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A well designed controlled drug delivery systems can overcome the problems of conventional theraphy and enhance the therapeutic efficacy of a given drug . For obtaining maximum therapeutic efficacy , it is necessary to deliver the agent to the target tissue , there by causing little toxicity and minimize side effects. In a sustained and controlled release fashion there are so many targeting approaches used for delivering a therapeutic substance to the target site. One of the major approach is using Microspheres as a carrier system for drugs.
Microspheres are defined as solid, free flowing powders approximately spherical particles ranging in size from 1 to 1000Âµm. They are made up of polymeric ,waxy materials or other protective materials such as synthetic polymers (eg :-PLGA ,PLA) . Modified natural polymers include albumin,gelatin, chitosan, casein. The non -biodegradable polymers such as ethylcellulose, hydroxypropylmethylcellulose, celluloseacetate and polyvinylpyrollidone .
The term microcapsule should be used for reservoir type devices whereas microspheres are monolithic or matrix type microparticles. The particles can be embedded within a polymeric matrix in either a solid aggregate state or a molecular dispersion to form microspheres. The particles can be coated by a solidified polymeric envelope to form microcapsules.
The microencapsulation reasons are enormous . In some cases , the core must be isolated from its surroundings. eg;- isolating vitamins from deteriorating effects of oxygen . In other cases, the main objective was not to isolate the core completely but to control the rate at which it leaves the microcapsule as in the controlled release rate fashion.
The air suspension technique consists of solid particulate of core materials dispersed in a supporting air stream .The spray solution (polymer) should be coated on the air suspended particles. Inside the coating chamber , suspended particles moves on an upward direction. The chamber design and its operating parameters bring about a recirculating flow of the particles through the coating zone portion of the chamber .During each time particles passes through the coating zone , the core materials receives an increase in the amount of coating materials .The cyclic process is repeated , for several times .The process depend on the purpose of microencapsulation , desired coating thickness, core particles are throughly encapsulated. The supporting air stream also serves to dry the product during encapsulation process.
In step two , the liquid polymer coating is deposited at the interface between the core material and the liquid manufacturing vehicle phase. While coating the polymer solution , physical or chemical changes will occur this will results in the phase separation of the polymer . The polymer solution in a droplet form will unite to yield a two phase system i.e liquid - liquid The coating material which is an immiscible polymer of insoluble liquid polymer may be added directly .The monomers were dissolved in the liquid vehicle phase and polymerized at interface. Simple method is required for doing the microencapsualtion techniques. In this method the equipment consist of mainly jacketed tanks with variable speed agitators.
This technique was carried out in a liquid manufacturing vehicle phase ( o/w emulsion) by simple agitation of two immiscible liquids. The process involves dissolving polymer in a volatile solvent which is immiscible with the liquid manufacturing vehicle phase. Adrug also dissolved or dispersed in the coating polymer solution. By the process of agitation , the core coating material mixture should dispersed in the liquid manufacturing vehicle phase to obtain microspheres.
Continuation of agitation takes place until the solvent partitions into the aqueous phase is removed by evaporation .Finally the process results in hardening the microspheres which contain the active moiety of the drug Several methods can be used to achieve dispersion of the oil phase in the continuous phase. The most common method is the use of propeller style blade attached to a variable speed motor.
Various process variables includes methods of forming substances
Evaporation rate of the solvent for the coating polymer
Important factors to be considered when preparing microspheres by this method includes
choice of vehicle phase
solvent for the polymer coating as the choice greatly influence microcapsule properties
choice of solvent recovery techniques.
This techniques is applicable to a wide variety of liquid and solid core materials for producing microcapsules by using various polymers.
This methods involves the reaction of monomeric units at the interface existing between a core material substance and in a continuous phase the core material is dispersed. The core material is used as supporting phase consists of liquid or gas . The polymerization reaction occurs at liquid -liquid , liquid -gas ,solid -liquid or solid -gas interface.
Applications of microencapsulation
Technology have been used widely in the design of controlled release and sustained release dosage forms.
The bitter taste of drugs like paracetamol, nitrofurantoin can be minimized by using this technique.
To reduce gastric and other GI tract irritations the drugs have been microencapsulated
eg . Sustained release aspirin preparations have been reported to cause significantly less a GI bleeding than conventional preparations.
For easy handling and storage purpose , liquid can be converted to pseudo solid.
Hygroscopic properties of materials can be reduced by microencapsulation eg:- Nacl.
To reduce their odor and volatility the substances can be microencapsulated . eg:-CCl4
To provide protection to the core material against atmospheric effects microencapsulation technique has been employed eg:- Vit A.
Seperation of incompatible substances has been achieved by encapsulation .
Table No .2: Examples of some microencapsulated drugs
Purpose of encapsualtion
Final pdt form
Slightly water soluble solid
Islet of Langherhans
Sustained normalization of diabetic condition
Slightly water soluble solid
Taste masking ,SR , reduced gastric irrtiation
Tablet or capsule
Isosorbide di nitrate
Water soluble solid
Reduciton of volatility , SR
Slightly water soluble solid
Highly water soluble solid
Reduced gastric irritation
Water soluble enzyme
Permaeability of enzyme, substrate and rxn pdts.
Table No .3 : Microencapsulation process with their relative particle size ranges
Physico- mechanical process
Physico chemical process
Spray drying (5-5000Âµm)
Pan coating (600-5000Âµm)
Solvent evaporation (0.5-1000Âµm)
Fluid bed technology(20-1500Âµm)
Polymer -polymer incompatibility(0.5-1000Âµm
1.10.TECHNOLOGY INVOLVED IN DIFFUSION TYPE RELEASE SYSTEMS
In these systems, the release rate is determined by its diffusion through the polymer matrix.. There are two types of diffusion devices.
Reservoir devices - in which a core of drug is surrounded by a polymeric membrane.
Matrix devices - in which drug distribution should be uniformly in an inert polymeric matrix.
Microspheres represent matrix type drug delivery systems whereas micropellets represent reservoir type systems.
By theoretically , the Ficks's law of diffusion were used to controlled release rate of drugs from both capsule and matrix type system which defines the flux of diffusion Jd across a plane surface of unit area.
Jd = - Ddc/dx
D = diffusion of drug molecule in a medium of solid
dc/dx = concentration gradient of the drug molecules across a diffusion path of thickness dx
The negative sign indicates the flux of the drug in the decreasing concentration. In the matrix type of drug delivery systems , the concentration gradient is dependent on time and decreases progressively in response to the growing thickness of diffusional path, dx as times goes on. In these systems , the drug molecules can elute out of matrix through dissolution and then by diffusion through the polymer structure. The dry solid which is close to the surface of the device are first elute and then followed by that in the next layer. This is as shown in the figure 6.
Fig No.6: Schematic illustration of Controlled release of Drug molecules from matrix type drug delivery system
A = intial amount of drug solid impregnated in a unit volume of polymer matrix.
Cp = Solubility of drug in polymer phase
Cb = Concentration of the drug at the polymer -solution interface
C = Concentration of the solution in bulk of the elution solution
âˆ‚p = Thickness of drug depletion zone in matrix
âˆ‚d = Thickness of hydrodynamic diffusion layer device on the immediate surface
âˆ‚(âˆ‚p) = Differential thickness of depletion zone formed after more drug solid elutes out
The drug which is solid in nature dissolves first from the surface layer , when this layer becomes exhausted of the drug .The next layer starts to be depleted by dissolution and diffuses through the matrix to the external solution. In this fashion, the interface between the region containing the dissolved drug and that containing the dispersed drug moves into the interior as a front.
This equation can be used to express the release rate of the drug .
Q = DE/ T(2A-ECS)Cst x1/2
Q = Drug released in g/unit surface area
D = Diffusion coefficient of the drug
E = Porosity of the polymer matrix
T = Tortousity of the polymer matrix
Cs = Solubility of the drug (g/ml)
A = Concentration of the drug in the dosage form
Keeping all the parameters constant , Higuchi equation can be reduced to
M = kt â…“
Where , k is a constant.
The assumptions made in deriving the mathematical model are
During the release process a pseudo steady state is maintained .
The total volume of the drug present in the matrix is substantially greater than the saturation solubility of the drug in matrix ie , excess solute is present
Drug particles should be smaller in diameter then the average distance of diffusion.
The diffusion coefficient should be remains constant.
There is no interaction occurs between the drug and the matrix.
1.11.MECHANISM OF DRUG RELEASE FROM MICROPARTICLES
Drug release from degradable microspheres should based on the microstructure of particles and mechanism of erosion. The drug release is influenced by
Structure of microparticles
Properties of the biodegradable polymer itself.
The drug delivery through microparticles should exhibit a matrix type of internal solid dispersion of morphology structure. The drug may be insoluble in the solid matrix , and the drugs are released by two mechanism that involves both pore diffusion and polymer erosion. First water diffuses into the matrix dissolving the drug particles adjacent to the surface. The resulting osmotic pressure is take over charge by forming a tarteous channel to the surface and releasing a defined amount of drug in the initial drug burst .
Fig No. 7: Mechanism of drug release from microparticles
The burst effect is controlled by three factors
Drug polymer ratio
Particle size of dispersed drug
Particle size of the microspheres
The water should be penetrated in front continues diffusion takes place into the microparticulate core, the dispersed drug particles are dissolved by creating a network of water filled pores through which the drug diffused in a controlled manner and hence the pore diffusion mechanism takes place.
For example from gel beads , leakage of drug can occur is influenced by polymer concentration and mechanical treatment of beads. In physical shaking it produces more leakage when compared to packed beads in column.
In the open lattice structure , by allowing small leakage of proteins it provide high porosity for large substrates and efficient exchange of substrates and products. The crosslinking polymer such as chitosan ,polyacrylic acid, polyvinylalchol, protein and polyethylamine which are used to produce more stable, lower porosity complexes with improved leakage characteristics.
Delivery system for microspheres
For commercial use , microspheres should be placed in pharmaceutically acceptable oral delivery systems.
1.12. Microspheres - Parental Administrations
Microspheres have been used for intra venous and intra arterial targeting and drug delivery system.
Microspheres is injected into the veins to ensure passive targeting of drugs. The drug released is controlled by diffusion through the polymer matrix and by the erosion of polymer . The microspheres depends on their size and site of injection in playing the role
In order to target the RES microparticles of diameter smaller than 2Âµm can be injected in an intra -venous ,intrarterial and intra peritoneal manner. Intra venous injection of microspheres size from 3 to 12Âµm is intended to block the capillary of the lungs , liver and spleen .
Vessels can be hyper selectively embolized with drug loaded particulate materials of more than 10Âµm. These are used as particulate agents for the embolization of tumors and a steroids venous malformations. In these delivery systems, microspheres have two fold action as embolic agents and drug carriers.Microsphers of 100to 300Âµm size are the most appropriate embolic agents.They reach the intra lesional precapillary arteries and cause reduction
of blood flow.
1.13. STERILITY IS AN IMPORTANT CRITERION FOR PARENTRAL ADMINISTRATION
Microspheres intended for parentral administration should be
Most of the polymers degrade upon sterilization which can be inferred through a decrease in molecular weight , changes in viscosity and mechanical properties.Thus for the preparation of microspheres, aseptic processing is the most acceptable method .The polymer solution in methylene chloride can be easily filtered through 0.22Âµm filters and the final compounding of the product may be carried out in a sterile environment . It is important to establish sterility of the microspheres , not only on the surface , but also internally by dissolving microspheres in mild non- toxic solvents as DMSO or DMA and further subjecting to sterility testing .
1.14. BIODEGRABLE POLYMERS AS CARRIERS FOR EXTENDED RELEASE
Cross linked proteins and Hydrogels
Poly Vinyl Alchol(PVA)
Cross linked Poly Vinyl Pyrollidone (PVP)
NON BIODEGRADABLE POLYMER
Hydroxy Propyl Methyl Cellulose(HPMC)
Polyethyl Vinyl Acetate(PVA)
Poly Ether Urethane(PEU)
Poly Vinyl Chloride (PVC).
SCOPE AND PLAN OF WORK
SCOPE AND PLAN OF WORK
Aceclofenac is a Non Steroid Anti Inflammatory Drug (NSAID ) which is a phenyl acetic acid derivative . It shows effective anti inflammatory effect and analgesic properties . It is mainly used in Rheumatoid arthritis, Osteo arthritis and ankylosing agents.
After oral administration it is rapidly and effectively absorbed with 100% bioavailability.But its biological half- life is only 3-4 hours . Therefore it requires multiple dosing of drug for maintaining therapeutic effect throughout the day .The normal dose of aceclofenac is 100mg b.i.d. The frequent adverse side effects occurring with aceclofenac are GI disturbances , GI bleeding and peptic ulceration . To minimize the gastric erosion side effect , it is essential to provide an enteric coated dosage form . The short half -life and multiple administration makes aceclofenac a good candidate for the formulation of delayed release microspheres. The main aim of the study was to formulate the delayed release of microspheres of aceclofenac .In our studies we have adopted emulsion solvent evaporation technique to formulate the delayed release dosage forms.
The preparation and invitro evaluation of aceclofenac microspheres using Seven different polymers where carried out in the following stages.
Standard graph of aceclofenac
Preparation of microspheres by emulsion slovent evaporation technique
Morphology of microsphere (SEM)
Drug entrapment efficiency or incorporation efficiency
Invitro drug release
Parul Trivedi .et al17 ( 2008) in their "Preparation and characterization of Aceclofenac microspheres'' reported that microspheres by solvent evaporation technique using eudragit (S100 , RL100 and RS100) to provide controlled release and local side effects by can be minimized by avoiding the drug release in the upper GIT. The microspheres were prepared and subjected to micrometric evaluation, drug loading studies, and invitro drug release studies. The drug -polymer concentration in the dispersed phase will influence the particle size and drug release particulate of all the formulation are at higher pH values follows matrix Higuchi Model.
Tamizharasi S.etal23 ; (2007) in their work "Formulation , characterization and invitro release kinetics of aceclofenac loaded poly(â‚¬caprolactone ) microspheres" reported that drug to carrier ratio(1:4) showed high drug entrapment efficiency and drug released upto 15 hr were found to be sustained. There was no interaction between the drug and polymer.
Gohel MC. etal 33; (2005) in their work " Preparation and formulations of optimization of sugar cross linked gelation microspheres of Diclofenac sodium reported that sugar/ e.g glucose ,fructose can be used as cross linking agent of gelation for the preparation of modified release microspheres . The microspheres which are prepared by emulsion cross linking method revealed that ,the parameters such as drug to carrier ratio, volume of light paraffin and stirring rate were found to affect the morphology and drug release of microspheres.
Choudhary K.P.R. etal (59) 2000. The ethyl vinyl acetate of nifedipine microcapsules were prepared by emulsion solvent evaporation method using chloroform as solvent. The prepared microcapsules were subjected to SEM shows spherical discrete and free flowing . Drug content was uniform and microencapsulation efficieny was in the range of 79-99%. The release from the microcapsule was slow and extended release over more than 12 hours.
Latha S.etal .(47) ,2004 .The magnetic microspheres of ranitidine hydrochloride were prepared by emulsion solvent evaporation and reported its invitro characterization.
Mohammadi R.etal (48),2003. The microscopic method was used for the determination of contact angle of microspheres and it was reported .
Al-Helw .A.A. etal (68) . The cross linked chitosan microspheres had sustained release effect was reported.
A.P. Kakkar etal reported that Ibuprofen microspheres were prepared and evaluated. The prepared microspheres were subjected to SEM having good spherical geometry and smooth surface. Ibuprofen was selected as model drug for anti inflammatory because of shorter half life . Invitro release studies suggested that drug release from microspheres is above 60% after eight hours.
D.Perumal etal studied on The Microencapsualtion of Ibuprofen microspheres and Eudragit RS100 by the emulsion solvent evaporation method in 2001.
Nagoji K.E.V.etal (89) 2000. Compare the release profiles of Nifidipine form ethylcellulose matrices and microcapsules and reported that the drug release will be sustained .
Nath B.S etal (94) ,1995 . The Nitrofurantoin microspheres were prepared by extrusion congealing technique and the release kinetics of the drug from the microspheres was studied.
Gowthamarajan K.etal (35) 2003. The Microspheres of Eudragit L100 and S100 containing Insulin Protease Inhibitor and Bile salts by using solvent diffusion technique . The drug, polymers and adjuvants showed no interaction subjected to FTIR spectroscopy .Invitro release studies of the microspheres showed a prolonged hypoglycemic effect for three hours when compared with the i.v injection of bovine insulin.
Dandagi P.M.etal (43) 2004. The study has been carried out on the design and evaluation of micropellets of verampil hydrochloride by ionotorpic gelation technique using sodium alginate , HPMC and HPC of the nine formulations prepared. Only three formulations showed good results for flow behaviour ,drug entrapment efficiency , invitro dissolution, and stability studies . It was concluded that the prolonged release micropellets of verampil hydrochloride could be achieved with success by employing ionotropic gelation.
Dharmadhikari N.B.etal (95) 1994. The microparticulate drug delivery system for salbutamol sulphate were prepared by melt dispersion technique and its invitro characterization were reported.
Sandra kokisch etal (50) 2003. The polymeric microspheres were prepared for drug delivery to the oral cavity and invitro mucoadhesive potential were studied .
Hassan etal (78) 1992. A site specific delivery of anti cancer agents such as oxantrazole and 5-fluoro uracil were developed.
Jameela S.R. etal (64) 1995. Reported that glutraldehyde cross linked chitosan microspheres acts as a biodegradable drug delivery vehicle using mitoxantrone as the model drug.
Muzzarelli R.etal (71) 1999. The ampicillin loaded chitosan microspheres were prepared and showed a controlled release of the drug .
Jameela S.R .etal (66) 1998. The progesterone loaded chitosan microspheres were prepared and act as a long acting biodegradable controlled drug delivery system.