A Review of Microspheres: Types, Formulation Techniques, Characterization and Application

Microspheres are defined as spherical systems consisting of therapeutic agents dispersed either in a molecular (non-granular) system or in large particles within a polymer matrix. They can also be described as structures containing at least one continuous phase of one or more miscible polymers in which evenly dispersed drug particles are present. They typically exist with sizes ranging from 1 to 1000 micro-meters and can be in microcrystalline form, or present some form of drug-dispersion systems in certain solvents or solutions. Examples of drugs within microspheres can be compounded surgical materials or ballistics.

Microspheres and microcapsules are often used interchangeably, yet they represent different structures. When discussing microspheres (micrometrics), they have drug molecules that are evenly dispersed. Microcapsules represent a clear core in a clearly defined polymer shell. Sometimes both are referred to as micro-particles.

Microspheres can be made from any natural or synthetic polymer such as biodegradable polymers, ceramics, glass, or synthetic plastics. Polyethylene and polystyrene are commonly used polymeric microspheres, with polystyrene being of particular interest to biomedical researchers because they have strong binding and anti-ligand capacity for proteins and thus are appropriate for applications like cell sorting, antibody precipitation, and assorted immunoassays.

The primary advantage of microspheres is their ability to control the release of drugs, increasing bioavailability and minimizing side effects. Because of their small size, they can be widely distributed throughout the gastrointestinal tract to improve drug absorption and decrease localized mucosal irritation. Microencapsulation techniques allow delivery properties to be specifically tailored for sustained, delayed, or target delivery, and are therefore extremely valuable in mitigating the limitations of conventional drug regimens.

Microspheres Advantages:

1. Drugs with low solubility are more soluble when their particle size is reduced.
2. The microsphere's therapeutic effect is prolonged and sustained.
3. It maintains a consistent drug level in the blood, improving patient compliance.
4. Reduced toxicity and dosage.
5. They are excellent for drug distribution because they don't promote the enzymatic or photolytic breakdown of the drug.
6. Reduced frequency of dosages enhances patient compliance.
7. Improved use of medicine improves bioavailability and reduces side effects severity or frequency.
8. It helps protect against drug irritant action on GIT.
9. Compared to larger polymer implants, biodegradable microspheres do not require surgical insertion or removal because they are smaller.
10. Drug delivery controls release Biodegradable microspheres are used to control the release of drugs, reducing both toxicity and recurrent injection problems.
11. Odor and taste masking.
12. Liquids and oils are solidified for ease of use.
13. Protected from the environment (moisture, light, etc).
14. Improved powder rheology.
15. It facilitates dispersing water-insoluble compounds in aqueous media.

Limitations of Microspheres:

1. The dosage form will not release as intended.
2. The rate of release can be affected by dietary intake and the gut transit time. 
3. The rate of release can vary from one dose to another.
4. These dosage forms usually have higher drug load so damage to the release properties can increase possible toxicity.
5. The dosage forms should not be crushed into particles or chewed.

Materials Utilized for Preparation of Microspheres:

Polymers are the main materials utilized in microsphere formulation. The polymers are generally classified into two categories:

1. Natural Polymers:

Natural polymers are obtained from biological sources such as carbohydrates, chemically modified carbohydrates, and proteins. These materials are biocompatible, biodegradable, and frequently selected for drug delivery purposes due to their lower toxicity and ease of degradation.

1. Carbohydrates - Examples include:

• Starch
• Agarose
• Chitosan
• Carrageenan

2. Chemically Modified Carbohydrates:

These are altered to enhance their stability, solubility, and ability to carry drugs. Examples include:

• Polysearch
• Polydextran

3. Proteins:

Proteins occurring naturally in microsphere formulations are:

• Collagen
• Albumin
• Gelatine

2. Synthetic Polymers:

Synthetic polymers provide more control of physicochemical properties like degradation rate, mechanical strength, and release kinetics. These are further categorized as:

1. Biodegradable Polymers:

These naturally break down in the body to give non-toxic by-products. Some common examples are:

• Polyanhydrides
• Polylactides (PLA)
• Polyglycolides (PGA)
• Poly(lactic-co-glycolic acid) (PLGA)
• Polyalkyl cyanoacrylates

2. Non-Biodegradable Polymers:

These are employed in a situation where the drug release over an extended period or structural integrity is necessary. Some examples include:

• Polymethylmethacrylate (PMMA)
• Epoxy resins
• Acrolein
• Glycidyl methacrylate

Each of these polymer types possesses unique benefits based on the desired application, release profile, and delivery site. Choice of material is important to making the microsphere-based drug delivery system safe, effective, and functional.

Ideal Microsphere Properties:

In order to be used as successful drug delivery systems, microspheres need to have several ideal properties that would guarantee their therapeutic efficacy, as well as their stability and safety for the patients.

These include:

• Controlled and Sustained Drug Release: It should be feasible for microspheres to release the drug that is encapsulated in them in a manner that is both predictable and sustained so as to achieve uniform therapeutic levels and minimize the dosing frequency.
• Biocompatibility: The materials used for the production of microspheres should be absolutely safe for the human body and should not cause any kind of immune or inflammatory reaction due to which the product will be harmful to the patient.

• Biodegradability: Microspheres should degrade into harmless by-products which are readily removed from the body, particularly for those systems to be used for long-term implantation or application.
• High Drug Loading Capacity: High drug entrapment efficiency is crucial in order to reduce the quantity of carrier material needed and diminish the volume of the total dose.
• Particle Size Uniformity: Even particle size distribution (generally within the 1–1000 µm range) provides consistent drug release, enhanced bioavailability, and enhanced targeting.
• Stability: Microspheres must have no change in their physical, chemical, and functional integrity upon storage and over the course of the intended shelf life.
• Surface Properties: The microsphere surface should be smooth and can be altered to improve targeting capacity, minimize aggregation, and optimize interaction with biological systems.
• Reproducibility: The manufacturing process should repetitively produce microspheres with consistent properties from batch to batch.
• Sterilizability: Microspheres must be sterilizable without damage to their structure or drug content, especially for parenteral or implantable purposes.
• Ease of Administration: Microspheres must be easily administered via standard routes like oral, injectable, or inhalable form, depending on the use.

Types of Microspheres:

Microspheres are drug delivery systems with varied functionalities, compositions, or administration routes. The following are the broad types frequently researched and utilized in pharmaceutical and biomedical applications:

1. Bio adhesive Microspheres:

Bio adhesive microspheres are made to stick to mucosal surfaces like the buccal, ocular, nasal, rectal, and vaginal membranes with the help of water-soluble polymers. The sticking of bio adhesive microspheres at the place of absorption increases the time of stay at the site of absorption, hence enhancing drug bioavailability and therapeutic action by intimate and continuous contact with the absorption surface.

Fig.1 - Bio adhesive Microspheres

Magnetic microspheres are injected into the body for targeted drug delivery along with external magnetic fields. The systems use magneto tactic materials (e.g., chitosan, dextran) to move the microspheres to the desired location and thus expose less drug to the body.

Therapeutic Application: Delivery of chemotherapeutic drugs, especially for liver tumors.

Diagnostic Application: Used in imaging (e.g., detection of liver metastases) with super paramagnetic iron oxide nanoparticles.

3. Diagnostic Microspheres:

These microspheres are specially made for visualizing and diagnostic purposes. Besides being combined with or carrying drugs, contrast agents may also be injected into magnetic microspheres for local imaging of a given area due to the deposit of the target tissue under the influence of an external magnetic field.

4. Floating Microspheres:

Floating or gastro-retentive microspheres have a lower density than the gastric fluids so they float and stay in the stomach for longer periods. This extends gastric residence time, improves drug absorption in the upper gastrointestinal tract, and ensures controlled drug release, lowering dosing frequency and plasma drug fluctuation.

Fig.2 - Floating Microspheres

Radioactive microspheres are administered mainly for radio embolization therapy to treat cancer, especially liver cancers. They are usually 10–30 µm in size (larger than capillaries) and are injected intra-arterially, where they selectively become lodged within the tumour vasculature. The microspheres give off localized radiation (α, β, or γ rays), which delivers high doses to tumour tissue without damaging healthy tissue.

6. Mucoadhesive Microsphere:

Mucoadhesive microspheres are designed to stick to mucosal surfaces for the improvement of both localized and systemic drug release. Advantages are extended contact with the mucosa, greater drug absorption, improved bioavailability, and site-specific delivery. They can be administered through any of the mucosal routes such as ocular, nasal, gastrointestinal, and urinary tracts.

7. Polymeric Microsphere:

Polymeric microspheres are categorized depending on the polymer used:

1. Biodegradable Polymeric Microspheres:

Prepared from materials like PLGA, polylactic acid, and polyglycolic acid, these microspheres disintegrate into non-toxic products and are suited for controlled and sustained release.

2. Synthetic Non-Biodegradable Polymeric Microspheres:

Made of polymers including Polymethylmethacrylate (PMMA), these microspheres exhibit drug release over a long period and structural integrity where biodegradability is not needed.

Fig.3 - Biodegradable and Non-Biodegradable Polymeric Microspheres

There are numerous ways to make microspheres depending on the size, shape, drug release profile, and polymer type. The main classes of methods for preparing microspheres are physical, chemical, and physicochemical ones.

1. Single Emulsion Technique:

This method is largely used for the fabrication of microspheres from natural polymers such as proteins and carbohydrates. The polymer is dissolved in water and then, to disperse it, a non-aqueous medium (for instance, oil) is added. An emulsion of water-in-oil (w/o) is thus obtained. The crosslinking of the dispersed globules can be carried out by heat or by using chemical agents (e.g., glutaraldehyde, formaldehyde). Nevertheless, chemical cross-linking can make the drug contaminated with toxic reagents and affect drug stability and bioactivity.

Fig.4 - Single Emulsion Technique

The Double Emulsion (W/O/W) method is designed for the encapsulation of water-soluble drugs, proteins, peptides, and vaccines and is essentially the manufacture of a water-in-oil-in-water (W/O/W) emulsion. The drug in the internal aqueous phase is first combined with a polymer-dissolved organic phase and then, an external aqueous phase is added and mixed again. The method enables not only a high encapsulation efficiency but also the safety of the biomolecules that are fragile.

Fig.5 - Double Emulsion Technique (W/O/W)

One of the methods to produce microspheres is through polymerization where the monomers are subjected to chemical reactions that lead to the formation of polymer chains, which, in turn, encapsulate the drug.

1. Conventional Polymerization: It comprises the main processes of bulk, suspension, precipitation, emulsion, and micellar polymerization. The drug release can be either during or after polymerization. In suspension polymerization (sometimes called pearl polymerization), the monomers are suspended in a water medium.
2.  Interfacial Polymerization: Describes the reaction between monomers at the interfaces of two immiscible liquids that results in the formation of a polymer membrane around the core material.

4. Phase Separation (Coacervation) Technique:

The method exploits the separation of a polymer-rich phase (Coacervation) from a solution by adding a non-solvent or an incompatible polymer. The coacervation phase holds the drug and is attached to the microspheres to be fixed. Hydrophilic, hydrophobic, and lipophilic drugs can be encapsulated by this method, generally resulting in a high drug load.

Fig.6 - Phase Separation (Coacervation) Technique / Coacervation method

5. Spray Drying Technique:

One of the most frequent methods in which a drug solution with a polymer is sprayed into a hot chamber for drying, whereby the solvent is rapidly evaporated, and dry microspheres are formed. Besides this, it allows the production of a large quantity, the control of the particle size (generally 1–100 µm) and the use of materials that are sensitive to heat because of a short time of exposure.

Fig.7 - Spray Drying Technique

Essentially the same process as spray drying, however the microcapsules are solidified by the cooling of the molten blend or by the spraying into a non-solvent. Hence the method is suitable for drugs in the lipophilic phase and for substances like waxes, fatty acids, and polymers with a melting point of about 25°C (77°F).

Fig.8 - Spray Congealing Technique

The water-based polymer solutions (for instance, gelatine) are mixed with oil to make a w/o emulsion. After that, the cross-linking is activated by the use of a chemical such as glutaraldehyde. Generally, this technique is utilized in the manufacturing of gelatine-based microspheres and is suitable for hydrophilic drugs.

7. Solvent Evaporation Technique:

The drug is either dissolved or dispersed in a polymer solution and then, emulsified in a non-mixed continuous phase (generally oil). As the solvent is evaporated, microspheres are formed. This process is widely used for PLGA-based formulations and allows the production of monodisperse particles with tailored release profiles.

8. Ionic Gelation Technique:

This is a gentle, water-soluble method that is perfect for the encapsulation of biomolecules that are sensitive to the process. Alginate or chitosan type polymers are ionically cross linked by using divalent or trivalent cations (e.g., Ca²?, Al³?). The microspheres solidify when they come into contact with the ionic solution and are further stabilized. Besides being pH-sensitive, it also enables targeted delivery, mainly adapted to the intestinal environment.

Fig.9 - Ionic Gelation Technique