INTRODUCTION:

Microspheres are novel drug delivery system which has several benefits over conventional multi dose therapy. It enhances the therapeutic efficacy of a given drug. Microspheres are mainly free flowing powders consisting of proteins or synthetic polymers. Proteins or synthetic polymers are naturally biodegradable microspheres having a particle size less than 200 micrometer. Microsphere also used for the controlled release of drugs, vaccines, antibiotics, and hormones.

There are various approaches to delivering a therapeutic agent to the same target site in a continuously regulated fashion for release. Microsphere is act as carriers for drugs.

Properties of Ideal Microspheres:

1. Microspheres have ability to incorporate reasonably high concentrations of the drug.

2. Stability of the preparation with a clinically appropriate shelf life after synthesis.

3. Controlled particle size and dispersibility during injection in aqueous vehicles.

4. Active reagent released with good control over a large time scale.

5. Biocompatibility with a controllable biodegradability.

6. Susceptibility to chemical modification.

Advantages:

1. Particle size reduction for solubility enhancement of the poorly soluble drug.

2. To provide constant and prolonged therapeutic effect.

3. To provide constant drug concentration in blood

4. To reduce dose and toxicity.

5. To protect the drug from enzymatic and photolytic cleavage.

6. To reduce the dosing frequency and thereby improve the patient compliance.

Disadvantages:

1. More Expensive.

2. Reproducibility is less.

3. Stability problem due to temperature, pH, Solvent addition and evaporation^1,3.

Material Used:

For the preparation of Microspheres not only biodegradable substances have been investigated but also non-biodegradable substances investigated. These materials consist the polymers of different origins like natural and synthetic origin Synthetic polymers used as carrier materials like methyl methacrylate, acrolein, lactide, and their copolymers, ethylene vinyl acetate copolymer, polyanhydrides, etc. Natural polymers are also used like albumin, gelatine, starch, collagen, and carrageenan.

CLASSIFICATION OF POLYMER:

A) Natural Materials:

Natural Polymers obtained from different sources like proteins, carbohydrates and chemically modified carbohydrates.

i) Proteins (albumin, gelatin, collagen)

ii) Carbohydrate (starch, agarose, carrageenan)

iii) Chemically modified carbohydrates [poly (dextran acrylic), poly (starch acrylic)]

B) Synthetic Polymers:

Synthetic Polymers are mainly divided into two types i.e.

i) Non-biodegradable 4,5- Acrolein, Glycidyl methacrylate, Epoxy polymers, etc.

ii) Biodegradable (6)-Polyanhydrides, Polyalkylcyanoacryalates Lactides, and glycolides and their copolymers¹.

TYPES OF MICROSPHERES³:

Bioadhesive Microspheres:

By using the sticking property of water-soluble polymers, adhesion can be described as the sticking of the drug to the membrane. Adherence to the mucosal membrane of the drug delivery system such as buccal, ocular, rectal, nasal, etc. may be known as bio-adherence. These kinds of microspheres show an extended period of residence at the site of application and induce intimate contact with the site of absorption and yield better therapeutic action.

Magnetic Microspheres:

This type of delivery system is very important because that locates the drug at the site of the disease. In this larger amount of freely available medication may be supplemented by a smaller amount of magnetically guided medication. Magnetic carriers receive magnetic responses from materials used for magnetic microspheres, chitosan incorporated into a magnetic field, dextran, etc.

Radioactive Microspheres:

Radiotherapy embolization microspheres size 10-30 nm is larger than the capillary diameter and will be tapped into the first capillary bed when they meet. They are injected into the arteries that lead to the tumor of interest so that all these conditions of radioactive microspheres provide high doses of radiation to the targeted areas without damaging the normal surrounding tissues.

It differs from the drug delivery system, as radioactivity is not released from microspheres but acts from within a typical distance of a radioisotope, and the various types of radioactive microspheres are α emitters, β emitters, π emitters.

Polymeric Microspheres:

The various types of polymer microspheres can be classified as follows,

a) Microspheres of biodegradable polymers

b) Synthetic polymeric microspheres.

a) Biodegradable Polymeric Microspheres:

Natural polymers, e.g., starch, are used on the premise that they are naturally biodegradable, biocompatible, and also bioadhesive. Due to its high degree of swelling properties with an aqueous medium, biodegradable polymers prolong the residence time when contact with mucous membrane results in gel formation. The rate and extent of drug release are sustainably controlled by polymer concentration and release pattern. The main drawback is that the efficiency of the loading of biodegradable microspheres in clinical use is complex and the release of drugs is difficult to control. They provide however a wide range of applications in treatment based on microspheres.

b) Synthetic Polymeric Microspheres:

In addition to being used as bulking agents, fillers, embolic particles, drug delivery vehicles etc., synthetic polymeric microspheres are widely used in clinical applications and have been shown to be safe and biocompatible, but the main disadvantage of such microspheres tends to migrate away from the injection site and lead to potential risk, embolism, and further organ damage

Floating Microspheres:

The bulk density in floating types is less than the gastric fluid and thus remains buoyant in the stomach without affecting the rate of gastric emptying. The drug is released slowly at the desired rate, and it is found that the system is floating on gastric content and increases gastric residence and plasma concentration fluctuations.

METHOD OF PREPARATION^4-13:

A. Solvent Evaporation:

In this technique; The drug is dissolved in the polymer which was previously dissolved in chloroform. The resulting solution is applied to the aqueous phase, which contains 0.2 percent of PVP sodium as an emulsifier. The above mixture was agitated at 500 rpm. The drug and polymer (eudragit) were transformed into a fine droplet which solidified into rigid microspheres by solvent evaporation. Microspheres are collected by filtration, washed with demineralized water, and desiccated for 24 hours at room temperature.

I. Single Emulsion Technique:

1. The natural polymers are dissolved in an aqueous medium followed by dispersion in a non-aqueous medium like oil.

2. In the next step, the cross-linking of the dispersed globule is carried out.

3. The cross-link can be accomplished either by heating or by using chemical cross-linkers (glutaraldehyde, formaldehyde, chloride acid).

4. Heat denaturation is not suitable for thermolabile substances.

5. Once applied at the time of preparation and then subjected to centrifugation, drying, and isolation, chemical cross-linking suffers the disadvantage of unnecessary exposure of active ingredients to chemicals.

6. The nature of the surfactants used to stabilize the emulsion phases can greatly influence the size, size distribution, surface morphology, loading, drug release, and bio performance of the final multiarticulate product.

II. Double Emulsion Technique:

Figure 1: Double Emulsion Technique

B. Coacervation Phase Separation Technique:

I. Co-acervation thermal change:

Carried out by weighed volume of ethyl cellulose was dissolved by heating the cyclohexane with intense stirring at 80°C. The product was then finely pulverized and applied to the above solution with intense stirring, and the phase separation was achieved by reducing temperature and using ice bath. The above sample was then washed twice with cyclohexane and dried in air then passed through sieve (sieve no. 40) to obtain individual microcapsule.

II. Coacervation Non-Solvent Addition:

Developed by a weighed volume of ethyl cellulose, it was dissolved in toluene containing propyl isobutylene in a closed beaker with magnetic stirring at 500rpm for 6 hours and the product is distributed therein and stirring continues for 15 minutes. Petroleum benzoin is then extracted 5 times with continuous stirring. 1 After the microcapsules have been washed with n-hexane and dry air for 2 hours

C. Polymerisation:

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

I. Normal polymerization:

It is carried out using different techniques likes bulk, suspension, precipitation, emulsion and micellar polymerization processes. In bulk, a monomer or a combination of monomers is typically heated along with the initiator or catalyst to induce polymerisation. So obtained polymer can be moulded as microsphere. Drug loading can occur during the polymerisation process. Suspension polymerization, also called polymerization of beads or pearls. Here it is carried out by heating the monomer or mixture of monomers in a continuous aqueous environment as dispersion droplets. Emulsion polymerization varies from suspension polymerization due to the presence of the initiator in the aqueous process, which later spreads to the micelles surface.

II. Interfacial polymerization:

It requires the reaction of different monomers at the interface between the two immiscible liquid phases to shape a polymer film that basically encapsulates the dispersed level.

D. Spray Drying and Spray Congealing:

In Spray Drying technique,

1. The polymer is first dissolved in a suitable volatile organic solvent (dichloromethane, acetone)

2. The drug (solid form) is then dispersed in the polymer solution with high-speed homogenization.

3. In a stream of hot air this dispersion is then atomised.

4. The atomisation contributes to the formation of the small droplets or the fine mist from which the solvent evaporates, leading to the creation of the microspheres (size range 1-100μm).

5. The cyclone separator removes microparticles from the hot air, while the solvent trace is eliminated by vacuum drying.

6. All operation carried out under aseptic conditions.

E. Solvent Extraction:

1. Solvent evaporation method is used for the preparation of microparticles, involves removal of the organic phase by extraction of the organic solvent.

2. The method involves water miscible organic solvents such as isopropanol.

3. Organic phase is removed by extraction with water.

4. This process decreases the hardening time for the microspheres.

5. One variation of the process involves direct addition of the drug or protein to polymer organic solution.

6. 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.

Evaluation of Microspheres^8,13-18:

Particle Size and Shape:

Conventional light microscopy (LM) and scanning electron microscopy (SEM) are the most widely used processes for visualizing microparticles. Both can be used to determine the microparticulate shape and outer structure. In the case of double walled microspheres, LM provides control over coating parameters. The microsphere structures can be seen before and after the coating, and microscopic measurement of the change is possible. Unlike the LM33 SEM, it provides greater resolution. SEM helps to investigate the surfaces of the microspheres and may also be used to investigate double wall structures after cross-sectioning of the particles. Confocal fluorescence microscopy is used to characterize the structure of multiple walled microspheres. Laser light dispersion and multi-size coulter counter, instead of instrumental methods that can be used to define the volume, shape and morphology of the microsphere.

Electron Spectroscopy for Chemical Analysis:

Using the electron spectroscopy for chemical analysis (ESCA) the surface composition of the microspheres can be calculated. ESCA provides a means for determining surface atomic composition. The spectra obtained with ECSA can be used to evaluate the biodegradable microspheres' surface degradation.

Density Determination:

A multi volume pycnometer can be used to measure the density of the microspheres. Accurately weighed sample is placed inside the pycnometer of multi volume in a cup. At constant pressure, helium is deposited in the chamber and allowed to expand. This expansion leads to lower pressure inside the chamber. Two consecutive pressure reducing measurements are noted at different initial pressure. The volume and hence the microsphere carrier density is determined from two pressure readings.

Isoelectric Point:

The micro electrophoresis is a device used to measure the electrophoretic mobility of microspheres from which to determine the isoelectric point. The mean velocity is calculated by measuring the time of particle movement over a distance of 1mm at different Ph values ranging from 3-10 The electrical mobility of the particle may be determined by using this data. Electrophoretic mobility may be associated with the microspheres' surface-contained load, ionizable behaviour or ion absorption nature.

Angle of Contact:

The angle of contact is measured for determining a micro particulate carrier's wetting property. The nature of microspheres is determined in terms of hydrophilicity or hydrophobicity. This thermodynamic property is specific to solid and is affected by the presence of the component being adsorbed. The contact angle is measured at the interface between solid/air/water.

In vitro Methods:

Experimental methods are needed to determine the release characteristics and permeability of a drug through membrane. A number of in vitro and in vivo techniques have been recorded for this reason. Studies of the in vitro release of drugs is used as a quality control technique in pharmaceutical manufacturing, product growth, etc. Sensitive and reproducible release data arising from conditions specified physiochemically and hydrodynamically are required. The effect of technologically specified conditions and difficulty in simulating in vivo conditions has led to the development of a variety of methods for buccal formulations to be released in vitro; however, no standard in vitro method has yet been developed.

Drug Entrapment Efficiency:

By allowing washed microspheres to lysate, the capture efficiency of the microspheres or the percent entrapment can be determined. The lysate is then subject to the requirement of monograph determination of the active constituents. The effectiveness of encapsulation by percentage is calculated using the following equation:

% Entrapment = Actual Content/Theoretical x 100

Swelling Index:

The microsphere swelling index was determined using the formula,

Swelling index = (mass of swollen microspheres-mass of dry microspheres/mass of dry microspheres) 100.

Fourier Transform-Infrared Spectroscopy:

FT-IR is used to assess the degradation of the carrier system's polymeric matrix. Measuring alternative total reflectance (ATR) is investigated on the microspheres surface. The IR beam passing through the ATR cell reflected through the sample many times to mainly provide IR spectra of surface material.

Interface Diffusion System:

Dearden and Tomlinson develop this method. It is composed of four compartments. Compartment A represents the oral cavity and initially contained in a buffer a suitable concentration of drug. The compartment B, representing the buccal membrane, contained 1-octanol, and the body fluid compartment C, contained 0.2 M HCl. The D compartment representing the binding of proteins also contained 1-octanol. The aqueous phase and 1octanol were saturated one with the other before use. Samples were taken off and returned with a syringe to compartment A.

In-Vivo Methods:

For studying the permeability of intact mucosa consists of techniques that exploit the organism's biological response locally or systemically, and techniques that involve direct local measurement of the surface absorption or accumulation of penetrants. Some of the earliest and simplest studies of mucosal permeability used the systemic pharmacological effects that drugs produced after applying to the oral mucosa. However, in vivo studies using animal models, buccal absorption tests and perfusion chambers to study drug permeability are the most widely used methods.

Surface Amino Acid Residue:

The amino acid residue associated with the surface is determined by the conjugate of radioactive c14-actic acid. The residue of carboxylic acid is measured by means of a liquid scintillation counter and thus the residue of amino acids can be indirectly determined. EDAC is used for the condensation of the amino group and the carboxylic acid residue of c14 – acetic acid.

The method used to determine the free amino or the free residues of carboxylic acid is based on indirect estimation by measuring the radioactivity of acetic acid or glycine conjugate in the c14. However, the method's accuracy depends on the time allowed to conjugate the radioactive moiety and the free functional group's reactivity.

Carboxylic surface acid residue:

The residue of carboxylic acid on the surface is measured using radioactive glycine. The radioactive glycine conjugates are prepared with the microspheres by reaction of c14-glycine ethyl ester hydrochloride. The glycine residue is linked using the carbidiimide (EDAC) water soluble condenser 1- ethyl-3 (3-dimethyl amino propyl).The conjugate radioactivity is then measured with the help of a liquid scintillation counter. In this way the residue of carboxylic acid can be measured and associated. The free residue of carboxylic acid can be measured for hydrophobic or hydrophilic, or for any other microsphere derivative type.

APPLICATIONS OF MICROSPHERES IN PHARMACEUTICAL INDUSTRIES^9,19,20,21

Figure 2: Applications of Microsphere in Pharmaceutical Industries

1. Gene Delivery:

Because of its adhesive and transport properties in the GI tract, microspheres could be useful oral gene carrier. So, e.g., Chitosan, gelatin, viral vectors, cationic liposomes, complexes of polycation, and DNA plasmid gene therapy as well as insulin delivery.

2. Nasal drug delivery:

Polymer-based drug delivery systems such as micro-sphere, liposomes and gels have been shown to have good bio adhesive characteristics and swell easily when in contact with the nasal mucosa, increasing the drug's bioavailability and residence time to the nasal route. For example. Starch, dextran, chitosan+gelatin, albumin.

3. Oral Drug Delivery:

The ability of polymer-containing microspheres to form films enables its use as an alternative to pharmaceutical tablets in the formulation of film dosage forms. The pH sensitivity coupled with the reactivity of the primary amine groups makes microspheres more suitable for applications for oral drug delivery. For example. Gelatine, Chitosan.

4. Targeting by Using Micro Particulate Carriers:

The targeted idea is a well-established orthodoxy that is now gaining full attention a day. The drug 's response depends on its access and interaction with the receptor 's usually recorded pellet system that can be prepared using extrusion/spheronization technology such as microcrystalline cellulose (MCC) and chitosan, for example.

5. Buccal Drug Delivery:

Polymer is a good polymer for buccal delivery as it has muco/bioadhesive properties and can respond as an enhancer for absorption. Chitosan, Alginate for Sodium.

6. Intratumoral and local drug delivery:

Polymer films are manufactured to deliver paclitaxel in a therapeutically relevant concentration at the tumor site. Drug mixture has promising potential in oral cavity for use in controlled delivery e.g., Gelatin Chitosan, PLGA.

7. Colonic Drug Delivery:

Polymer was used to distribute insulin directly to the colon e.g., Chitosan: Chitosan.

8. Transdermal drug delivery:

Polymer has excellent Properties that form films. The drug release from the devices is affected by the film's membrane thickness and cross-linking. e .g. PLGA Chitosan, Alginate.

9. Gastrointestinal drug delivery:

Polymer granules with internal cavities prepared by deacidification are found to be buoyant when added to acidic and neutral media and provided a controlled release of the drug g. Eudragit, Ethyl Cellulose + Carbopol BSA, Gelatin.

10. Vaginal drug delivery:

Polymer, modified by the introduction of thioglycolic acid into the polymer's primary amino groups, is widely used for treating genitourinary tract mycotic infections, e.g., Chitosan PLGA, Gelatin.¹⁰

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Received on 12.07.2022 Modified on 24.09.2022

Asian J. Pharm. Tech. 2023; 13(2):105-110.

DOI: 10.52711/2231-5713.2023.00020