INTRODUCTION:

SMOKING¹:

Oral route of drug administration is by far the most preferable route for taking medications. However, short circulating half life and restricted absorption via a defined segment of intestine limits the therapeutic potential of many drugs. Such pharmacokinetic limitation leads 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.

Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site have had an enormous impact on the healthcare system.

Controlled release (CR) systems provide drug release in an amount sufficient to maintain the therapeutic drug level over extended period of time, with the release profiles controlled by the special technological construction and design of the system itself. Controlled release drug delivery systems are being developed to avoid many difficulties associated with traditional methods of administration. Controlled release drug delivery includes devices such as liposomes, hydrogels, polymer based discs, rods, nanoparticles, pellets or microparticles that can encapsulate the drug and from which the therapeutic agents are released at controlled rates for long periods of time from days to months¹.

As variety of carrier systems have been used for controlled release drug delivery, biodegradable polymer microspheres are one of the most common types and hold several advantages. Microspheres are small spherical particles prepared by polymeric, waxy or protective materials with diameter ranging in size from 1 to 1000µm and can be manufactured from various natural and synthetic polymeric material. They can encapsulate many types of drugs including small molecules, proteins and nucleic acids and are easily administered through a syringe needle³.

Table 1: Benefit characteristics of oral controlled-release drug delivery systems²

Benefit	Reason
Therapeutic advantage	Reduction in drug plasma level fluctuations; maintenance of a steady plasma level of the drug over a prolonged time period, ideally simulating an intravenous infusion of a drug
Reduction in adverse side effects and improvement in tolerability	Drug plasma levels are maintained within a narrow window with no sharp peaks and with area under curve of plasma concentration versus time curve comparable with total area under curve from multiple dosing with immediate release dosage forms. This greatly reduces the possibility of side effects as the scale of side effects increase as we approach the maximum safe concentration.
Patient comfort and compliance	Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance.
Reduction in healthcare cost	The total cost of therapy of the controlled release product could be comparable or lower than the immediate-release product. With reduction in side effects, the overall expense in disease management also would be reduced

Ideal Characteristics of microspheres:

Ÿ The ability to incorporate high amount of drug.

Ÿ They should have controlled particle size and dispersability in aqueous vehicles for injection.

Ÿ Release of drug with a good control over a long period of time.

Ÿ They should be biodegradable.

Advantages of Microspheres:

Ÿ They provide constant drug concentration in blood and prolonged therapeutic effect.

Ÿ Reduce dosing frequency and thereby increase patient compliance.

Ÿ They protect the drug from enzymatic cleavage hence found to be the best for drug delivery of proteins.

Ÿ Microspheres protect the GIT from irritant effect of drug.

Ÿ Controlled release delivery of biodegradable microspheres used to control drug release rates thereby decreasing toxic side effects and eliminating the inconvenience of repeated injections.

Limitations of Microspheres:

· The cost of materials and processing of the controlled release formulations is higher than other formulations.

· Reproducibility is less.

· Process parameters such as change in temperature, pH, solvent addition, rpm of agitation may influence the stability of core particles.

· Polymeric microspheres are more susceptible to aggregation; to avoid this aggregation complex procedures are required⁴.

POLYMERS USED FOR CONTROLLED RELEASE:

The properties of the polymer microspheres such as their surface characteristics, release pattern of the drug and clearance, size and shape of microspheres are influenced by type of microspheres are used to prepare them. Suitable polymers that can be used to form polymer microspheres include soluble and insoluble, biodegradable and nonbiodegradable. These can be hydrogels, homopolymers, copolymers or blends, natural or synthetic polymers.

Ÿ Hydrophilic polymers: These are water soluble polymers that swell indefinitely in contact with water and eventually undergo complete dissolution.

Ÿ Hydrogels: These are water swellable materials, usually a cross-linked polymer with limited swelling capacity.

Ÿ Thermoplastic polymers: These polymers include the non-erodible neutral polystyrene and the semi crystalline bioerodible polymers, which generate the carboxylic acid groups as they degrade, e.g. polyanhydrides and polylactic acid. Various synthetic polymers used for controlled release formulations include polyvinyl alcohol, polyamides, polycarbonates, polyalkylene glycols, methylcellulose, ethyl cellulose hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethylcellulose⁵.

Various biocompatible polymers used in bioadhesive formulations include cellulose-based polymers, ethylene glycol polymers and its copolymers, oxyethylene polymers, polyvinyl alcohol, polyvinyl acetate.

Various biodegradable polymers used in bioadhesive formulations are poly (lactides), poly (glycolides), poly (lactide-co-glycolides), polycaprolactones, and polyalkyl cyanoacrylates. Polyorthoesters, polyphosphoesters, polyanhydrides, polyphosphazenes are the recent additions to the polymers.

PREPARATION OF MICROSPHERES:

Single Emulsion Technique:

Several Proteins and carbohydrates can be prepared by this technique. Natural polymers are dissolved in aqueous medium and the followed by dispersion in oil phase. Cross linking of this dispersion is done by one of these methods: 1. Cross linking by heat: Cross linking is done by adding the dispersion into heated oil, but this method is unsuitable for the thermolabile drugs. 2. Chemical cross linking agents: - Cross linking is done by using chemical agents i.e. formaldehyde, calcium chloride, glutaraldehyde etc. Chitosan solution (in acetic acid) by adding to Liquid paraffin containing surfactant resulting formation of w/o emulsion can be used for preparation of microspheres.

Double Emulsion Techniques:

It is best suited method for water soluble drugs, peptides, proteins and the vaccines. Natural as well as synthetic polymers can be used for preparing microspheres by this method. Multiple emulsions i.e. W/O/W is prepared by pouring the primary w/o emulsion into aqueous solution of poly vinyl alcohol. This w/o/w emulsion put at constant stirring for 30 min. Microspheres are collected by filtration under the vacuum.

Phase separation and Coacervation technique:

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. 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.

Spray drying and Spray congealing:

These methods are based on the drying of the mist 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.

Solvent Evaporation:

This process is carried out in a liquid manufacturing vehicle phase. The microcapsule coating is dispersed in a volatile solvent which is immiscible with the liquid manufacturing vehicle phase. A core material to be microencapsulated is dissolved or dispersed in the coating polymer solution. With agitation the core material mixture is dispersed in the liquid manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then heated if necessary to evaporate the solvent for the polymer of the core material is disperse in the polymer solution, polymer shrinks around the core. If the core material is dissolved in the coating polymer solution, matrix – type microcapsules are formed. The core materials may be either water soluble or water in soluble materials. Solvent evaporation involves the formation of an emulsion between polymer solution and an immiscible continuous phase whether aqueous (o/w) or nonaqueous⁶.

Ionotropic Gelation Method:

Ionotropic gelation technique has the ability of cross-linking of polyelectrolytes in presence of counter ions to form hydrogels. As it includes use of alginates, gellan gums, chitosan and other cellulose derivatives or polymers which are biodegradable, ionotropic gelation technique can be widely used for encapsulation of drug and even cells. These natural polyelectrolytes have a property of coating on the drug core and acts as release rate retardant containing certain anions on their chemical structure. These anions forms meshwork structure by combining with polyvalent cations and induce gelation by binding mainly to the anion blocks. Microspheres are prepared by dropping the drug loaded polymeric solution into the aqueous solution of polyvalent cations such as Ca2+, Ba2+ through needle. The cations forms a three dimensional lattice of ionically crossed linked moiety by diffusing into the drug loaded polymeric drops. There are two methods by which microspheres can be prepared External ionotropic gelation and Internal gelation/Emulsification. These methods differ from each other in the source of cross linking ion. In external ionotropic gelation cross linker ion is used externally i.e. drug loaded polymeric solution is dropped to externally available cross linking solution through needle. While in internal gelation cross linker ion is incorporated within the polymeric solution⁷.

FACTORS CONTROLLING DRUG DELIVERY RATES:

Controlled release is an attainable and desirable characteristic for drug delivery systems. Structure of the matrix where the drug is contained and the chemical properties associated with both the polymer and the drug are the main factors that influence the drug release rate. Conventional oral delivery is not rate controlled. A drug encapsulated in a slowly degrading matrix provides the opportunity for slower release effects, but polymer degradation is not the only mechanism for the release of a drug. The drug release is also diffusion controlled as the drug can travel through the pores formed during sphere hardening. The most desirable release profile would show a constant release rate with time. Factors that affect the release rate are as follows:

Polymer chemistry and erosion mechanism:

The type of polymer used in microsphere fabrication and the way in which the polymer degrades affect drug release kinetics. Depending on the rate of hydrolysis of their functional groups, polymers are categorized in two types: surface eroding and bulk eroding^{8, 9}.

Bulk-eroding polymers, typified by PLGA, readily allow permeation of water into the polymer matrix. As a result, microspheres fabricated from bulk-eroding polymers degrade throughout the microsphere matrix and the resulting monomers, oligomers and drug diffuse out of the sphere into the surrounding medium (Fig. 1A). Bulk-eroding polymer microspheres are often characterised by either a biphasic or triphasic release profile. The first phase is often a ‘burst’ of drug, as much as 50% of the total drug load released during the first few hours of incubation. The burst is thought to be a result of the drug located at or near the surface of the sphere or in pores/voids connected to the surface. After the burst, the monomers, oligomers and drug diffuse out of the sphere into the surrounding medium, forming a network of pores within the sphere. As time goes on, this network of water-filled pores increases in size until the sphere literally falls apart. If there is drug remaining in the sphere at the time the sphere reaches this critical state, there may be a third phase, where the entire amount of remaining drug is released as a result of the collapse.

Fig. 1: Polymer erosion in and drug release from microspheres fabricated from (A) bulk-eroding polymers and (B) surface- eroding polymers.

In contrast, surface-eroding polymers, such as polyanhydrides, are composed of relatively hydrophobic monomers linked by labile bonds. In this way, they are able to resist the penetration of water into the polymer bulk, while degrading quickly into oligomers and monomers at the polymer/water interface via hydrolysis. Drug is released at the micro- sphere surface as the polymer breaks down around it and also, typically to a lesser extent, by diffusion through the polymer phase toward the particle surface (Fig. 1B). If the drug of interest is homogeneously dispersed throughout the microsphere, the largest rate of release will occur at the beginning of the degradation. As time proceeds, the surface area of the sphere decreases and as a result the release rate decreases asymptotically¹⁰.

Polymer molecular weight:

Degradation of polymer microspheres shows a clear dependence on the molecular weight (MW) of the polymer. The rate of drug release from particles containing higher MW polymers is initially high, followed by a decrease which was then followed again by an increase. Degradation is the main release mechanism for low molecular weight polymers after the initial burst stage. Spheres containing high molecular weight polymers likely undergo initial slow drug release due to diffusion, followed by the main drug release due to degradation.

Blends of structurally different polymers:

Physical blending of two polymers can affect the release profiles of polymer spheres. Blending of two polymers of different molecular weights allows the manipulation of the timing associated with the degradation release. Blending of polymers increases density of microspheres and therefore molecular weight loss is slower during degradation. Therefore, drug release rate is slower from the polymer matrix.

Effects of the loaded drug:

In some cases the drug employed can induce polymer chain scission through nucleophilic degradation. Typically this is observed in medications containing amines whose nitrogen atom is nucleophilic. Drugs or polymers containing sterically available amines increased the rate of polymer degradation. Drug release profile is also depends on distribution of drug in the medium. Drug release begins at the sphere surface followed by release from the inner layers of the sphere; therefore the diffusional distance between the initial drug location inside the sphere affects the release profile. Drug uniformly dispersed in the sphere matrix can increase the initial burst effect.

Size distribution:

The release profiles are also dependent on the size of the microspheres; the rate of drug release was found to decrease with increasing sphere size. Therefore, by mixing microspheres of different sizes it is possible to obtain another degree of controlling release. More importantly, zero-order kinetics can be obtained by combining the proper formulation of microsphere sizes.

However, the effect of microsphere size can be significantly more complicated. As microspheres degrade, larger particles accumulate more of the acidic degradation products (e.g., lactic and glycolic acids from PLGA), leading to a more acidic microclimate. The reduced pH can, in turn, result in faster degradation/erosion of the particle and, subsequently, faster drug release.

Excipients:

A variety of excipients may be added to microsphere formulations to stabilize the emulsion during fabrication and to stabilize the drug during fabrication and/or release. The excipients may also impact drug release rates through several different mechanisms that depend on the microsphere system and the nature of the excipient. For example, to improve the encapsulation of BSA in microspheres of poly (ε-caprolactone) (PCL) and 65:35 PLGA, Yang et al. included PVA in the BSA solution to stabilize the primary emulsion, resulting in a more uniform BSA distribution in the microspheres (Yang). Increasing concentrations of PVA better prevented coalescence of the inner aqueous-phase droplets. As a result, increasing PVA concentration decreased the initial burst of protein and the overall release rates¹⁰.

Porosity:

Sphere porosity can affect the release kinetics. Studies show that highly porous matrix released a drug at a considerably higher rate than its non-porous counterpart. Factor related to sphere porosity is the initial burst effect, which corresponds to a rapid initial release of drug and is normally followed by relatively controlled linear release. This is attributed to the leaching which occurs at the outer wall of the sphere as it becomes hydrated. This can be minimized by formation of a non-porous outer sphere skin which can be controlled by sphere fabrication temperature¹¹

pH controlled release:

Drug release from the microspheres can be pH dependant. By the incorporation of pHsensitive groups, microspheres can be targeted to various biological environments or to specific organs. Until pH of shell degradation attains there is no drug releases from the polymeric matrix¹¹.

RECENT ADVANCES OF CONTROLLED RELEASE MICROSPHERES:

Controlled-release microspheres are in development for a number of interesting and important applications, especially for delivery of large, fragile drugs like proteins and nucleic acids. Several recent examples are described below:

Controlled release vaccines:

Vaccination has been highly successful for controlling or even eradicating many important types of infectious diseases, and new or improved vaccines are being heavily investigated for AIDS, hepatitis B, anthrax. .A frequent problem is the need for repeated administrations usually injections to ensure long-lasting immunity. One promising alternative is a single shot vaccine in which a drug delivery device provides the necessary boosters at specified times after administration having ability to more precisely control the time course of vaccine delivery may lead to more effective vaccination with current antigens and may allow utilization of antigens that were previously ineffective.

In one recent study, Moynihan et al. encapsulated a synthetic hepatitis B surface antigen in microspheres of oligosaccharide ester derivatives (OEDs) of trehalose using a double emulsion-solvent extraction/evaporation procedure¹². The OED microspheres induced immune responses in mice, similar to those obtained by the use of PLGA encapsulation. In addition, the OED microspheres maintained antigenicity at room temperature, in contrast to PLGA microspheres. Puri et al. reported a unique approach in which ovalbumin (OVA), a non-toxic biodegradable protein, encapsulated muramyl dipeptide (MDP). In this case, the micro- sphere-forming material, OVA, served as the delivery matrix as well as the antigen, and the encapsulant, MDP, was the adjuvant. The MDP-loaded microspheres induced antibody response in mice for 3 months following a single-shot injection¹³. These results demonstrated that sustained release of adjuvant, rather than antigen, can aid in the development of a single-shot vaccine.

DNA encapsulation:

Much research has focused on development of gene delivery vectors including viruses¹⁴, liposomes¹⁵ and polymers^16-18. However, parenteral administration of naked plasmid DNA (pDNA) leads to gene expression and controlled release of pDNA from polymeric matrices, microspheres¹⁹. One of the earliest reports of DNA microencapsulation demonstrated oral delivery of plasmid DNA in polyanhydrides nanoparticles. Somewhat surprisingly, the authors described expression of the reporter gene, β-galactosidase, in intestinal tissue and liver 5 days after a single oral dose of the DNA-loaded particles. A study was reported a year later. Hedley et al. showed that plasmid DNA encoding an antigen and encapsulated in PLGA microspheres of an appropriate size ( ̴7 μm) was phagocytosed by professional antigen-presenting cells and effectively activated cytotoxic T lymphocytes²⁰.This approach to DNA vaccination has been continuously developed by a number of groups, with excellent results.

Ophthalmic Drug Delivery:

Microspheres developed using polymer exhibits favorable biological behavior such as bioadhesion, permeability enhancing properties, and interesting physicochemical characteristics, which make it a unique material for the design of ocular drug delivery vehicles²¹. E.g. Chitosan, Alginate, Gelatin.

Oral drug delivery:

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

Gene delivery:

Microspheres could be a useful oral gene carrier because of its adhesive and transport properties in the GI tract. Eg. Chitosan, Gelatin, viral vectors, cationic liposomes, polycation complexes.

Nasal drug delivery:

Polymer based drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and swell easily when in contact with the nasal mucosa increases the bioavailability and residence time of the drugs to the nasal route²². Eg. Starch, Dextran, Albumin, Chitosan, Gelatin

Buccal drug delivery:

Polymer is an excellent polymer to be used for buccal delivery because it has muco/bioadhesive properties and can act as an absorption enhancer²³. E.g.Chitosan, Sodium alginate

Gastrointestinal drug delivery:

Polymer granules having internal cavities prepared by de acidification when added to acidic and neutral media are found buoyant and provided a controlled release of the drug²⁴. E.g. Eudragit, HPMC, Carbopol BSA, Gelatin.

Colonic drug delivery:

Polymeric microspheres can be used for targeting drug delivery to the colon for the colon diseases such as colon cancer, inflammatory bowel syndrome. Colon-speciﬁc bioadhesive microspheres can be used for protection of peptide drugs from the enzyme rich part of the GIT and to release the biologically active drug at the desired site for its maximum absorption. The absorption efﬁciency of Vancomycin by colonic placement of the bioadhesive microspheres was found to be equivalent to absorption of the peptide without absorption enhancers²⁵.

CONCLUSION:

Polymeric microspheres have shown great promise for the delivery of therapeutic agents due to their biocompatibility, ease of administration and capability for long-term sustained release. In addition, microspheres are useful for delivering several types of compounds, including small molecule drugs, protein therapeutics, vaccines and gene therapy agents. The controlled release of medications from polymer microspheres is achievable by manipulating the physical and chemical properties of the polymer as well as those of the microsphere. Factors such as polymer chemistry, polymer molecular weight, blends of structurally different polymers, amount of loaded drug and excipients inﬂuence the release proﬁle and can be tailored to ﬁt a desired release. For fabrication, encapsulation and stabilization of microspheres, future research will put increasing emphasis on targeting of particles to specific sites in the body. Till date, microspheres have been employed primarily as depot systems in which therapeutic agents are released locally, near the area in which the microspheres were administered. However, delivery of highly potent, locally acting drugs, such as chemotherapeutics and other anticancer compounds, may require localized delivery, but the required site may not be accessible by a syringe. Targeting of microspheres and nanospheres could enhance such therapies by providing selective drug delivery to specific tissues or cells where the drug is needed most. The present review article shows that microspheres are better choice of drug delivery system than many other types for controlled drug delivery of drugs.

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Received on 28.06.2018 Modified on 30.07.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3): 193-199.

DOI: 10.5958/0975-4377.2018.00030.7