A Review On

Microspheres technology and its application
By

Gunja Chaturvedi
(I.D no- 2008H146101)

Submitted in partial fulfilment of the course PHA G632: Dosage Form Design

Date of Submission 01/04/2009 Submitted to Dr. R. N Saha (Instructor In-charge)

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE, PILANI, RAJASTHAN – 333 031 April 2009

REVIEW ON MICROSPHERES
Chaturvedi Gunja , Bhagav Prakash, Prof. R.N Saha Birla Institute of Technology and Science, Pilani, Rajasthan (India) 3 Faculty of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 4 Dean, Faculty Division-3, Birla Institute of Technology & Science, Pilani, Rajasthan (India) Abstract :Nonideal pharmaceutical, pharmacokinetic, and therapeutic properties often combine to reduce the effectiveness of certain compounds. For the vectoring of such compounds to target areas, liposomes, nanoparticles, and microspheres have been suggested. Since organ distribution of the latter is dependent upon their size and shape, it is reasonable to attempt second-order targeting of microspheres on this basis. The range of techniques for the preparation of microspheres offers a variety of opportunities to control aspects of drug administration.This approach facilitates accurate delivery of small quantities of potent drugs ,reduce drug concentrations at sites other than the target organ or tissue and protection of labile compounds before and after administration and prior to appearance at the site of action. Keywords: microspheres, formulation parameters, biodegradable polymers,matrix and reservoir type microspheres, particle size, ,colonic drug delivery, ,nasal delivery.

Contents: Introduction  Definition and description  History  Potential use of microspheres  Microspheres manufacture by different methods  Approaches related to formulation and process parameters in microsphere manufacturing  Effect of process and formulation parameters on inernal morphology of microspheres loaded with hydrophobic drug  Proteins encapsulated in microspheres and its stability  Preparation of Biodegradable Microspheres and Matrix Devices Containing Naltrexone ● Approaches towards drug targeting using microspheres  Nasal delivery  Colonic drug delivery ● References

Introduction The range of techniques for the preparation of microspheres offers a variety of opportunities to control aspects of drug administration.This approach facilitates the accurate delivery of small quantity of the potent drugs ,reduced drug concentration at the site other than the target site and the protection of the labile compound before and after the administration and prior to appearance at the site of action.The behaviour of the

drugs in vivo can be manipulated by coupling the drug to a carrier particle. The clearance kinetics,tissue distribution, metabolism and cellular interaction of the drug are strongly influenced by the behaviour of the carrier. The exploitation of these changes in pharmacodynamics behaviour may lead to enhanced therapeutic effect. However ,an intelligent approach to therapeutics employing drug carriers technology requires a detailed understanding of the carrier interaction

with critical cellular and organ systems and of the limitations of the systems with respect to the formulation procedures and stability. A variety of agents have been used as drug carrier, including immunoglobulins serum proteins ,liposomes, microspheres ,nanoparticles ,microcapsules and even cells such as erythrocytes. The characteristics of microspheres containing drug should be correlated with the required therapeutic action and are dictated by the materials and the methods employed in the manufacture of delivery systems. [1] DEFINITION AND GENERAL DESCRIPTION Microspheres can be defined as solid, approximately spherical particles ranging in size from 1 to 1000 µm.They are made of polymeric,waxy or other protective materials,that is biodegradable synthetic polymers and modified natural products such as starches,gums ,proteins,fats and waxes.The natural polymers include albumin and gelatine, the synthetic polymer include polylactic acid and polyglycolic acid. The solvents used to dissolve the polymeric materials chosen according to the polymer and drug solubilities and stabilities ,process safety and economic considerations. Microspheres are small and have large surface-to-volume ratio. At the lower end of their size range they have colloidal properties. The interfacial properties of microspheres are extremely important ,often indicating their activity. [1] HISTORY The concept of packaging microscopic quantities of materials within microspheres dates back to the 1930s and the work of Bungenberg de Jong and coworkers on entrapment of substances within coacervates. The first commercial application of encapsulation was by the National Cash Register Company for the manufacture of carbonless copying paper. The technology and applications have advanced over the last several dacades. [1]

THE POTENTIAL USE OF MCROSPHERES IN PHARMACEUTICAL INDUSTRY  Conversion of oils and other liquids to solids for ease of handling  Taste and odour masking  Increasing the stability of the drug against the environmental conditions  To delay the volatilisation  Separation of incompatible materials  Improvement of flow properties of powders  Safe handling of toxic substances  Improve the solubility of water insoluble substances by aiding in dispersion of such material in aqueous media  Production of sustained release,controlled release and targeted medications  Reduce the dose dumping potential compared to large implantable devices. [1]

Microspheres manufacture The most important physicochemical characteristics that may be controlled in microsphere manufacture are: - Partical size and distribution - Polymer molecular weight - Ratio of drug to polymer - Total mass of drug and polymer Different methods of microspheres manufacturing are: - Wax coating and hot melt - Spray coating and pan coating - Coacervation - Spray drying - Solvent evaporation and precipitation - Freeze drying - Chemical and thermal cross – linking

Wax coating and hot melt: wax may be used to coat the core particles, encapsulating the drug by dissolution or dispersion in molten wax. The waxy solution or suspension is dispersed by high speed mixing into cold solution, such as cold liquid paraffin. The mixture is agitated for at least one hour. The external phase (liquid paraffin) is then decanted and the microspheres are suspended in a non- miscible solvent and allowed to air dry. Wax coated microspheres ,while inexpensive and often used,release drug more rapidly than polymeric microspheres. Carnauba wax and beeswax can be used as the coating materials and these can be mixed in order to achieve desired characteristics. Spray coating and pan coating: spray coating and pan coating employ heatjacketed coating pans in which the solid drug core particles are rotated and into which the coating material is sprayed. The core particles are in size range of micrometers upto few millimetres. The coating material is usually sprayed at angle from the side into the pan. The process is continued until an even coating is completed. Coating a large number of particles may provide a safer and more consistent release pattern than coated tablets. In addition,several batches of microspheres cab be prepared with different coating thickness and mixed to achieve specific controlled release pattern. Coacervation : This process is a simple separation of macromolecular solution into two immiscible liquid phases,a dense coacervate phase,which is relatively concentrated in macromolecules and a dilute equilibrium phase. In presence of only one macromolecule this process is referred to as simple coacervation. When two or more macromolecules of opposite charge are present ,it is referred to as complex coacervation. Former one is induced by various parameters like change in temperature, addition of non-solvent or microions , which results in dehydration of macromolecules because they promote polymer-polymer interactions over polymer- solvent interaction. And the latter is induced by large number of

variables like pH,ionic strength,macromolecule concentration,macromolecule ratio and macromolecular weight which results in a larger number of controllable parameters. These can be manipulated to produce microspheres with specific properties. Spray drying: It is single step,closedsystem process applicable to wide variety of materials,including heat-sensitive materials. The drug and polymer coating materials are dissolved in suitable solvent(aqueous or non-aqueous) or the drug may be present as a suspension in the polymer solution. Alternatively, it may be dissolved or suspended within an emulsion or coacervate system. For example,biodegradable polylactide microspheres can be prepared by dissolving the drug and the polymer in methylene chloride. The microsphere size is controlled by the rate of spraying,the feed rate of the polymer drug solution,the nozzle size ,the temperature in drying and collecting chambers,and the size of the two chambers. The quality of the spray dried products are improved by the addition of plasticizers that promote the polymer coalescence and film formation and enhance the formation of smooth surfaced and spherical microspheres. Solvent evaporation: For this method the drug and the polymer must be soluble in organic solvent,frequently methylene chloride. The solution containing polymer and drug may be dispersed in an aqueous phase to form droplets. Continuous mixing and elevated temperatures may be employed to evaporate the more volatile organic solvents and leave the solid polymer-drug particles suspended in an aqueous medium. The particles are finally filtered from the suspension. Precipitation : It is a variation on the evaporation method. The emulsion consists of polar droplets dispersed in a non-polar medium. Solvent may be removed from the droplets by the use of a cosolvent. The resulting increase in the polymer concentration causes precipitation forming a suspension of microspheres.

Freeze Drying: This technique involves the freezing of the emulsion and the relative freezing points of the continuous and dispersed phases are important. The continuous phase solvent is usually organic and is removed by sublimation at low temperature and pressure. Finally the dispersed phase solvent of the droplets is removed by sublimation,leaving polymerdrug particles. Chemical and thermal cross- linking: microspheres made from natural polymers are prepared by a cross-linking process; polymer include gelatin, albumin ,starch and dextran. A water-oil emulsion is prepared ,where the water phase is a solution of polymer that contains drug to be incorporated. The oil phase is a suitable vegetable oil or oil - organic solvent mixture containing an oil soluble emulsifier. Once the desired water-oil emulsion is formed ,the water soluble polymer is solidified by thermal treatment or addition of a chemical cross-linking agent such as glutaraldehyde to form a stable chemical cross link as in albumin. If chemical or heat cross linking is used , the amount of chemical and the period and intensity of heating are critical in determining the release rates and swelling properties of the microspheres. [1],[2],[3],[4] Approaches related to formulation and process parameters in microsphere manufacturing 1.Effect of process and formulation parameters on inernal morphology of microspheres loaded with a hydrophobic drug: ABT627 is a newly synthesized drug for the treatment of prostate cancer. It is a lipophilic drug ,and taking it as a model drug the effect of continuous phase/ dispersed phase ratio(CP/DP ratio),PLGA concentration ,continuous phase pH ,polyvinyl alcohol concentration and initial drug loading on the physicochemical characteristics of the developed microspheres was studied and internal morphology of the microspheres was analyzed by stereological method to elucidate the distribution and the release mechanism of the drug from microspheres.

Fig 1. structure of ABT627

From the above studies it was found that for the encapsulation of the hydrophobic substances into PLGA matrix, CP/DP ratio is a crucial factor. It was observed that the drug loading increased significantly with increasing CP/DP ratio accompanied by decreasing the burst effect. At the CP/DP ratio 20,the microspheres with a core shell structure were observed and the internal porosity of the microspheres decreased with increasing the CP/DP ratio. Increasing the PLGA concentration ,increased particle size but decreased drug release rate was observed. Increasing the PVA concentration in continuous phase from 0.1% to 0.5% increased the drug release rate. The maximum solubility of the drug in PLGA microspheres is approximately 30% under which it was dispersed in PLGA matrix in a molecular state. Its release rate was decreased with increasing the intial drug loading. ABT627 was slowly released from the PLGA microspheres over 30 days by a combination of pore diffusion and polymer degradation. During the first 13 days,it was released mainly by diffusion supported by unchanged internal morphology of the microspheres after 7 days of release. Internal morphology observation after incubating the microspheres for 17 days indicated that ABT627/PLGA microspheres were mainly degraded by auto-catalyzation from inside,as revealed by core-shell structure of the microsphere at the release stage.
[5],[6],[7]

2.Reversible protein precipitation to ensure stability during encapsulation within PLGA microspheres: although the purpose has been limited due to physical and chemical instability. Due to relatively high enzymatic susceptibility and short half life,much attention has been paid to their delivery from systems controlling local release. Since a solid-state protein exhibits restricted conformational flexibility,non-aqueous encapsulation approaches have emerged to ensure protein stability upon encapsulation within biodegradable polyester microspheres.Various methods like spraydrying or spray-freeze drying have been reported for the preparation of small protein particles. Although these methods can generate protein particles ,they present some drawbacks for microencapsulation that they are technically complex and lead to low protein recovery and also may denature the proteins. The aim of this study was to develop a non- denaturing method to prepare protein particles. Freeze –drying has often been used to obtain protein particles without protein loss but it induce the formation of large particles. To obtain fine particles and preserve protein integrity,proteins have been freeze- dried with PEG which induces a two –phase separation. This approach has been used for protein microencapsulation by solid/oil/water (s/o/w) and s/o/o techniques. However ,the remaining amount of PEG in the freeze-dried protein products leads to an important initial burst (20% in 1 hr) upon release from PLGA microspheres, and so an adaptation of the process was necessary. So in order to obtain protein particles without these disadvantages,from an aqueous solution protein precipitation was induced via isoelectric precipitation, reduction of dielectric constant by addition of watermiscible organic solvents ,the reduction of the protein charge by changing the pH and the addition of the polymers or salts. In this study, an organic solvent ,Glycofurol ,was employed by preference to induce the formation of fine protein particles. It was chosen as a precipitant because it is non-

production of various proteins has become possible with the recent advances in biotechnology,their use for therapeutic toxic PLGA solvent which could be used to prepare PLGA microspheres. Moreover ,it is a protic solvent containing hydrogen attached to oxygen so that it is able to form hydrogen bonds or to donate a proton such as in stabilizing PEG. The presence of glucofurol induces a liquid –liquid phase separation resulting in a protein – rich phase and a protein –poor phase. The addition of salt (sodium chloride) helped in collecting the maximum amount of protein precipitates by reducing the electrostatic repulsive interactions between charged proteins and promoting attractive hydrophobic interactions. The reason behind selecting sodium chloride was related to its possible use in parenteral pharmaceutical formulations and to its intermediate location in the lyotrophic series and also it decreases theprotein solubility very little with minimal denaturant effects. The various process parameters discussed above were modified to optimize the precipitation efficiency of four model proteins : lysozyme,αchromotrypsin ,peroxidase and βgalactosidase. As monitored by enzymatic activity measurement of rehydrated particles ,conditions to obtain more than 95% of the reversible precipitates were defined for each protein. The study of the rehydrated particles by absorbance spectroscopy, fluorescence spectroscopy and circular dichroism showed an absence of structuralperturbation after precipitation. The protein particles were then microencapsulated within PLGA microspheres using s/o/w technique. The average encapsulation yield was around 80% and no loss of protein activity occurred after the encapsulaton step. Additionally , a lysozyme in vitro release study showed that all of the released lysozyme was biologically active. So this method of protein precipitation is appropriate for the encapsulation in PLGA microspheres of various proteins without inactivation. [8],[9],[10]

3. Preparation of Biodegradable Microspheres and Matrix Devices Containing Naltrexone: Naltrexone is an opiate antagonist used mainly as an adjunct to prevent relapse in detoxified opioid-dependent patients. It is currently given orally as tablets or capsules in a daily dose of 50 mg. Naltrexone is orally active with a relatively short half-life and subject to extensive hepatic first-pass metabolism.Naltrexone provides no euphoric effects, and there are no observable pharmacological consequences when a patient discontinues the drug. For naltrexone treatment to be effective, a sufficient level of the drug concentration must be maintained. The minimum effective concentra-tion of naltrexone for the treatment of opiate addiction is estimated to be in the range of 0.5 to 1.0 ng/mL. Detoxified patients are advised to continue the naltrexone therapy for 4 to 8 months. This treatment typically requires the patient to self-administer dosages of the drug several times a week. The main drawback in naltrexone treatment protocol is patient compliance. A possible means of improving patient compliance and concomitant rehabilitation is the use of controlled drug delivery systems of opioid

antagonists. In this study ,poly(L-lactide) (PLA) microspheres containing naltrexone prepared by sol-vent evaporation technique were compressed at temperatures above the Tg of the polymer. The effect of different process parameters, such as drug/polymer ratio and stirring rate during preparation of micro-spheres, on the morphology, size distribution, and in vitro drug release of microspheres was studied.

Fig.2.Effect of particle size on drug release from microspheres with 20% drug loading

Fig.4. Effect of drug loading on drug release from microspheres with the same size range Fig.3. Effect of particle size on drug release from microspheres with 40% drug loading By increasing the stirring speed from 400 to 1200 rpm, the mean diameter of microspheres decreased from 251 μm to 104 μm. The drug release rate from smaller microspheres was faster than from larger microspheres. However, drug release from microspheres with low drug content (20% wt/wt) was not affected by the particle size of microspheres.

Increasing the drug content of microspheres from 20% to 50% wt/wt led to signifi-cantly faster drug release from microspheres. It was also shown that drug release from matrix devices pre-pared by compression of naltrexone microspheres is much slower than that of microspheres. No burst re-lease was observed with matrix devices. Applying higher compression force, when compressing micro-spheres to produce tablets, resulted in lower drug release from matrix devices. The results suggest that by regulating different variables, desired release profiles of naltrexone can be achieved using a PLA micropar-ticulate system or matrix devices. [16],[17],[18] Approaches towards using microspheres drug targeting

1.Spray –dried microspheres based on methylpyrrolidinone chitosan as new carrier for nasal administration of metoclopramide : In recent years,chitosan derivatives have been studied to improve polymer solubility at different pH values and to promote the permeability of anionic drugs thereby avoiding the precipitation of the drug –polymer complexes.5 – methylpyrrolidinone chitosan (MPC) is a chitosan derivative in which the amino group of the glucosamine units of the polysaccharide backbone are partially substituted by methylpyrrolidinone(MP) in position 5. It belongs to the class of the gel –forming reabsorbable biopolymeric substituted chitosans possessing documented biological significance. This chitosan derivative combines the biocompatibility of chitosan and the hydrophilic characteristics of the pyrroilidinone moiety ,being particularly susceptible to the hydrolytic action of lysozyme. Nasal delivery has generated interest as an alternative route for the administration of drugs and biomolecules that are susceptible to enzymatic or acidic degradation and first –pass hepatic metabolism. Possible pathways for a drug to permeate across the nasal mucosa are passive transport ation ,carrier mediated ,transcytosis and transport through intercellular tight junctions. However ,the

nasal delivery has limitations which have restricted its use to the delivery of a few drug molecules. The permeability of nasal mucosa is normally low for the polar molecules: for small polar drugs the bioavailability is generally in the region of 10% and for the peptides such as calcitonin and insulin normally not above 1%. Another factor of importance for the low membrane transport is the general rapid clearance of the administered formulation from the nasal cavity due to mucociliary clearance mechanism. It has been shown that for both liquid and powder formulations that are not mucoadhesive ,the half life of clearance are in order of 15 -20 mins. So in this study chitosan derivative MPC is used to produce microspheres for nasal delivery of metoclopramide. The mechanism of action of chitosan in improving the transport of polar drugs across the epithelial membrane is believed to be combination of bioadhesion and transient opening of tight junctions in the cell membrane to enable the passage of the polar drugs. A non –derivatized chitosan has been used as comparison and metoclopramide hydrochloride has been chosen as model drug. The metoclopramide loaded MPC microspheres were made by spray –drying technique. They showed similar properties of microparticles made by chitosan chosen as reference with respect to size and in vitro release behaviour. And the microspheres based on MPC are characterized by better mucoadhesiveness,less swelling capability and more prolonged ex –vivo permeation profile than the particles containing chitosan,moreover they are able to provide a gel (when they come in contact with aqueous solutions) which shows different properties dependent upon the medium used. These properties make microspheres based on derivatized chitosan suitable for nasal administration,infact the mucoadhesiveness might prolong the residential time of the formulation inside the nasal cavity while a moderate swelling could avoid potential mucosal damages or inconveniences to the possible users.
[11],[12],[13]

2.Development of enteric –coated calcium pectinate microspheres intended for

colonic drug delivery: Among the various strategies proposed to target orally administered drugs to the colon ,those based on drug release triggered by colon microflora are generally considered the most effective regarding target selectivity. And for this purpose the natural biodegradable polymers such as pectins are employed due to their ability to act as specific substrate for colonic microflora and also combined with their high safety,non –toxicity and biocompatibility characteristics. Most of the colon targeted drug delivery system developed so far are single –unit systems. On contrary ,multi – particulate systems can offer several advantages over single –unit formulations like quick spread out on their arrival to the colon,with a sharp increase in the surface area exposed to bacterial breakdown that produces rapid drug release and thereby improves the drug absorption. In this study enteric –coated calcium pectinate microspheres are formulated as a colon – targeted delivery system and Theophylline is used as a model drug since it is well absorbed in the large intestine in humans and both its anti –asthma activity and pharmacokinetic properties make it an interesting candidate for such kind of modified –release preparations. The influence of pectine type ,calcium ion concentration and cross –linking time on both drug entrapment efficiency and dug release pattern was investigated. And the effect of varying the level of the pH – dependent coating polymer (Eudragit S100) was also evaluated. The Ca pectinate microsphere(MS) prepared with CF020 i.e low –methoxylated amidated pectins were better than those obtained with AU701 i.e low –methoxylated pectins ,for both their greater stability during storage and more regular and homogeneous morphological properties. The shape of the former MS was poorly influenced by the variations in Ca concentrations maintaining a homogeneous spherical form also at lower Ca concentration.while the latter required at least 20% w/v of Ca ion concentration for obtaining MS of satisfactory and well reproducible morphological properties. This finding lead to an important conclusion that the choice of the most

suitable pectin type is very essential considering that increase in Ca amounts gave rise to a decrease in rate of drug release. From the release test performed under pH gradient and in presence of pectinolytic enzymes in simulated colonic medium it was revealed that the Ca – pectinate MS did not undergo any selective colonic –microflora triggered drug release mechanism and the observed slowing down effect of free Ca ions in the enzymatic degradation rate of the pectin matrix can only partially concur to explain the almost complete lack of activity shown by pectinolytic enzymes. Inspite of this unexpected result,the CF020 MS ,realized with low Ca chloride concentration (2.5% w/v) and coated with an appropriate thickness pf a pH –dependent polymeric film (100%w/v), demonstrated to be suitable to adequately modulate drug release through a mixed approach of pH and transit –time control,completely avoiding drug release during the first 2 h in gastric ambient,limiting to less than 10% release in the following 2 h and reaching 100% release in the colonic simulated medium within less than 24 hours.[14],[15] Conclusion:Drugs can be targeted to specific sites in the body using microspheres. Degree of targeting can be achieved by localization of the drug to a specific area in the body(for example in lungs),to a particular group of cells(for example, kupffer cells) and even to the intracellular structures(such as lyzosomes or cell nucleus). The rate of drug release from the microspheres dictates their therapeutic action. Release is governed by the molecular structure of the drug and the polymer,the resistance of the polymer to degradation ,and the surface area alongwith the porosity of the microspheres. The internal structure of the microspheres can vary as a function of the microencapsulation process employed. Controlled drug release from microspheres occurs by diffusion of the drug through a polymeric excipient, diffusion of the entrapped drug through the pores in the polymeric microspheres. Microspheres with high drug content release the active ingredient more rapidly than with a low

load. Physicochemical properties of the drug and excipient such as permeability of one in the other, identity of the polymer, degree of crystallinity ,inclusion of plasticizers and fillers and thickness of the polymer influences the drug release rate.

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