1. INTRODUCTION:

Microspheres are solid spherical particles ranging in size from 1-1000μm. They are spherical free flowing particles consisting of proteins or synthetic polymers. The microspheres are free flowing powders consisting of proteins or synthetic polymers, which are biodegradable in nature¹. There are two types of microspheres;

§ Microcapsules

§ Micromatrices

Microcapsules are those in which entrapped substance is distinctly surrounded by distinct capsule wall and micromatrices in which entrapped substance is dispersing throughout the microspheres matrix. Solid biodegradable microspheres incorporating a drug dispersed or dissolved through particle matrix have the potential for the controlled release of drug. They are made up of polymeric, waxy, or other protective materials, that is, biodegradable synthetic polymers and modified natural products².

1.1 Advantages:

§ Microspheres provide constant and prolonged therapeutic effect.

§ Reduces the dosing frequency and thereby improve the patient compliance.

§ They could be injected into the body due to the spherical shape and smaller size.

§ Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects³.

1.2 Limitation:

Some of the disadvantages were found to be as follows.

§ The costs of the materials and processing of the controlled release preparation, are substantially higher than those of standard formulations.

§ The fate of polymer matrix and its effect on the environment.

§ The fate of polymer additives such as plasticizers, stabilizers, antioxidants and fillers.

§ Reproducibility is less.

§ Process conditions like change in temperature, pH, solvent addition, and evaporation/agitation may influence the stability of core particles to be encapsulated.

The environmental impact of the degradation products of the polymer matrix produced in response to heat, hydrolysis, oxidation, solar radiation or biological agents.

2. Types of microspheres:

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 bio adhesion. These kinds of microspheres exhibit a prolonged residence time at the site of application and causes intimate contact with the absorption site and produces better therapeutic action. Carrier technology offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such as microspheres, Nano spheres, 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 capacity⁴.

Magnetic microspheres:

This kind of delivery system is very much important which localizes the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. The different types are therapeutic magnetic microspheres and diagnostic microspheres⁵.

A) Therapeutic magnetic microspheres:

It is used to deliver chemotherapeutic agent to liver tumor. Drugs like proteins and peptides can also be targeted through this system.

B) Diagnostic microspheres:

It can be used for imaging liver metastases and also can be used to distinguish bowel loops from other abdominal structures by forming nano size particles supramagnetic iron oxides.

Floating microspheres:

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

Polymeric microspheres:

The different types of polymeric microspheres can be classified as follows and they are biodegradable polymeric microspheres and synthetic polymeric microspheres⁶.

A) 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 release⁷.

B) 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.

Radioactive microspheres:

Radio embolization therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they come across. They are injected to the arteries that lead to tumour of interest. So these radioactive microspheres deliver high radiation dose to the targeted areas without damaging the normal surrounding tissues. It differs from drug delivery system, as radio activity is not released from microspheres but acts from within a radioisotope typical distance and the different kinds of radioactive microspheres are αemitters, β emitters, γ emitters⁸.

Mucoadhesive microspheres:

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

3. Method of Preparation:

Microspheres are prepared by using following methods.

1) Spray Drying

2) Solvent Evaporation

3) Single emulsion technique

4) Double emulsion technique

5) Phase separation coacervation technique

6) Spray drying and spray congealing

7) Solvent extraction

8) Quassi emulsion solvent diffusion

1) Spray Drying:

In Spray Drying technique, polymer is first dissolved in volatile organic solvent such as dichloromethane, acetone, etc. The drug in solid form is then dispersed in to polymeric solution with the high-speed homogenization. This dispersion is then atomized in hot air stream. The atomization leads to the form the small droplets from which the solvent evaporates instantly leads the formation of the microspheres in the size range 1-100 μm. Microparticles are separated from hot air by the cyclone separator while the trace of solvent is removed by vacuum drying. Major advantage of this process is feasibility of operation under aseptic conditions⁹.

2) Solvent Evaporation:

This process is carried out in vehicle phase of liquid manufacturing. The microcapsule coating is dispersed in the volatile solvent which immiscible with the vehicle phase of liquid manufacturing. A core material which is microencapsulated is dissolved in the coating polymer solution. Agitation with the core material mixture is dissolved in the liquid manufacturing vehicle phase to obtain appropriate size microcapsule. Then the mixture is heated if necessary to evaporate and the solvent for the polymer of the core material is dissolved in the polymer solution, around the core polymer shrinks. If core material is dissolve in the coating polymer solution, matrix type microcapsules are formed. The core materials are either water soluble or soluble materials.

3) Single emulsion technique:

The micro particulate carriers of the natural polymers i.e. proteins and carbohydrates are prepared by the single emulsion technique. Natural polymers are dissolved in aqueous medium which is followed by the dispersion in non-aqueous medium like oil. In next step, the cross linking of dispersed globule is carried out. The cross linking can be achieved by the heat or by using the chemical cross linkers. T chemical cross linking agents used are glutaraldehyde, formaldehyde, acid chloride. Heat denaturation is not suitable for the hermolabile substance. Chemical cross linking having the disadvantage of excessive exposure of active ingredient to chemicals if added at time of preparation and then subjected to centrifugation, washing, separation, nature of the surfactants used to stabilize the emulsion phases can greatly influence by the size, size distribution, surface morphology and loading drug release, and bio per- formance of the final multiparticulate product.

4) Double emulsion technique:

This method of microspheres preparation involves formation of multiple emulsions or double emulsion of type w/o/w and is best suited to the water soluble drugs, peptides, proteins and vaccines. This method can be used with the both natural as well as synthetic polymers. The aqueous protein solution is dispersed in the lipophilic organic continuous phase. This protein solution may contain the active constituents¹⁰.

5) Phase separation coacervation technique:

This process is based on the principle of the decreasing the solubility of polymer in organic phase which affect the formation of polymer rich phase called the coacervates. In this method, drug particles are dispersed in a solution of polymer and an incompatible polymer is added to system which makes first polymer for the phase separation.

6) Spray drying and spray congealing:

These methods are based on the drying of the mist of polymer and drug in the air. Depending upon removal of the solvent or cooling of the solution, this two processes are named spray drying and spray congealing¹¹.

7) Solvent extraction:

Solvent evaporation method is used for the manufacturing of microparticles and involves removal of the organic phase by extraction of the non-aqueous solvent. This method involves the water miscible organic solvent which is isopropanol.

8) Quassi emulsion solvent diffusion:

A novel quasi-emulsion solvent diffusion method used for the manufacturing of the controlled release microspheres of drugs with acrylic polymers has been reported in the literature. Microsponges can be manufactured by the quassi emulsion solvent diffusion method by using external phase which contains distilled water and polyvinyl alcohol. The internal phase consists of the drug, ethanol and polymers. Firstly the internal phase is manufactured at 60ºC and after then added to the external phase at room temperature. Then emulsification the mixture is continuously stirred for 2 hours. Then the mixture can be filtered for separate the microsponges¹².

4. Physicochemical evaluation:

a) Particle size and shape:

Particle size can be determined by optical microscopy with the help of calibrated eyepiece micrometer. The size of around 100 microspheres is measured and their average particle size is calculated

D mean = ∑ n d/∑ n

Where, n = number of microspheres checked; d = Mean size

b) Density determination:

The density of 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 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 microsphere carriers is determined¹³.

c) Isoelectric point:

The isoelectric point can be measured by using micro electrophoresis apparatus by measuring electrophoretic mobility of microspheres. The mean velocity at different pH value from 3-10 is calculated by measuring the time of particle movement over a distance of 1 nm.

d) Angle of contact:

The angle of repose Ø of microspheres, which measures the resistance to particle flow is calculated as where, 2h/d is the surface area of free standing height of microspheres heap that is formed after making microspheres flow from the glass funnel

e) Electron spectroscopy for chemical analysis:

The surface chemistry of microspheres can be determined by using electron spectroscopy for chemical analysis (ESCA). ESCA provides a means for the determination of atomic composition of the surface. The spectra obtained using ESCA can be used to determine the surface degradation of biodegradable microspheres¹⁴.

f) Fourier transform infrared spectroscopy:

Drug polymer interaction and degradation of microspheres can be assessed by FTIR.

g) Drug entrapment efficiency:

Weighed amount of microsphere are taken and crushed. Then dissolved in buffer solution with the help of stirrer and filtered. The filtrate is assayed by UV spectrophotometer at particular wavelength by using calibration curve.

Drug Entrapment efficiency is calculated by dividing actual weight of microspheres by the theoretical weight of drug and polymer multiplied by 100.

h) Percentage yield:

It is calculated as the weight of microspheres obtained from each batch divided by total weight of drug and polymer used to prepare that batch multiplied by 100.

i) Swelling index:

It is determined by measuring the extent of swelling of microspheres in a particular solvent. The equilibrium swelling degree of microspheres is determined by swelling of 5 mg of dried microspheres poured in 5 ml of buffer solution overnight in a measuring cylinder. It is calculated by given formula.

Swelling index =

Mass of swollen microsphere – Mass of dried microspheres / mass of dried microsphere

j) In vitro Dissolution apparatus method:

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 varies from 100-500 ml and speed of rotation from 50-100 rpm¹⁵.

k) In vivo method:

Method for studying the permeability of intact mucosa comprises of technique that gives the biological response of the organism locally or systemically and those that involve direct local measurement of uptake or accumulation of penetrate at their surface. The most widely used methods of in vivo studies include using animal models, buccal absorption tests¹⁶.

l) Animal models:

It is used mainly for the screening of series of compounds, investigating the mechanisms and evaluating a set of formulations. Animal model such as dogs, rats, pigs and sheep etc. are reported. Generally the procedure involves anesthetizing the animal followed by administration of dosage form, withdrawing blood at different time intervals and analyzing¹⁷.

m) Buccal absorption test:

It is most suitable and reliable method for measuring the extent of drug loss from human oral cavity for single and multi-component mixtures of drugs. The test has been successfully used to investigate the relative importance of drug structure, contact time, initial drug concentration and pH of solution while drug is held in oral cavity. The test is carried to measure the kinetics of the drug absorption by swirling a 25 ml sample of the test solution for 15 min by human volunteers followed by the expulsion of the solution. The amount of the drug remaining in the expelled volume is then determined to assess the amount of drug absorbed¹⁸.

n) In vitro/in vivo correlation:

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 correlation”. Such correlations allow one to develop product specifications with availability. Orally rapid dissolving films must be disintegrated using USP disintegration equipment. Depending on the formulation, disintegration times can vary, although they commonly range from 5 to 30 seconds. However, there is no formal advice for oral fast-dissolving films¹⁹.

5. Applications of microspheres:

a) In vaccine Delivery:

The prerequisite of a vaccine is protection against the microorganism or its toxic product. Biodegradable delivery system for vaccines that are given by Parentral route may overcome the shortcoming of conventional vaccines. Several parenteral vaccines have been encapsulated in biodegradable polymeric microspheres, including the tetanus and diphtheria vaccine²⁰.

b) Monoclonal Antibodies:

Monoclonal antibodies targeting microspheres are immune microspheres. This targeting is used to achieve selective targeting to specific sites. Monoclonal antibodies are extremely specific molecules. Maps can be attached to microspheres by any of following methods:

§ Non-specific adsorption and specific adsorption

§ Direct coupling

§ Coupling via reagent

c) Imaging:

Particle size range of microspheres is an important factor in determining the imaging of particular sites using radio labeled microspheres. The particles injected intravenously apart from the portal vein will become entrapped in the capillary bed of lungs. This phenomenon is exploited for scintigraphic imaging of tumour masses in lungs using labeled human serum albumin microspheres²¹.

d) Topical Porous Microspheres:

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

e) Targeting Drug Delivery:

The concept of targeting i.e. site specific drug is a well-established dogma, which is gaining full attention. The therapeutic efficacy of drug relies on its access and specific interaction with its receptor.

f) Medical Application:

§ Release of proteins, peptides and hormones over the extended period of time.

§ Passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by intra arterial/ intravenous application.

§ Magnetic microspheres can be used for stem cell extraction and bone marrow purging.

§ Used for various diagnostic tests for infectious disease like bacterial, viral and fungal.

g) Radioactive Application:

Can be used for embolisation of liver and spleen tumors. Used for radio synvectomy of arthritis joints, local radiotherapy, interactivity treatment, Imaging of liver, spleen, bone marrow, lung and even imaging of thrombus in deep vein thrombosis can be done²².

h) Other Application:

Fluorescent microspheres can be used for membrane based technology for flow cytometry, cell biology, microbiology, Fluorescent Linked Immuno-Sorbent Assay. Yttrium 90 can be used for primary treatment of hepatocellular carcinoma and also used for pre transplant management of HCC with promising results.

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 & genetic materials, safe, targeted, specific and effective in-vitro delivery and supplements as miniature version of diseased organ and tissues in the body.

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Received on 14.03.2023 Modified on 12.05.2023

Asian J. Res. Pharm. Sci. 2023; 13(3):235-240.

DOI: 10.52711/2231-5659.2023.00041