distributed in non-aqueous mediums, such as oils. In next step, cross linking is carried out by either of two following methods;¹⁸.

3.1.1 Cross linking by heat:

Cross linking by heat is carried out by adding the dispersion, to previously heated oil. Heat denaturation is however, not suitable for the thermolabile drugs.

3.1.2 Chemical cross linking:

Chemical cross liking is done with the help of agents such as glutraldehyde, Formaldehyde, terephthaloyl chloride, diacid chloride, etc. This approach has the problem of exposing active components to chemicals if chitosan solution (in acetic acid) is added to liquid paraffin with a surfactant during preparation, resulting in a w/o emulsion. To make metformin hydrochloride microspheres, a 25% solution of glutaraldehyde is used as a crosslinking agent¹⁹.

 

 

Figure 2: Single emulsion technique¹³

 

3.2 Double emulsion technique:

The method of double emulsion solvent evaporation/extraction is ideal for incorporating water-soluble drugs, peptides, proteins, and vaccines into microspheres. It involves dispersing a protein solution in a lipophilic organic continuous phase, homogenizing it, and adding polyvinyl alcohol to form a double emulsion. The emulsion is then removed by solvent evaporation or extraction, resulting in solid microspheres. This method has been successfully used to incorporate hydrophilic drugs, vaccines, proteins/peptides, and conventional molecules.

 

Figure 3: Double emulsion technique¹⁴

3.3 Polymerization technique:

Microspheres are prepared using many polymerization processes, including:

• Normal polymerization 
• Interfacial polymerization

3.3.1 Normal polymerization:

Bulk polymerization:

To start the polymerization and complete the process, a monomer or a combination of monomer and initiator is often heated. To help or quicken the pace of the reaction, the catalyst or initiator is introduced to the reaction mixture. The resulting polymer can be broken up into microspheres or molded. Adsorptive drug loading or drug addition during the polymerization process are two possible approaches for drug loading.

The suspension polymerization:

Heating the monomer or combination of monomers containing active ingredients (drugs) as droplets dispersing in a continuous aqueous phase is how it is done. Other additives and an initiator could also be included in the droplets.

The emulsion polymerization:

Nonetheless, is distinct from suspension polymerization since the initiator is present in the aqueous phase and diffuses to the micelle or emulsion globule surface afterwards¹⁷.

3.3.2 Interfacial polymerization:

The interfacial polymerization process involves two reactive monomers, one dissolved in the continuous phase and the other distributed there. The second monomer is emulsified during the continuous phase, often aqueous. The monomers diffuse quickly and polymerize quickly at the interface. The polymer's solubleness in the emulsion droplet can affect the carrier form. Temperature, vehicle composition, monomer concentration, and reactivity can affect polymerization. Particle size can be regulated by adjusting the size of dispersed phase droplets or globules. Controlling the polymerization process requires maintaining monomer concentration.

 

 

 

 

Figure 4: Polymerization technique¹⁶

 

3.4 Phase separation coacervation technique:

Specifically made to prepare the reservoir type of the system, that is, to encapsulate pharmaceuticals that are soluble in water, like as proteins and peptides, and medications that are hydrophobic, like steroids. The medication or protein in a matrix-type device is soluble in the polymer phase. The method works on the basis of reducing the polymer's solubility in the organic phase to influence the development of the coacervates, a polymer-rich phase. The creation of two phases, one of which is the supernatant depleted of polymer, can be caused by adding a third component to the system, therefore exacerbating the situation. This method involves dissolving the polymer in an appropriate solvent first, and then dispersing the drug if hydrophilic in an aqueous solution or if hydrophobic by dissolving it in the polymer solution itself. Next, phase separation is achieved by adjusting the conditions of the solution^21,18. 

 

 

Figure 5: Phase separation coacervation technique¹⁷

 

3.5 Spray drying and spray congealing:

Spray drying and spray congealing are two processes that occur when the solvent is removed or the solution cools. The fundamental process of spray drying is evaporation, while the mechanism of spray congealing is a phase inversion from a liquid to a solid. With the exception of energy flow, both procedures are comparable. The most used industrial method for drying and forming particles is spray drying. Because of this, spray drying is the best method when the final product needs to meet exacting requirements for bulk density, particle shape, residual moisture content, and particle size distribution.

Principle: Spray drying consists of three phases:

• Atomization: the transformation of a liquid stream into tiny droplets. 
• Mixing: this process includes directing a hot gas stream through spray droplets, causing liquids to evaporate and leaving behind dry particles. 
• Dry: The powder is collected after being dried and removed from the gas stream.

The method of double emulsion solvent evaporation/extraction is ideal for incorporating water-soluble drugs, peptides, proteins, and vaccines into microspheres. It involves dispersing a protein solution in a lipophilic organic continuous phase, homogenizing it, and adding polyvinyl alcohol to form a double emulsion. The emulsion is then removed by solvent evaporation or extraction, resulting in solid microspheres. This method has been successfully used to incorporate hydrophilic drugs, vaccines, proteins/peptides, and conventional molecules.

 

 

 

Figure 6: Spray drying and spray congealing²⁰

 

 

3.6 Solvent extraction:

For the emulsion to develop between the polymer solution and an immiscible continuous phase in both the non-aqueous (w/o) and aqueous (o/w) phases. In their 2000 study, Bogataj et al. used the evaporation technique to create microspheres utilizing liquid paraffin and acetone as solvents. After dispersing the medication solution (in acetone) in chitosan solution, the combination was emulsified in liquid paraffin and agitated. The microsphere suspension underwent filtration, washing, and drying. Additionally, magnesium stearate was used as an agglomeration-preventing agent. The findings demonstrated that as the amount of magnesium stearate utilized to prepare the microspheres increased, the average particle size dropped. examined the comparison between hyaluronic acid and gelatin microcapsules made by complicated coacervation and mucoadhesive microspheres of hyaluronic acid, chitosan glutamate, and a mixture of the two made by solvent evaporation^24,25.

 

 

 

Figure 7: Solvent Extraction Technique²¹

 

 

4. Evaluation of Microspheres:

4.1 Particle size and shape:

Scanning electron microscopy (SEM) and conventional light microscopy (LM) are commonly used to study microparticles, revealing their external structure and form. LM allows control over coating settings, while SEM offers higher resolution. Conflocal fluorescence microscopy characterizes multiple-walled microspheres, while laser light scattering and multisize Coulter counter can also be used²⁶.

 

4.2 Electron spectroscopy for chemical analysis:

Confocal fluorescence microscopy evaluates structural features of microspheres with many walls. In addition to instrumental approaches, multisize microspheres can be examined for size, shape, and morphology. Coulter Counter and Laser Light Scattering^27,38.

4.3 Attenuated total reflectance Fourier Transform-Infrared Spectroscopy:

The carrier system's polymeric matrix degradation is assessed using FT-IR. Alternate total reflectance (ATR) is mainly used to measure the surface of the microspheres. Infrared spectra of the sample's surface material were mostly obtained by many reflections of the IR beam that passed through the ATR cell. ATR-FTIR analysis yields surface composition information about the microspheres based on circumstances and production processes.

4.4 Density determination:

A multivolume pycnometer can determine the density of microspheres. The multi volume pyrometer is filled with a precisely weighed sample that is placed in a cup. The chamber is filled with constant pressure helium, which is then allowed to expand. The pressure inside the chamber decreases as a result of this expansion. There are two sequential pressure decrease readings recorded, each at a different beginning pressure. Two pressure readings are used to calculate the volume and, consequently, the density of microsphere carriers²⁸.

4.5 Isoelectric point:

An instrument called a micro electrophoresis is used to evaluate the electrophoretic mobility of microspheres in order to identify their isoelectric point. Particle movement over a distance of 1 mm is timed to determine the mean velocity at various pH levels between 3 and 10. This information can be utilized to determine the particle's electrical mobility. The electrophoretic mobility of microspheres is influenced by their surface charge, ionisable behaviour, and ion absorption^27,37.

4.6 Drug entrapment efficiency:

A measured quantity of microspheres is removed and broken apart. then, with the aid of a stirrer, dissolved in buffer solution and filtered. Using a calibration curve, the filtrate is tested at a certain wavelength using a UV spectrophotometer ³⁹.                                                 

Drug Entrapment efficiency =    × 100                                                        

4.7 Percentage yield:

It is computed by dividing the total weight of the medicine and polymer needed to make each batch by the weight of microspheres that were obtained from it, then multiplying the result by 100

4.8 Swelling index:

It is ascertained by measuring the degree of microsphere swelling in a certain solvent. To achieve equilibrium swelling, five milligrams of dried microspheres are mixed with five millilitres of buffer solution and kept overnight in a measuring cylinder. It is computed using the provided formula.

Swelling index =  × 100                                                                                                                                                                           

4.9 In vitro methods:

This approach determines a drug's membrane permeability and release qualities. The in vitro approach is used in product development, pharmaceutical manufacturing, and other areas as a quality control procedure. It is essential to have sensible and repeatable release data that are generated from settings that are chemically, physically, and hydrodynamically characterized^26,27.

4.10 Interface diffusion method:

Dearden and Tomlinson devised this methodology. There are four sections in it. Compartment A, which symbolizes the oral cavity, started out with a suitable amount of medication in a buffer. One octanol is found in compartment B, which represents the buccal membrane, and 0.2M HCl is found in compartment C, which represents bodily fluids. One octanol is also present in compartment D, which symbolizes protein binding. The 1-octanol and aqueous phases are saturated with one another before to use. The samples are taken out and placed back into compartment A using a syringe^18,36.

4.11 In vivo method:

The permeability of intact mucosa is evaluated using techniques that offer biological reactions locally or systemically, as well as direct assessments of drug absorption or accumulation at the surface. A typical way to doing in vivo investigations is the use of animal models and buccal absorption tests²⁰.

4.12 Animal models:

Its primary uses include screening a range of chemicals, looking into their mechanisms, and assessing a number of formulations. There are reports on animal models, including pigs, lambs, dogs, and rats. The process usually entails anesthetizing the animal, giving the dosage, taking blood samples at various intervals, and analyzing²².

4.13 Buccal absorption test:

This technique is reliable for determining drug loss from the human oral cavity for both single- and multi-component medication mixes. It has been used to investigate the impact of drug structure, contact time, initial drug concentration, and solution pH on drug retention. Human volunteers swirl a 25 ml sample of the test solution for 15 minutes²⁵.

5. Application of microspheres:^29,30

5.1 Microspheres in vaccine delivery:

A vaccination requires immunity to the microbe or any of its harmful byproducts. The perfect vaccination should meet the following criteria: it should be affordable, safe, easy to use, and effective. Safety and minimizing negative responses are two complicated issues. The technique of administration has a direct bearing on both the safety factor and the level of antibody response. One potential solution to address the shortcomings of traditional vaccines is the use of biodegradable delivery vehicles for parenteral vaccinations. Parenteral (subcutaneous, intramuscular, and intradermal) carriers are of interest because they provide a number of benefits, such as:

• Improved antigen city by adjuvant action
• Modulation of antigen release
• Stabilization of antigen.

5.2 Targeting using micro particulate carriers:

Targeting, or site-specific medication delivery, is a well-established idea that is receiving a lot of attention. The drug's ability to specifically engage and get access to its target receptors determines how effective it is as a treatment. The drug action is mediated by the employment of a carrier system, which allows the drug to exit the pool in a repeatable, effective, and targeted manner^31,35.

5.3 Monoclonal antibodies facilitated microspheres targeting:

Immunological microspheres are those that are targeted by monoclonal antibodies. Selective targeting to particular places is accomplished using this targeting. The molecules known as monoclonal antibodies are very selective. Monoclonal antibodies (Mabs) with their high specificity can be used to direct microspheres containing bioactive compounds to specified locations. By covalent coupling, mab spheres may be directly linked to the microspheres. The antibodies can be attached to the free aldehyde, amino, or hydroxyl groups on the microspheres' surface. Microspheres can be equipped with maps using any of the following techniques:

• Nonspecific adsorption and specific adsorption
• Direct coupling 
• Coupling via reagent^40.

5.4 Imaging:

The microspheres have been utilized for targeting and have undergone substantial research. Radiolabeled microspheres can be used for imaging a variety of cells, cell lines, tissues, and organs. When it comes to imaging specific areas, the microspheres' variety of particle sizes is crucial. The intravenous particles will become caught in the lung's capillary bed if they are injected somewhere other than the portal vein. Labelled human serum albumin microspheres are used to image lung tumours using scintigraphy³².

5.5 Topical porous microspheres:

Microsponges are porous microspheres with interconnecting gaps ranging in particle size from 5 to 300 µm. They contain active chemicals and can be used in creams, lotions, and powders. Microsponges are effective topical transporters for a variety of active substances, including emollients, perfumes, and essential oils. Microsponges are non-collapsible structures with porous surfaces, allowing for controlled release of active chemicals^33,34.

6. 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 increasing numbers of studies in which microspheres have been used in more diverse applications and it is evident that the range of potential applications is enormous. 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.

Acknowledgment: 

Would like to thank our guide Mrs. Trushali. A. Mandhare who took his valuable time to guide us throughout the process.

Conflict of interest:

The authors have no conflicts of interest.

Funding source:

No specific grant from any funding agency. 

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