Drug Delivery Systems (DDS) is a strategic tool for growing markets/signs, expanding item life cycles and creating opportunities. DDS make a noteworthy commitment to worldwide pharmaceutical deals through market division, and are developing day by day quickly. DDS are winding up progressively modern as pharmaceutical researchers obtain a superior comprehension of the physicochemical and biochemical parameters relevant to their exhibition¹. In spite of enormous headways in drug delivery, multiparticulate oral dose structures obtained an inside stage in the field of pharmaceutical innovative work for accomplishing the deferred discharge oral definitions; in this way give gigantic chances and broadening the outskirts of future pharmaceutical improvement.

These formulations release the drug at a time instead of quickly after administration into the body. It also offers structure adaptability and clinical advantages than single units, for example, short gastric retention time, reduce peak plasma fluctuations, and minimize the potential side effects due to dose dumping and numerous technological, therapeutical advantages over single- unit forms ². Multiparticulate drug delivery systems (MDDS), frequently used through oral route, comprise of the variety of little discrete units that display various qualities. Together, these qualities offers the desired controlled release of the dose. It depends on subunits such as granules, beads, microspheres, pellets, spheroids and Minitab. In MDDS, drug substances are isolated into number of subunits, commonly comprise of thousands of round particles having width of about 0.05-2.00 mm. To manage or to suggest absolute portion of these subunits are packed into a tablet or filled into a sachet or capsules³.

Microspheres:

Oral route of drug administration is the most preferable route for taking medications. However, their short circulating half-life and restricted absorption via a defined segment of intestine limits the therapeutic potential of many drugs. Such a pharmacokinetic limitation leads in many cases to frequent dosing of medication to achieve therapeutic effect. Rational approach to enhance bioavailability and improve pharmacokinetic and pharmacodynamics profile is to release the drug in a controlled manner and site specific manner. Microspheres are small spherical particles, with diameters 1μm to 1000μm. They are spherical free flowing particles consisting of proteins or synthetic polymers which are biodegradable in nature. There are mainly two types of microspheres; microcapsules and micromatrices, which are described as, Microcapsules are those in which entrapped substance is distinctly surrounded by distinct capsule wall and micromatrices in which entrapped substance is dispersed throughout the matrix. These microspheres are categorized on the basis of their therapeutic effect and properties described as below and was shown in Figure 1. Microspheres are sometimes referred to as microparticles. Microspheres can be manufactured from various natural and synthetic materials. Microsphere play an important role to improve bioavailability of conventional drugs and minimizing side effects^4-8.

Ideal characteristics of microspheres:

1. Microsphere size may be critical to the proper function of an assay, or it may be secondary to other characteristics. Considering traditional diagnostic methods, the test or assay format commonly dictates particle size, such as the use of very small spheres (~0.1- 0.4μm) to ensure satisfactory wicking in lateral flow tests, or the use of larger, cell-sized spheres (~4-10μm) for bead-based flow cytometric assays.

2. Common microsphere compositions include polystyrene (PS), poly-methyl methacrylate (PMMA), and silica. These materials possess different physical and optical properties, which may present advantages or limitations for different applications. Polymer beads are generally hydrophobic, and as such, have high protein binding abilities. However, they often require the use of some surfactant (e.g. 0.01-0.1% Tween® 20 or SDS) in the storage buffer to ensure ease of handling. During synthesis, functional monomers may be co-polymerized with styrene or methyl methacrylate to develop beads with surface reactive groups. Functional groups may be used in covalent binding reactions, and also aid in stabilizing the suspension. Silica microspheres are inherently hydrophilic and negatively charged. Consequently, aqueous silica suspensions rarely require use of surfactants or other stabilizers. Carboxyl and amine functionalized silica spheres are available for use in common covalent coating protocols, and plain silica microspheres may be modified using a variety of silanes to generate functional groups or alter surface properties.

3. Microspheres may be coated with capture molecules, such as antibodies, oligonucleotides, peptides, etc. for use in diagnostic or separation applications. Microsphere coatings are typically optimized to achieve desired specific activity, while minimizing nonspecific interactions. Consideration should also be given to the required stability, development time frame and budget, and the specific biomolecule to be coated. These factors will aid in determining the most fitting coating strategy for both short and long-term objectives. Standard microsphere products support three basic coating strategies: adsorption, covalent coupling, and affinity binding.

4. Many applications in the life sciences demand added properties, such as fluorescence or a visible colour, or iron oxide inclusions for magnetic separations. Polymer spheres (and polymer based magnetic spheres) are often internally dyed via organic solvent swelling, and many standard products are available. Dye concentrations can be adjusted to produce beads with different intensities to meet special needs, such as Quantum Plex™ for multiplexed flow cytometric assays, or our Dragon Green or Flash Red Intensity Standards, which support imaging applications and associated instrument QC. Many surface or internally labelled fluorescent beads are also available as specialized flow cytometry standards ⁹.

Advantages of microspheres:^{10, 11}

1. Microspheres provide prolonged and constant therapeutic effect.

2. Microspheres reduce the dosing frequency and therefore improve the patient compliance.

3. Microspheres provide controlled, sustained and targeted delivery of the drug.

4. Microspheres produce more reproducible drug absorption.

5. Drug discharge in stomach is hindered and that’s why local unwanted effects are reduced.

6. In case of microspheres, better therapeutic effect for short half-life of drugs can be achieved.

7. Microspheres provide freedom from drug and recipients incompatibilities especially with buffer.

8. Microspheres reduce dose dumping and provide the protection of drugs against environment.

9. Microspheres also mask the taste and odour.

10. Microspheres avoids the first pass metabolism and reduce the chances of G.I. irritation.

11. Microspheres enhance the biological half-life and also improve the bioavailability.

Disadvantages of microspheres: ¹²

Some of the disadvantages were found to be as follows

1. The modified release from the formulations.

2. The release rate of the controlled release dosage form may vary from a variety of factors like food and the rate of transit though gut.

3. Differences in the release rate from one dose to another.

4. Controlled release formulations generally contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage form may lead to potential toxicity.

5. Dosage forms of this kind should not be crushed or chewed.

Polymers used to prepare Microspheres:

Microspheres used usually are polymer and A polymer (/ˈpɒlɪmər/; Greek poly-, "many" + -mer, "part") is a large molecule, or macromolecule, composed of many repeated subunits ¹³.

They are classified into two types:

1. Synthetic Polymers

2. Natural polymers

1. Synthetic polymers:

These are divided into two types.

a) Non-biodegradable polymers:

Poly methyl methacrylate (PMMA), Acrolein, Glycidyl methacrylate, Epoxy polymers.

b) Biodegradable polymers:

Lactides, Glycolides & their copolymers, Poly alkyl cyanoacrylates, Poly anhydrides.

2. Natural polymers:

Natural polymer 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 ¹⁴.

Types of Microspheres:

Figure 1: Pictorial Representation of Microsphere’s types

1. Bioadhesive microspheres:

Adhesion can be defined as sticking of drug to the membrane by using the sticking property of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane such as buccal, ocular, rectal, nasal etc can be termed as bioadhesion. The term “bioadhesion” describes materials that bind to biological substrates’, such as mucosal members. Adhesion of bioadhesive drug delivery devices to the mucosal tissue offers the possibility of creating an intimate and prolonged contact at the site of administration. This prolonged residence time can result in enhanced absorption and in combination with a controlled release of drug also improved patient compliance by reducing the frequency of administration. Carrier technology offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such as microspheres, nanospheres, liposomes, nanoparticles, etc., which modulates the release and absorption of the drug. Microspheres constitute an important part of these particulate drug delivery systems by virtue of their small size and efficient carrier capacity¹⁵.

2. Magnetic microspheres:

This kind of delivery system is very much important which localises 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. Therapeutic magnetic microspheres are used to deliver chemotherapeutic agent to liver tumour. Drugs like proteins and peptides can also be targeted through this system^16,17.

3. 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, and the system is found to be floating on gastric content and increases gastric residence and increases fluctuation in plasma concentration. Moreover it also reduces chances of dose dumping. It produces prolonged therapeutic effect and therefore reduces dosing frequencies. Drug (ketoprofen) is given in the form of floating microspheres^18-20.

4. Radioactive microspheres:

Radio embolization therapy microspheres sized 10-30 nm are of larger than the diameter of the capillaries and gets tapped in first capillary bed when they come across. They are injected in the arteries that leads them to tumour of interest so all these conditions 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,
22.

5. Polymeric microsphere:

The different types of polymeric microspheres can be classified as:

Biodegradable polymeric microspheres:

Natural polymers such as starch are used with the concept that they are biodegradable, biocompatible, and also bioadhesive in nature. Biodegradable polymers prolongs the residence time when contact with mucous membrane due to its high degree of swelling property with aqueous medium , results gel formation. The rate and extent of drug release is controlled by concentration of polymer and the release pattern in a sustained manner. The main drawback is, in clinical use drug loading efficiency of biodegradable microspheres is complex and is difficult to control the drug release²³.

Synthetic polymeric microspheres:

The interest of synthetic polymeric microspheres are widely used in clinical application, moreover that also used as bulking agent, fillers, embolic particles, drug delivery vehicles etc. and proved to be safe and biocompatible. But the main disadvantage of these kind of microspheres, are tend to migrate away from injection site and lead to potential risk, embolism and further organ damage ^{24, 25}.

Various techniques used to prepare microspheres:

Microspheres are prepared by following techniques:-

1. Solvent extraction:

Solvent evaporation method is used for the preparation of microparticles, involves removal of the organic phase by extraction of the organic solvent. The method involves water miscible organic solvents such as isopropanol. Organic phase is removed by extraction with water. This process decreases the hardening time for the microspheres. 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 ²⁶.

2. Cross linking method:

Thermal cross-linking-

Citric acid, as a cross-linking agent was added to 30 mL of an aqueous acetic acid solution of chitosan (2.5% w/v) maintaining a constant molar ratio between chitosan and citric acid (6.90 × 10³ mol chitosan: 1 mol citric acid). The chitosan cross-linker solution was cooled to 0 °C and then added to 25 mL of corn oil previously maintained at 0 °C, with stirring for 2 minutes. This emulsion was then added to 175 mL of corn oil maintained at 120 °C, and cross-linking was performed in a glass beaker under vigorous stirring (1000 rpm) for 40 minutes. The microspheres obtained were filtered and then washed with diethyl ether, dried, and sieved ²⁷.

Chemical cross linking-

A 2.5% (w/v) chitosan solution in aqueous acetic acid was prepared. This dispersed phase was added to continuous phase (125 mL) consisting of light liquid paraffin and heavy liquid paraffin in the ratio of 1:1 containing 0.5% (w/v) Span 85 to form a water in oil (w/o) emulsion. Stirring was continued at 2000 rpm using a 3- blade propeller stirrer). A drop-by-drop solution of a measured quantity (2.5 mL each) of aqueous glutaraldehyde (25% v/v) was added at 15, 30, 45, and 60 minutes. Stirring was continued for 2.5 hours and separated by filtration under vacuum and washed, first with petroleum ether (60 °C-80 °C) and then with distilled water to remove the adhered liquid paraffin and glutaraldehyde, respectively. The microspheres were then finally dried in vacuum desiccators ²⁸.

3. Spray drying or spray congealing:

These methods are based on the drying of the moist of the polymer and drug in the air. Depending upon the removal of the solvent or cooling of the solution, the two processes are named 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 1-100 μm. Microparticles are separated from the hot air by means of the cyclone separator while the traces of solvent are removed by vacuum drying. One of the major advantages of the process is feasibility of operation under aseptic conditions. The spray drying process is used to encapsulate various penicillins. Thiamine mononitrate and sulpha ethylthiadizole are encapsulated in a mixture of mono and diglycerides of stearic acid and palmitic acid using spray congealing. Very rapid solvent evaporation, however leads to the formation of porous microparticles ^29,
30.

4. Emulsion technique:

Single emulsion- The micro particulate carriers of natural polymers i.e. those of proteins and carbohydrates are prepared by single emulsion technique. The natural polymers are dissolved or dispersed in aqueous medium followed by dispersion in non-aqueous medium like oil. Next cross linking of the dispersed globule is carried out. The cross linking can be achieved either by means of heat or by using the chemical cross linkers as shown in Figure 2. The chemical cross linking agents used are glutaraldehyde, formaldehyde, di acid chloride etc. Heat denaturation is not suitable for thermo labile substances. Chemical cross linking suffers the disadvantage of excessive exposure of active ingredient to chemicals if added at the time of preparation and then subjected to centrifugation, washing, separation ³¹.

Figure 2: Processing scheme for microspheres-preparation by single emulsion technique

Double emulsion-

Double emulsion method of microspheres preparation involves the formation of the multiple emulsion or the double emulsion of type w/o/w and is best suited to water soluble drugs, peptides, proteins and the vaccines. This method can be used with both the natural as well as synthetic polymers. The aqueous protein solution is dispersed in a lipophilic organic continuous phase. This protein solution may contain the active constituents. The continuous phase is generally consisted of the polymer solution that eventually encapsulates of the protein contained in dispersed aqueous phase. The primary emulsion is subjected then to the homogenization or the sonication before addition to the aqueous solution of the poly vinyl alcohol (PVA). This results in the formation of a double emulsion. The emulsion is then subjected to solvent removal either by solvent evaporation or by solvent extraction a number of hydrophilic drugs like leutinizing hormone releasing hormone (LH-RH) agonist, vaccines, proteins/ peptides and conventional molecules are successfully incorporated into the microspheres using the method of double emulsion solvent evaporation/ extraction ³² as shown in Figure 3.

Figure 3: Processing scheme for microspheres-preparation by double emulsion technique

5. Emulsion solvent diffusion:

A novel quasi-emulsion solvent diffusion method to manufacture the controlled release microspheres of drugs with acrylic polymers has been reported in the literature. Microsponges can be manufactured by a quasi-emulsion solvent diffusion method using an external phase containing distilled water and polyvinyl alcohol. The internal phase consists of drug, ethanol and polymer. The concentration of polymer is in order to enhance plasticity. At first, the internal phase is manufactured at 60 ºC and then added to the external phase at room temperature. After emulsification process, the mixture is continuously stirred for 2 hours. Then the mixture can be filtered to separate the microsponges. The product is then washed and dried by vacuum oven at 40 ºC for a day ^{33, 34}.

6. Ionic gelatin method:

Alginate/ chitosan particulate system for Nateglinide release was prepared using this technique. Different % (w/v) of Nateglinide was added to 2 % (w/v) aqueous solution of sodium alginate. In order to get the complete solution stirring is continued and after that it was added drop wise to a solution containing Ca2+ and chitosan solution in acetic acid. Microspheres which were formed were kept in original solution for 6 hr. & 24 hr. for internal gellification followed by filtration for separation. The complete release was obtained at pH 7.4 but the drug did not release in acidic pH ³⁵.

7. Polymerization:

The polymerization techniques conventionally used for the preparation of the microspheres are mainly classified as:

Normal polymerization:

It is carried out using different techniques as bulk, suspension, precipitation, emulsion and micellar polymerization processes. In bulk, a monomer or a mixture of monomers along with the initiator or catalyst is usually heated to initiate polymerization. Polymer so obtained may be moulded as microspheres. Drug loading may be done during the process of polymerization.

Suspension polymerization:

Also referred as bead or pearl polymerization. Here it is carried out by heating the monomer or mixture of monomers as droplets dispersion in a continuous aqueous phase. The droplets may also contain an initiator and other additives. Emulsion polymerization differs from suspension polymerization as due to the presence initiator in the aqueous phase, which later on diffuses to the surface of micelles. Bulk polymerization has an advantage of formation of pure polymers.

Interfacial polymerization:

It involves the reaction of various monomers at the interface between the two immiscible liquid phases to form a film of polymer that essentially envelops the dispersed phase ³⁶.

8. Phase saparation coacervation:

This process is based on the principle of decreasing the solubility of the polymer in organic phase to affect the formation of polymer rich phase called the coacervates. In this method, the drug particles are dispersed in a solution of the polymer and an incompatible polymer is added to the system which makes first polymer to phase separate and engulf the drug particles. Addition of non-solvent results in the solidification of polymer. Poly lactic acid (PLA) microspheres have been prepared by this method by using butadiene as incompatible polymer. The process variables are very important since the rate of achieving the coacervates determines the distribution of the polymer film, the particle size and agglomeration of the formed particles. The agglomeration must be avoided by stirring the suspension using a suitable speed stirrer since as the process of microspheres formation begins the formed polymerize globules start to stick and form the agglomerates. Therefore the process variables are critical as they control the kinetic of the formed particles since there is no defined state of equilibrium attainment ^{37, 38}.

9. Hydroxy appetite (hap) microspheres in sphere morphology:

This was used to prepare microspheres with peculiar spheres in sphere morphology microspheres were prepared by o/w emulsion followed by solvent evaporation. At first o/w emulsion was prepared by dispersing the organic phase (Diclofenac sodium containing 5% w/w of EVA and appropriate amount of HAP) in aqueous phase of surfactant. The organic phase was dispersed in the form of tiny droplets which were surrounded by surfactant molecules this prevented the droplets from co-solvency and helped them to stay individual droplets. While stirring the DCM was slowly evaporated and the droplets solidify individual to became microspheres ³⁹.

Evaluation Parameters of Microsphere:

Physicochemical Evaluation Characterization:

The characterization of the micro particulate carrier is an important phenomenon, which helps to design a suitable carrier for the proteins, drug or antigen delivery. These microspheres have different microstructures. These microstructures determine the release and the stability of the carrier.

1. Particle size and shape:

The most widely used procedures to visualize microparticles are conventional light microscopy (LM) and scanning electron microscopy (SEM). Both can be used to determine the shape and outer structure of microparticles. 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. SEM allows investigations of the microspheres surfaces 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. Laser light scattering and multi size coulter counter other than instrumental methods, which can be used for the characterization of size, shape and morphology of the microspheres ⁴⁰.

2. Electron spectroscopy for chemical analysis:

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

3. Attenuated total reflectance-Fourier Transform: Fourier Transform-Infrared (FTIR) spectroscopy is used to determine the degradation of the polymeric matrix of the carrier system. The surface of the microspheres is investigated measuring alternated total reflectance (ATR). The IR beam passing through the ATR cell 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 upon manufacturing procedures.

4. Density determination:

The density of the microspheres can be measured by using a multi volume pycnometer. Accurately weighed sample in a cup is placed into the multi volume pycnometer. 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 microsphere carrier is determined.

5. Isoelectric point:

The micro electrophoresis is an apparatus used to measure the electrophoretic mobility of microspheres from which the isoelectric point can be determined. The mean velocity at different pH values ranging from 3-10 is calculated by measuring the time of particle movement over a distance of 1 mm. By using this data the electrical mobility of the particle can be determined. The electrophoretic mobility can be related to surface contained charge, ionisable behaviour or ion absorption nature of the microspheres.

6. Angle of contact:

The angle of contact is measured to determine the wetting property of a micro particulate carrier. It determines the nature of microspheres 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 contact is measured at the solid/ air/ water interface. The advancing and receding angle of contact are measured by placing a droplet in a circular cell mount above objective of inverted microscope. Contact angle is measured at 200 °C within a minute of deposition of microspheres ⁴¹.

7. In-vitro methods:

There is a need for experimental methods which allow the release characteristics and permeability of a drug through membrane to be determined. For this purpose, a number of in-vitro and in-vivo techniques have been reported. 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 physico chemically and hydro dynamically defined conditions are necessary. The influence of technologically defined conditions and difficulty in simulating in-vivo conditions has led to development of a number of in-vitro release methods for buccal formulations; 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. The dosage form in this method is made to adhere at the bottom of the beaker containing the medium and stirred uniformly using overhead stirrer. Volume of the medium used in the literature for the studies varies from 50-500 ml and the stirrer speed form 60-300 rpm.

Dissolution apparatus:

Standard USP or BP dissolution apparatus have been used to study in-vitro release profiles using both rotating elements, paddle and basket. Dissolution medium used for the study varied from 100-500 ml and speed of rotation from 50-100 rpm ⁴².

8. 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 penetrants at the surface. Some of the earliest and simple studies of mucosal permeability utilized the systemic pharmacological effects produced by drugs after application to the oral mucosa. However the most widely used methods include in-vivo studies using animal models, buccal absorption tests, and perfusion chambers for studying drug permeability.

9. In-vitro/In-vivo correlations:

Correlations between in-vitro dissolution rates and the rate and extent of availability as determined by blood concentration and or urinary excretion of drug or metabolites are referred to as “in-vitro/in-vivo correlations”. Such correlations allow one to develop product specifications with bioavailability.

Percent of drug dissolved in-vitro Vs peak plasma concentration:

One of the ways of checking the in-vitro and in-vivo correlation is to measure the percent of the drug released from different dosage forms and also to estimate the peak plasma concentrations achieved by them and then to check the correlation between them. It is expected that a poorly formulated dosage form releases amount of drug than a well formulated dosage form, and, hence the amount of drug available for absorption is less for poorly formulated dosage form than from a well formulated dosage form.

Percent of drug dissolved Vs percent of drug absorbed: If the dissolution rate is the limiting step in the absorption of the drug, and is absorbed completely after dissolution, a linear correlation may be obtained by comparing the percent of the drug absorbed to the percent of the drug dissolved. If the rate limiting step in the bioavailability of the drug is the rate of absorption of the drug, a change in the dissolution rate may not be reflected in a change in the rate and the extent of drug absorption from the dosage form.

Dissolution rate Vs absorption rate:

The absorption rate is usually more difficult to determine than the absorption time. Since the absorption rate and absorption time of a drug are inversely correlated, the absorption time may be used in correlating the dissolution data to the absorption data. In the analysis of in-vitro and in-vivo drug correlation, rapid drug absorption may be distinguished from the slower drug absorption by observation of the absorption time for the dosage form. The quicker the absorption of the drug the less is the absorption time required for the absorption of the certain amount of the drug. The time required for the absorption of the same amount of drug from the dosage form is correlated.

10. Swelling index:

Swelling index was determined by measuring the extent of swelling of microspheres in the given buffer. To ensure the complete equilibrium, exactly weighed amount of microspheres were allowed to swell in given buffer. The excess surface adhered liquid drops were removed by blotting and the swollen microspheres were weighed by using microbalance. The hydrogel microspheres then dried in an oven at 60° C for 5 h until there was no change in the dried mass of sample. The swelling index of the microsphere was calculated by using the formula;

Swelling index = (mass of swollen microspheres – mass of dry microspheres/mass of dried microspheres) x 100.20

Application of Microspheres in Pharmaceutical Industry:

1. Microspheres in vaccine delivery:

An ideal vaccine must fulfill the requirement of efficacy, safety, convenience in application and cost. Biodegradable delivery systems for vaccines that are given by parenteral route may overcome the shortcoming of the conventional vaccines. The interest in parenteral (subcutaneous, intramuscular, intradermal) carrier lies since they offer specific advantages including Improved antigenicity by adjuvant action, modulation of antigen release, stabilization of antigen.

2. Targeting using micro particulate carriers:

The concept of targeting, i.e. site specific drug delivery is a well-established dogma, which is gaining full attention. The therapeutic efficacy of the drug relies on its access and specific interaction with its candidate receptors. The ability to leave the pool in reproducible, efficient and specific manner is centre to drug action mediated by use of a carrier system.

3. Monoclonal antibodies mediated microspheres targeting:

Monoclonal antibodies targeting microspheres are immune microspheres. This targeting is method used to achieve selective targeting to the specific sites. Monoclonal antibodies are extremely specific molecules. They can be directly attached to the microspheres by means of covalent coupling.

4. Chemoembolization:

Chemoembolization is an endovascular therapy, which involves the selective arterial embolization of a tumour together with simultaneous or subsequent local delivery the chemotherapeutic agent.

5. Imaging:

The particle size range of microspheres is an important factor in determining the imaging of particular sites using radio labelled microspheres. The particles injected intravenously apart from the portal vein will become entrapped in the capillary bed of the lungs. This phenomenon is exploited for the scintiographic imaging of the tumour masses in lungs using labelled human serum albumin microspheres.

6. Topical porous microspheres:

Microsponges are porous microspheres having myriad of interconnected voids of particle size range 5-300 µm. These microsponges having capacity to entrap wide range of active ingredients such as emollients, fragrances, essential oils etc., are used as the topical carries system ⁴³.

7. Medical application:

They releases proteins, hormones and peptides over extended period of time. They helps in Gene therapy with DNA plasmids and also delivery of insulin. There is a vital role in vaccine delivery for treatment of diseases like hepatitis, influenza, pertussis, and ricin. They involves in passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by intra-arterial/ intravenous application as well as Tumour targeting with doxorubicin. Microspheres helps in the treatments of leishmaniasis. Magnetic microspheres can be used for stem cell extraction and bone marrow purging. Microspheres also used in isolation of antibodies, cell separation and toxin extraction by affinity chromatography. Various diagnostic tests for infectious diseases like bacterial, viral, and fungal can be done by using microspheres ⁴⁴.

8. Radioactive microsphere’s application: Microspheres can be used for radio embolization of liver and spleen tumours. They also used for radio synvectomy of arthritis joint, local radiotherapy, interactivity treatment. Imaging of liver, spleen, bone marrow, lung and even imaging of thrombus in deep vein thrombosis can be done by using them ⁴⁵.

Additionally, some marketed formulations offering MDDS are mentioned in Table 1.

Table 1: Marketed formulations offering MDDS

S. No	Brand Name	API	Manufacturer/Company
1.	Brexin L.A	Chlorpheniramine Pseudoephedrine	Savage Laboratories, Bangalore
2.	Fastin	Phentermine	Berlex Laboratories, USA
3.	Coreg CR	Carvedilol phosphate	GSK
4.	Dilgard XL 180	Diltiazem hydrochloride	Smith kline & French, Mumbai
5.	Bontril SR	Phendimetrazine Tartrate	Carnick laboratories, Inc
6.	InnoPran XL	Propranolol Hydrochloride	GSK
7	Inderal	Propranolol Hydrochloride	Astrazeneca US Ltd.
8.	Compazine	Prochlorperazine	Smith & French, Mumbai
9.	Focalin XR	Dexmethylphenidate	Novartis
10	Spansule	d-amphetamine sulfate	GSK
11.	Ibugesic SR 300	Ibuprofen	CIPLA Ltd, Ahmadabad
12	Cymbalta	Duloxetine Hydrochloride	Eli Lilly and Company, USA
13	Nicobid T.S	Niacin	U.S Vitamin, USA

CONCLUSION:

Microspheres are superior option of drug delivery systems than others because it has a number of considerable advantages such as detection of bimolecular interactions and better patient consistence. Microspheres has developed as an effective methodology for upgrading the bioavailability and controlled release drug delivery of different specialists. Absorption of drug in the gastrointestinal tract is a profoundly factor strategy and prolonging gastric retention of the dosage form extends the time for drug absorption. These frameworks additionally give marvellous opportunities in the structuring of new controlled and delayed release oral preparations, in this way expanding the boondocks of advanced pharmaceutical improvement. In spite of the fact that there are number of troubles to be worked out to accomplish extend gastric retention, an enormous number of organizations are centring toward commercializing this procedure. The principle focal thought of this review is to make energizes in scientists and researchers about this novel topic “Microsphere”.

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Received on 09.01.2020 Modified on 24.04.2020

Research J. Pharm. and Tech. 2021; 14(6):3461-3470.

DOI: 10.52711/0974-360X.2021.00602