M Sam, D Gayathri, V Prasanth, B Vinod
M Sam, D Gayathri, V Prasanth, B Vinod. NSAIDs As Microspheres. The Internet Journal of Pharmacology. 2007 Volume 6 Number 1.
Nonsteriodal anti-inflammatory drugs (NSAIDs) are amongst the most commonly prescribed medications in the world. Almost all the NSAIDs available in the market have severe side effects. As awareness of the GI side effects associated with NSAIDs increases, safety becomes a primary requisite in treatment. A trend in NSAID development has been to improve therapeutic efficacy and reduce the severity of GI side effects through altering dosage forms by modifying release of the formulations to optimize drug delivery. One such approach is using polymeric microspheres as carriers of drugs. A brief review of the NSAIDs which are incorporated into microspheres, the polymers used, various methods of preparation,
Non steroidal anti-inflammatory drugs (NSAIDs)
The use of Nonsteriodal anti-inflammatory drugs (NSAIDs) began over 100 years ago with the introduction of salicylic acid for the treatment of rheumatic diseases. Now NSAIDs are amongst the most commonly prescribed medications in the world owing to their efficacy as anti-inflammatory, anti-thrombotic, anti-pyretic, and analgesic agents. During the past 30 years, there has been a substantial increase in the number of clinically available NSAIDs. They annually account for 70 million prescriptions and 30 billion over-the-counter (OTC) medications sold in the United States alone. (1)
Despite the diversity of their chemical structures, these NSAIDs all share the same therapeutic properties alleviating swelling, redness and pain of inflammation, reducing fever and curing headache. However, numerous reported adverse drug reactions, case-control, and post-marketing surveillance studies have revealed that NSAIDs are associated with extensive side effects, the most prevalent being GI disturbances (2).
Side effects also include interfering with the birth process and damaging the kidney. Indeed epidemiological studies have characterized the degree of gastric damage caused by different compounds. An estimated 34-46% of the patients on NSAID therapy would have some form of GI side effects. In USA alone some 100000 patients on NSAIDs are hospitalized each year because of perforations, ulcers, or bleeding in the stomach and about 15000 of these die in intensive care (3). Koch M et al studied the average risk for GI ulceration and reported that gastric ulcers were 3.6% and 6.8% with up to2 weeks and more than 4 weeks use of NSAIDs, and duodenal ulcers the average risks were 3.0% and 4.0% with <2 weeks and >4 weeks use of NSAIDs respectively. (4)
These adverse effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. NSAIDs exert their clinical effects by inhibiting cyclooxygenase (COX), thereby blocking the synthesis of prostaglandins. Cyclooxygenase exists in at least two different isoforms COX-1 and COX-2. COX- 1 is expressed constitutively and is present in most cells under physiological conditions, whereas COX-2 is induced in response to inflammatory stimuli. A major change in the use of NSAIDs occurred with the discovery of COX-2 inhibitors. In the beginning it was thought that COX- 2 inhibitors eliminate the side effects of COX-1. But the latest findings from clinical trials and other sources reported that their side effect profile is almost similar to that of older NSAIDs. These COX-2 inhibitors are contraindicated in kidney dysfunction and congestive heart failure where the extent of effect is severe than in the case of some COX-1 inhibitors (5). More reports on safety have to come for the complete acceptance of COX- 2 inhibitors. Therefore older COX-1 NSAIDs are still in use. More over many of the COX- 2 inhibitors available now are having higher elimination half-life. There fore there is no much potential in formulating them into controlled release dosage forms. Hence this article deals with older COX- 1 inhibitors.
Most of the conventional NSAIDs have a shorter half-life, which requires frequent dosing and thus reduces the patient compliance. As awareness of the GI side effects associated with NSAIDs increases, safety becomes a primary requisite in treatment.
Why a new drug delivery system?
Development of new drug molecule is expensive and time consuming. Improving safety efficacy ratio of “old” drugs has been attempted using different methods such as individualizing drug therapy and therapeutic drug monitoring. Delivering drug at controlled rate, slow delivery, and targeted delivery are other very attractive methods and have been pursued very vigorously (6).
For drugs with short half-lives and with a clear relationship between concentration and response, it will be necessary to dose at regular, frequent intervals in order to maintain the concentration within the therapeutic range. Higher doses at less frequent intervals will result in higher peak concentrations with the possibility of toxicity. For some drugs with wide margins of safety, this approach may be satisfactory.
A trend in NSAID development has been to improve therapeutic efficacy and reduce the severity of upper GI side effects through altering dosage forms of NSAIDs by modifying release of the formulations to optimize drug delivery. These formulations are designed to increase patient compliance through a prolonged effect and reduce adverse effects through lowered peak plasma concentrations.
Further, currently available slow release oral dosage forms, such as enteric coated/ double-layer tablets which release the drug for 12-24 hours still result in inefficient systemic delivery of the drug and potential gastrointestinal irritation. Therefore, currently available slow release oral dosage forms of NSAIDs induces systemic effects and the drug is not efficiently used at the site of inflammation.7
Formulations can affect the safety of preparations by controlling the rate of release of the drug at sensitive sites, by delivering drug to specific sites to minimise systemic exposure, or delivering drug in such a way as to change the rate or extent of the formation of toxic metabolite.
Controlled release dosage forms cover a wide range of prolonged action formulations, which provide continuous release of their active ingredients at a predetermined rate and predetermined time. One such approach is using polymeric microspheres as carriers of drugs. Many authors have reported that nanoparticles and microparticles have a tendency to accumulate in the inflammed areas of the body. Microspheres can be described as small particles (in 1-1000 micrometer size range) for use as carriers of drugs and other therapeutic agents. The term microspheres describe a monolithic spherical structure with the drug or therapeutic agent distributed throughout the matrix either as a molecular dispersion or as a dispersion of particles. They can also be defined as a structure made up of continuous phase of one or more miscible polymers in which the particulate drug is dispersed at the macroscopic or molecular level. Microsphere based drug delivery systems have received considerable attention in recent years.
Advantages and disadvantages of NSAID microspheres
The following advantages make them a promising means for the delivery of NSAIDs. Microspheres provide constant and prolonged therapeutic effect, which will reduce the dosing frequency and thereby improve the patient compliance. They could be injected in to 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 effects. Microsphere morphology allows a controllable variability in degradation and drug release.
Many authors have reported that nanoparticles and microparticles have a tendency to accumulate in the inflamed areas of the body. It was reported that microspheres of NSAIDs reduces the GI toxic effects, exhibit sustained action and ofcourse increase patient and therapeutic compliance. Microencapsulation for oral use has been employed to sustain the drug release, and to reduce or eliminate gastrointestinal tract irritation. In addition, multiparticulate delivery systems spread out more uniformly in the gastrointestinal tract. This results in more reproducible drug absorption and reduces local irritation when compared to single-unit dosage forms such as nondisintegrating, polymeric matrix tablets. Unwanted intestinal retention of the polymeric material, which may occur with matrix tablets on chronic dosing, can also be avoided (7,8,9,10,11).
At the same time they encounter with the disadvantages of common modified release formulations. The release rate of controlled-release products can be altered by various factors including food and the rate of transit through the gut. There may be some differences in the release rate from one dose to another, but these have been minimised by modern formulations. Extended-release or controlled release products generally contain a higher drug load and any loss of integrity of the release characteristics of the dosage form may lead to potential toxic problems. Some extended-release products can be divided to provide half-doses, others should only be taken whole. Dosage forms of this category should not be crushed or chewed as the slow-release characteristics may be lost and toxicity may result. Further larger size of extended-release products may cause difficulties in ingestion or transit through the gut. Even though they have number of pharmacological advantages, the distal intestinal toxicological manifestations of sustained release and enteric-coated NSAID formulations should not be forgotten. One consequence has been to shift the site of GI inflammation from the stomach to the small intestine, where damage can remain asymptomatic until more serious problems arise. (12)
However, each novel drug delivery systems has to be evaluated on its merits. One cannot generalise about novel delivery systems, or even established sustained release systems, because of the different manner in which they achieve their effect.
Number of research works have been carried out and reported on this topic. On the theoretical basis and the
Commonly Used Polymers
Controlled drug delivery occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner. NSAIDs release pattern can be modified by micro encapsulation with choice of suitable biodegradable polymer on the basis of its crystallinity, hydrophobicity, copolymer ratio and its molecular weight. Due to biodegradability and reputation as safe materials ,aliphatic polyesters like poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polycaprolactone are used to modify release of NSAIDs.
Microspheres of biodegradable and non-biodegradable polymers have been investigated for NSAIDs depending on final application. Biodegradable polymers have many advantages that they degrade in biological fluids, can be injected, implanted or inserted in to the body, they are non toxic and surgical removal of the polymer skeleton is not required. Therefore microspheres using various kinds of biodegradable polymers and methods have been studied extensively during the past two decades. These materials degrade within the body as a result of natural biological processes and eliminated. Most biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically acceptable and progressively smaller compounds.
The use of natural biodegradable polymers as drug carriers has received considerable attention in dosage form design. They remain attractive primarily because they are natural products of living organisms, readily available, relatively inexpensive and capable of a multitude of chemical modifications. A majority of investigations of natural polymers as matrices in drug delivery systems have centered on proteins and polysaccharides. Synthetic biodegradable polymers have advantages like high purity, available in different molecular weights; can be easily and reproducibly prepared. Many NSAIDs have been formulated into microspheres using biodegradable and non-biodegradable polymers and various methods for oral, parenteral and topical applications. To be successfully used in controlled drug delivery formulations, a material must be chemically inert and free of leachable impurities. It must also have an appropriate physical structure, with minimal undesired aging, be readily processable, should not invoke an inflammatory or toxic response, is metabolized in the body after fulfilling its purpose, leaving no trace, is easily processable into the final product form, must have acceptable shelf life and easily sterilizable. The molecular weight and viscosity of the polymer solution are the critical parameters in the preparation of microspheres.
The commonly employed polymers for the preparation of microspheres of NSAIDs are given in
Biodegradation has been accomplished by synthesizing polymers that have hydrolytically unstable linkages in the backbone. The most common chemical functional groups with this characteristic are esters, anhydrides, orthoesters, and amides.
The dispersion of NSAIDs into biodegradable polymeric matrices of poly-lactide-co-glycolide microspheres, is a good approach to obtain the therapeutic effect at a predetermined time (controlled release) and at the same time minimising the side effects of drugs. ‘In vitro' studies on these systems are extensively reported in the literature (13). Bozdag S et al. prepared the microspheres of naproxen sodium using BSA and PLGA biodegradable polymers. They prepared Naproxen Sodium loaded microsphere formulation using natural Bovine Serum Albumin (BSA) and synthetic biodegradable polymers such as poly (lactide-co-glycolic acid) (PLGA) (50:50 MW 34 000 and 88 000 Da) for intra-articular administration, and to study the retention of the drug at the site of injection in the knee joint. The mean particle size for BSA microspheres was found to be 10.0 µm, for PLGA microspheres, 9.0 and 5.0 µm for MW 34 000 and 88 000 Da, respectively. For in vivo studies, monoarticular arthritis was induced in the left knee joints of rabbits by using ovalbumin and Freund's Complete Adjuvant as antigen. A period of 4 days was allowed for the formation of arthritis in the knee joints, and then the drug loaded microspheres were injected directly into the articular cavity. At specific time points, gamma scintigrams were obtained to determine the residence time of the microspheres in knee joints, in order to determine the most suitable formulation. Their study indicated that PLGA, a synthetic polymer, is more promising than the natural type BSA microspheres for an effective treatment of of mono-articular arthritis (9).
Polylactides, polyglycolides, and their copolymers will break down to lactic acid and glycolic acid, enter the Kreb's cycle, and be further broken down into carbon dioxide and water and excreted through normal processes. Degradation may take place through bulk hydrolysis, in which the polymer degrades in a fairly uniform manner throughout the matrix. But in the case of polyanhydrides and polyorthoesters, the degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system.
The drug content, entrapment efficiency, surface morphology, release rate, particle size, etc of the prepared microspheres were highly dependent on the molecular weight of the polymer used.
Chitosan is a polysaccharide with a structure compatible to cellulose. Chitosan is positively charged and is mucoadhesive. Chitosan is said to have wound-healing effects as well as anti-acidic, anti-ulcer and cholesterol-lowering properties and a tendency to reduce gastric irritation. Retention of drug delivery systems in the stomach prolongs the GI transit time, which helps in the improvement of oral bioavailability of basic drugs. Amal H. EL-Kamel et al evaluated the stomach protective activity of ketoprofen floating microparticles. Ketoprofen loaded microparticles were found to be less ulcerogenic and they protected the stomach probably by preventing the intimate contact of ketoprofen with gastric mucosa (15). Therefore oral formulations of Chitosan based drug delivery systems of NSAIDs may be useful.
Influence on drug loading and drug release of different molecular weight chitosan microspheres was studied by Genta I et al using Ketoprofen as a model drug. Chitosans of 70,000 (LC), 750,000 (MC), and 2,000,000 (HC) molecular weight were employed alone or as mixtures (HC/LC 1:1-1:2 w/w). Microspheres characterized by different theoretical polymer/drug ratios were prepared (2:1, 1:1, 1:2 w/w). Satisfactory ketoprofen contents were obtained for all batches of chitosan microspheres with the theoretical polymer/drug ratio 1:2 w/w; microspheres made of HC/LC (1:2 w/w) were characterized by good drug content and encapsulation efficiency independent of polymer/drug ratio. Prepared chitosan microparticulate delivery systems could modulate ketoprofen release within 48 hr. Microspheres consisting of HC/LC (1:2 w/w) were the most suitable formulation in controlling drug release. (10)
Ketoprofen gastroresistant microspheres were prepared by spray-drying using common pH dependent polymers, such as Eudragit S and L, CAP, CAT and HPMCP. The long ketoprofen recrystallization time was a serious hindrance to the preparation of microspheres having drug content higher than 35%. Microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray diffractometry and in vitro dissolution studies, and used for the preparation of tablets (11).
Sustained release diclofenac sodium microcapsules were prepared using polymerized rosin as a novel wall-forming material by a solvent evaporation technique and suggested that the microcapsules could be used for development of implant/depot systems, primarily due to a sustained/controlled release capability and potential biocompatibility of polymerized rosin. The solution system of drug and polymerized rosin dissolved in isopropyl alcohol and acetone was sprayed with the help of a 0.5 mm nozzle spray gun in liquid paraffin maintained at 600C in the stirring condition. Varying drug: polymer ratios were employed for microcapsule preparation. The microcapsules showed sustained release curves at pH 7.4 phosphate buffer for up to 10 h. The in vitro dissolution study confirmed the Higuchi-order release pattern (13).
Albumin based drug delivery systems are having much importance for the treatment of arthritis, since albumin has a tendency to deposit at the inflamed joints. The rate of drug release from injected albumin microspheres and the rate at which the microspheres themselves degrade in the body are controlled by their degree of cross-linking. Microsphere cross-linking can be accomplished by heat denaturation of the albumin or through use of chemical cross-linking agents such as formaldehyde or glutaraldehyde. The heat cross-linked albumin microspheres exhibit a biphasic release of entrapped drugs. Such biphasic release is thought to be desirable for injectable drug delivery systems, since a therapeutic “loading dose” of drug can be provided initially in a fast release phase followed by a subsequent slower sustained release of drug necessary to maintain therapeutic blood levels (16).
Egg albumin-chitosan microspheres containing indomethacin was produced by coacervation method. This method was simple and eliminated the use of organic solvents. The interaction between negatively charged egg albumin molecules in phosphate buffer, pH 7.2, or sodium hydroxide solution and positively charged chitosan molecules dissolved in diluted acetic acid to form an insoluble precipitate was the principle for the formation of the microspheres. High incorporation efficiencies were achieved in most cases and ranged between 63.3 % and 92.39 %, while particle sizes were 435.2 up to 693.9 micron for the different batches. The pH of the encapsulation media significantly affected the properties of the microspheres. As the pH of the encapsulation media was increased, the incorporation efficiency, particle size, and flowability decreased, along with increase of drug release rate (17).
Mathew ST et al prepared ketorolactromethamine loaded albumin microspheres by emulsion cross-linking method and analysed effect of different factors on drug entrapment. They could obtain particle size below 40µm and the release pattern was biphasic, characterized by an initial burst effect followed by a slow release. The release mechanism was regulated by drug polymer ratio and amount of cross-linking agent (47)
Polymer blends/block copolymer
Combination of synthetic and or natural polymer for the preparation of microspheres is an approach to improve the entrapment efficiency and to control the particle size.
Methoxy poly (ethylene glycol) (MePEG) and poly (epsilon-caprolactone) block co polymer
Kim SY et al prepared the drug-loaded polymeric nanospheres composed of the methoxy poly (ethylene glycol) (MePEG) and poly (epsilon-caprolactone) (PCL) that showed a narrow size distribution and average diameter of less than 200 nm. They could obtain nanospheres having a relatively high drug-loading efficiency of about 42% when the feed weight ratio of indomethacin (IMC) to polymer was 1:1. From the invitro and invivo studies it was found that the MePEG/PCL block copolymeric nanosphere system could be considered as promising biodegradable and biocompatible drug carrier vehicles for parenteral use and may be useful as sustained release injectable delivery systems for NSAIDs (14).
Ketoprofen has been incorporated into polymeric microspheres by a spray drying process using cellulose acetate trimellitate (CAT)/ethylcellulose (EC) blends by Giunchedi P et al. Drug loaded microspheres were obtained by spray-drying organic solutions of the two polymers and the drug. (12).
Methods Of Preparation
Micro particulate drug delivery technology represents one of the frontier areas of science, which involves multidisciplinary scientific approach, contributing to human health care. Microencapsulation is a technology devoted to entrapping solids, liquids or gases inside one or more polymeric coatings. The techniques adopted for the preparation should satisfy certain criteria. It should have the ability to incorporate reasonably high concentration of the drug. The particle size should be controlled by altering certain parameters and it should release the active agent with good control over a prolonged time. For parenteral preparations it is desirable to reduce the size of the particles in order to minimize the irritant reaction at the site of injection. The microspheres prepared should be stable and have a good shelf life.
The methods used for the preparation of other active agents are adopted for the preparation of microspheres containing NSAIDs. The selection of method depends on the particle size required, route of administration, duration of drug release, etc. All these characteristics will ultimately relate to the other variables like rpm, method of crosslinking, duration of crosslinking, evaporation time, co-precipitation etc. The microspheres are separated from the reaction mixture by filtration, centrifugation or freeze-drying. Recovery of the prepared microspheres depends up on the size of the particles and the particle characteristics such as composition and swellability. Relatively large and rigid particles are separated by filtration or decantation. Ultracentrifugation is used for separating smaller particles. This step is followed by washing the microspheres in order to remove the residual solvents, surfactant and other additives. The washed microspheres are then air dried, vacuum dried, freeze dried, or reconstituted with an appropriate medium for subsequent use.
Processes of preparing microspheres that enable control of well-defined particle characteristics such as size, size distribution, and functionality are becoming increasingly important for a variety of applications. However, either the particle size range that is achievable, or the types of materials that can be utilized in the process limit some of the current methods of microsphere preparation. Micron size of particles is typically prepared via dispersion or suspension polymerization techniques. For suspension polymerization, control of particle size distribution can be difficult because of the mechanical factors that control the particle size.
Spray drying technique
Ketoprofen-loaded microspheres made with a polymeric blend were prepared by a spray-drying technique. Spray drying techniques involves dispersing the core material in a liquefied coating material and spraying the core-coating mixture in to the environment to effect solidification of coating. Solidification is accomplished by rapid evaporation of the solvent in which coating material is solubilised. Organic solutions of two polymers, cellulose acetate butyrate (CAB) and poly(epsilon-caprolactone) (PCL), in different weight ratios, and of ketoprofen were prepared and sprayed, in different experimental conditions, achieving drug-loaded microspheres (18).The process control variables in this technique were feed material properties, feed rate, method of atomization and drying rate. Spray drying method is rapid, reproducible and easy to scale up. But due to the fast drying process the polymer may lose its crytallinity.
Emulsion crosslinking method
Emulsion crosslinking technique using mineral oil or vegetable oil as oil phase and drug polymer solution as aqueous phase is simple and widely used method for the preparation of NSAIDs. Crosslinking can be achieved by chemical agent or heat. Viscosity of the oil phase, concentration of the crosslinking agent, duration of crosslinking, etc are the different parameters, which affect the release rate and entrapment efficiency. Gelatin A microspheres of ketorolac tromethamine for intranasal systemic delivery were developed using the emulsification-crosslinking technique. The drug was dispersed in the polymer gelatin and formulated into a w/o emulsion with liquid paraffin, using glutaraldehyde as a crosslinking agent (19)
Encapsulation of diclofenac sodium into crosslinked chitosan microspheres and the effect of crosslinking agent were studied by Kumbar SG et al. Microspheres of chitosan crosslinked with three different crosslinking agents viz, glutaraldehyde, sulphuric acid and heat treatment were prepared to encapsulate diclofenac sodium. Chitosan microspheres were produced in a w/o emulsion followed by crosslinking in the water phase by one of the crosslinking methods. Encapsulation of drug was carried out by soaking the already swollen crosslinked microspheres in a saturated solution of diclofenac sodium. The in-vitro release studies were performed in 7.4 pH buffer solution. Microspheres produced were spherical and had smooth surfaces, with sizes ranging between 40-230 micron. The crosslinking of chitosan took place at the free amino group in all the cases. Polymer crystallinity increased after crosslinking. The percentage of drug loading into the microspheres was found to be up to 28-30% w/w for the sulphuric acid-crosslinked microspheres, whereas 23-29 and 15-23% of loadings were obtained with glutaraldehyde (GA)- and heat-crosslinked microspheres, respectively. Among all the systems in this study, the 32% GA crosslinked microspheres showed the slowest release i.e. 41% at 420 min. The fastest release of 81% at 500 min was shown when heat crosslinked for 3 h. Drug release from the matrices deviated slightly from the Fickian process (26).
Multiple emulsion method
Evaluation of process parameters involved in chitosan-ketoprofen microsphere preparation by the o/w/o multiple emulsion method was reported by Pavanetto F et al. Moreover, the influence of critical variables (concentration of acetic acid in the polymer solution and drug-polymer ratio) on microsphere morphology and drug content was evaluated. Two chitosans of different molecular weights and deacetylation degree were employed. The multiple emulsion method produced well-formed microspheres with good yields. Acetic acid concentration in the polymeric solutions influenced particle size and drug content of the microspheres. The highest drug encapsulation efficiencies were obtained for the lowest theoretical drug/chitosan ratio (20).
A new oral controlled-release drug delivery system for indomethacin was developed with two polymers using a multiple-emulsification technique. Powdered drug was dispersed in methylcellulose solution, which was emulsified in ethyl cellulose solution in ethyl acetate. The primary emulsion thus formed was re-emulsified in aqueous medium. During this phase, discrete microspheres were formed under optimized conditions. The in vitro drug release followed first-order diffusion-controlled dissolution. More than 85% of the drug was released over 6 hour at pH 6.2 for all dissolution batches. (23)
Emulsion solvent evaporation
A simple emulsion solvent evaporation method for the preparation of indomethacin, ibuprofen, and ketoprofen was described by Roland Bodmeier and Huagang Chen. The polymer and drug were co-dissolved in water-immiscible organic solvent. The organic solution was poured into the aqueous phase containing 0.25% w/v poly(viny1 alcohol). The resulting O/W emulsion was agitated continuously for 90 minutes at room temperature and under ambient pressure. The microspheres were collected by filtration, washed with deionized water, and dried. The dried spheres were passed through a 60 mesh stainless-steel sieve and stored at room temperature. (24)
Gonzalez-Rodriguez ML et al. reported alginate/chitosan particulate systems for diclofenac sodium release by ionic gelation (Ca2+ and Al3+). 25% w/v of the drug was added to 1.2%w/v aqueous solution of sodium alginate. The solution was stirred till a complete solution was formed. This solution was added dropwise to a solution containing Ca2+ or Al3+ and chitosan solution in acetic acid. The microspheres formed were left into the original solution for 24 hours for internal gelification. The product is separated by filtration. The release of sodium diclofenac was prevented at acidic pH, while it was complete in a few minutes when pH was raised up to 6.4 and 7.2. The alginate/chitosan ratio and the nature of the gelifying cation controlled the release rate of the drug (21). The particle size ranged from 2-4 mm but the encapsulation efficiency was 98%.
Spray coating- Wurster process
Prolonged-release microcapsules of diclofenac sodium (DS), applicable as an oral suspension for twice-a-day administration were designed by Hideki Ichikawa. The microcapsules with a mass median diameter of around 100 microns and high drug content exhibited a preferably prolonged release of highly water-soluble DS when prepared by the Wurster process–a spray coating method using a spouted bed assisted with a draft tube. The microcapsule was composed of a calcium carbonate core of 32–44 microns, a drug-layer of DS, hydroxypropyl cellulose and polyethyleneglycol 6000, an undercoat of Eudragit L30D and a release-sustaining coat of Eudragit RS30D. Eudragit L30D films were undercoated to decrease the solubility of DS within the environment of the microcapsules and thereby to prolong the drug release. This made it possible to decrease the amount of Eudragit RS30D membrane required to prolong the drug release, leading to decrease in the particle size of products and achievement of high drug content. Thus, prolonged release microcapsules with a mass median diameter of 92 microns and a drug content of 29% were obtained (25). Wurster process has the advantage that wide variety of coating materials can be used and coating can be applied in the form of solvent solutions, aqueous solutions, emulsions, dispersions and hot melt.
Aqueous dispersion method
Relatively little importance has been given to effect of the rate and method of cooling on properties of drug matrices. R.S. Al-Kassas et al studied effect of the rate and method of cooling on the particle size of ibuprofen microparticles. Ibuprofen microspheres were prepared using an aqueous dispersion method. The method was adopted so that factors like cooling time and stirring rate could be altered. Particle size analysis showed that both the parameters significantly affected the mean particle size although the effects were independent of each other. In vitro release fitted to several models, the Higuchi square root of time model gave the best fit (27).
Chitosan microspheres of indomethacin by an aqueous process were described by Aggarwal A et al. The influence of formulation variables on indomethacin content in the microspheres and time for indomethacin release from the microspheres was investigated. Amongst various variables, the indomethacin:chitosan ratio and amount of crosslinking agent were found to be important. (22).
Controlled-release egg albumin-chitosan microspheres containing indomethacin as a model drug were successfully prepared by coacervation method. This method is simple and utilizes aqueous system for the preparation. This process consists of 3 steps under continuous stirring.
The formation of three phases:
Dispersing a core material in a solution of coating polymer
Immiscible polymer in liquid state. (Coating material phase)
Coating is accomplished by controlled physical mixing of coating solution and core material in liquid manufacturing vehicle phase.
Rigidisation could be achieved by thermal, chemical crosslinking or desolvation techniques.
The interaction between negatively charged egg albumin molecules in phosphate buffer, pH 7.2, or sodium hydroxide solution and positively charged chitosan molecules dissolved in diluted acetic acid to form an insoluble precipitate was the principle for the formation of the microspheres. Incorporation efficiencies of the microspheres were high and ranged between 63.3 and 92.39, while particle sizes were 435.2 to 693.9 micron for different batches. As the pH of the encapsulation media was increased, from pH 3.77 up to pH 4.91 the incorporation efficiency, particle size, and flowability decreased, along with increase of drug release rate. It was also observed that high concentration of albumin solution and accordingly the increase of albumin-to-chitosan weight ratio were accompanied with increases in incorporation efficiency and particle size with improved microsphere flowability and slow drug release. (28)
Hot-melt encapsulation method
Lin WJ and Kang WW compared the performance of indomethacin microparticles and their release properties after coating with chitosan and gelatin, respectively. Here the poly (epsilon-caprolactone) (PCL) microparticles were prepared by the hot-melt encapsulation method. This method is having a disadvantage that thermolabile substances cannot be used. But it is reproducible with respect to yield and size distribution. All of the coated microparticles retained their spherical shape irrespective of the type of coating material, and the particle size of coated microparticles was similar to the uncoated ones. The indomethacin encapsulation efficiency was in the range of 8.65 % - 8.81 % for uncoated microparticles and 8.22 %- 8.68 % for coated microparticles. The release of indomethacin from uncoated microparticles followed a two-exponential release profile, where indomethacin was rapidly released within 4 hour during the first release phase, after that approximately 20% of the drug was continuously and slowly released for up to 24 hour in the second phase. The similar release profile was observed from coated microparticles irrespective of the times of coating and the types of coating material. Both the natural coating materials, chitosan and gelatin, efficiently reduced the initial burst release and the first phase of drug release, but did not alter the second phase of drug release. (29)
Emulsion-solvent diffusion technique
Floating microparticles of ketoprofen were prepared in order to improve the residence time in the colon by A.H. El-Kamel et al using the emulsion-solvent diffusion technique.. The drug polymer mixture dissolved in a mixture of ethanol and dichloromethane (1:1) was dropped into 0.2% sodium lauryl sulfate solution. The solution was stirred with a propeller-type agitator at room temperature for 1 hour at 150 rpm. The formed floating microparticles were filtered, washed with water and dried at room temperature in a desiccator. The floating microparticles were sieved and collected. (30)
Terminal Sterilization Of Microspheres For Parenteral Use
Sterilization of the microspheres for injectable or implantable formulation is considered as an important step in the method of preparation. The effect of the irradiation dose (25 kGy) exposure on the formulation was evaluated by Fernandez-Carballido A and co-workers. They have produced microspheres loaded with ibuprofen, for intra-articular administration using poly (D, L-lactic-co-glycolic) acid (PLGA) by the solvent evaporation process. Labrafil M 1944 CS was included in the formulation as an additive in order to modulate the release rate of drug. After preparation, the microspheres were sterilized by gamma-irradiation. The sterilization procedure employed did not alter the physicochemical characteristics of the formulation. Dissolution profiles of formulations remained same before and after sterilization. Size Exclusion Chromatography (SEC) revealed no significant change in the polymer molecular weight. Stability data of the sterilized formulation showed no significant alterations in the ibuprofen release rate or in the molecular weight of the PLGA. (31)
But in certain cases the irradiation used for sterilization affected the particle size and release behaviour of microspheres. Sema Cal?s et al studied the influence of irradiation on the physicochemical properties of naproxen sodium and diclofenac sodium incorporated in poly (lactide-co-glycolide) microspheres. The biodegradable microspheres were irradiated at doses of 5, 15 and 25 kGy. Drug loading of irradiated and non-irradiated microspheres had remained same. But there was significant difference in the particle sizes of the irradiated as compared to the non-irradiated formulations. The rate of drug release increased with increasing irradiation dose. (32)
The method adopted for in-vitro and in-vivo evaluation varies depends up on the route of administration of the microspheres. Physicochemical characterization of these microspheres includes drug entrapment, particle size analysis, measurement of zeta potential, polymer drug interaction studies etc.
For oral administration the
Francesco Castelli et al conducted
The correlation between the erosion process and release kinetics of indomethacin loaded chitosan microspheres was studied by Orienti et al. The chitosan microspheres were prepared by covalently linking with citric acid. The release kinetics correlated with the concentration of chitosan in the microsphere preparative mixture and the pH of the release medium. Deviations from Fickian to zero order kinetics were observed at higher concentrations of chitosan and at pH 7.4. The variations induced by these parameters on drug diffusion and solubility in the matrix undergoing erosion were analyzed (34). The effects of temperature and two different pH (2.67 and 7.00) on poly-epsilon-caprolactone (P epsilon CL) nanospheres loaded with flurbiprofen (aqueous suspensions) were studied by Lacoulonche F et al to investigate their influence on the stability and physicochemical characteristics of these drug delivery systems. The drug release behavior was also studied. Release of the associated flurbiprofen occurred very fast on high dilution in a buffered medium. The stability of the polymeric system depended on the temperature and the initial pH value; it was more degradable with the particles stored at 400C with an initial pH value of 2.67 (35).
Karasulu E et al prepared lipophilic microspheres of indomethacin using cetostearyl alcohol, stearyl alcohol and cetyl alcohol and the release of drug was studied on the basis of USP criteria. The effects of drug-lipid ratio, the size of microspheres and carboxymethylcellulose sodium as a hydrophilic polymer on the drug release were investigated. In vitro dissolution studies were performed using USP XXIII apparatus I at pH 6.2. Release profiles were evaluated according to first order, Higuchi square root of time and Hixson-Crowell cube root models. The best fit was found with the square root of time model for the microspheres (125-250 micron) prepared in 1:4:1 drug-lipid-copolymer ratio using stearyl alcohol (36).
Ghaly ES et al used the melt dispersion technique and aqueous vehicle to entrap ibuprofen into wax carrier (carnauba wax) with the aid of surfactant Pluronic L-62. The in-vitro dissolution of ibuprofen in phosphate buffer pH 7.2 showed that microspheres prepared with low amount of drug (1.5 g) released 58.1% of ibuprofen after 6 hours, while microspheres prepared with high amount of drug (6.0 g) released only 38.9% of ibuprofen (37).
S. Bhaskaran. et al prepared ketorolac tromethamine loaded PLA microspheres with different polymer composition by phase separation coacervation induced by non solvent addition method. All microspheres showed initial burst release, followed by fickian diffusion of drug (43).
Ethylcellulose microspheres loaded with ibuprofen were prepared with and without polystyrene, to retard drug release from ethylcellulose microspheres. Ibuprofen-loaded ethylcellulose microspheres with a polystyrene content of 0-25% were prepared by the solvent evaporation technique. The in vitro release studies were performed to study the influence of polystyrene on ibuprofen release from ethylcellulose microspheres. The microspheres showed 28-46% of drug loading and 80-92% of entrapment, depending on polymer/drug ratio. The prepared microspheres were spherical in shape and had a size range of 0.1-4 micron. Ethylcellulose/polystyrene microspheres showed prolonged drug release and less burst effect when compared to microspheres prepared with ethylcellulose alone. Microspheres prepared with an ethylcellulose/polystyrene ratio of 80:20 gave a required release pattern for oral drug delivery. The presence of polystyrene above this ratio gave release over 24 h. High correlation was obtained in Higuchi and Korsmeyer-Peppas models. The drug release from ethylcellulose/polystyrene microspheres was found to be diffusion controlled (38).
Oral NSAIDs cause gastrointestinal disturbances at a high incidence, which is an obstacle in increasing doses to obtain sufficient therapeutic effect. More over parenteral NSAIDs are required to maintain a certain level of blood concentration. Formulation of NSAID microspheres for parenteral administration is satisfactory as they can avoid the contact with GI tract, resulting in enhanced effect with less dose of drug. Depending on the particle size they can be administered via different routes viz Intramuscular, Intraarticular, Subcutaneous, etc. The
Poly (lactide-co-glycolide) (PLG) was used to deliver diclofenac in the form of microspheres, subcutaneously. The pharmacokinetic and pharmacodynamic studies in the adjuvant induced arthritic rats showed that microspheres produced steady therapeutic levels of the drug in the plasma for about 16 days following a single subcutaneous injection. The in situ gel-formation provided significantly higher maximum plasma concentration and inhibition of inflammation was maintained for about 10 days (39).
Chandrashekar G and Udupa N have reported controlled-release parenteral formulations of diclofenac sodium, for intraarticular administration. For in vivo studies, Technetium-99m labeled polyclonal human immunogammaglobulin was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post-therapy in rabbits showed no significant difference in the group treated with PLGA (50:50) (mw 34000) diclofenac sodium microspheres compared to control groups (40).
Tuncay M et al prepared and evaluated albumin microspheres loaded with diclofenac sodium. The microspheres so prepared were injected directly to the knee joints of rabbits after the induction of arthritis in knee joints and the therapeutic efficacy of the formulations were found to be greater than the plain drug (41).
In vitro and in vivo evaluation of sustained release chitosan-coated ketoprofen microparticles were described by Yamada T et al. Simple ketoprofen microspheres were prepared by the dry-in-oil method using ethylcellulose (EC) as a matrix polymer. Further, the microspheres modified by addition of polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC), called MS-P and MS-H, respectively, were prepared. The in vitro release from Microsphere, MS-P and MS-H was examined in the JP XIII second fluid, pH 6.8, at 370C and 60 rpm. Chitosan-coated ketoprofen microparticles (Chi-MP) were prepared by the precipitation of droplets of chitosan solution containing MS, and their adhesion to the rat small intestinal mucosa was tested. The plasma concentrations after duodenal administration were investigated for ketoprofen powder suspension, MS and Chi-MP. The particle size was raised with the increase in amount of ketoprofen added. The drug content and addition of PEG or HPC affected the drug release rate. The microspheres with moderate drug content, prepared by addition of modest amount of PEG, exhibited better gradual drug release. Chi-MP showed a good mucoadhesion. The maximum plasma concentration of ketoprofen for Chi-MP was less than one-third of that for ketoprofen powder suspension. Chi-MP tended to show the higher and steadier plasma level than MS (42).
Coating the NSAID microsphere with polyethylene glycol further retards the drug release and Improved the mean residence time of the microspheres.
NSAIDs are found to be good candidate for controlled release dosage forms owing to the severe GI side effects that they exhibit. Due to the greater stability and wider manufacturing techniques microspheres are preferred over other colloidal drug delivery systems. They are compatible with most of the natural and synthetic polymers and can be used for both parenteral and oral administration. The route of administration, physicochemical properties of drug, toxicity and the site of action are the other factors that determine the method of preparation and drug carrier for NSAID microspheres. Chitosan is the most widely studied polymer for the preparation of NSAID microsphere for oral use and synthetic polymers were used for parenterals use. Studies indicated that the NSAID microspheres were superior to the conventional formulations with respect to bioavailability and pharmacodynamic properties. The literature revealled that micro-particulate
delivery reduces marked fluctuations in plasma between peak and
trough levels at the time of next dosages. But the safety profile of these drug delivery systems for NSAIDs is not encouraging or not reported extensively so as to conclude that they ate the best for this drug class. But most of