Pharma Tips

Pharmaceutical Microsphers

By: Mitul Shah | Views: 3721 | Date: 14-Jun-2010

In recent year there has been on accelerating interest in the development of modified release dosage formulations and so, modified release drug products have established and retained a place in the market based on their uniqueness and their clinical advantages in the practice of medicine.

INTRODUCTION OF MODIFIED RELEASE DOSAGE FORM :-
In recent year there has been on accelerating interest in the development of modified release dosage formulations and so, modified release drug products have established and retained a place in the market based on their uniqueness and their clinical advantages in the practice of medicine.
The controlled or modified drug system is to a make a therapeutic agent. Do its best when administered into the body. This means a high therapeutic effect with a minimal toxicity. Normally the drug administered in the body it is not only interacting with the target cells but also with the normal healthy cells which often results in toxic effects & to obtained maximum therapeutic efficacy, it become necessary to deliver the agents to the target tissue in the optimal amount for the right period of time thereby causing little toxicity and minimal side effects.
And also with this above fast there are also to treat a disease effectively the drug dose regimen should be scheduled in such away that the plasma level dose not decrease below the minimum effective cons. However, frequent administration is burden to a patient.  Thus, ways to a painted.  Thus, ways to maintain an effective plasma level for a long period of time are often desired to increase patient compliance.
Thus the absorption rate of the drug into the body can be decreased by reduction of the of release of the drug from the dosage from. Some dosage forms are designed for rapid and complete release of there medicaments in the body where other products formulated for latter purpose have n referred to as sustained release, sustained action, prolonged action, controlled release, extended release, timed release, extended release, timed release, extended  release, timed release, depot and repository dosage forms.
The compendia describe all such dosage from under one category as modified release dosage forms. In other word all such drug delivery systems can be called as non-immediate release delivery system.
Modified release dosage forms those dosage forms for which the drug release characteristic are chosen to accomplish  therapeutic objective not offered by conventional dosage from such as solution,ointments,compressed tablets and capsular in these cases.
So, various approaches have been used in delivering a therapeutic substance to the target site in modified release dosage from. One out of these approaches is using polymeric micro spheres as carries for drugs.
INTRODUCTION OF MICRO SPHERES:-
There is growing interest in the development of homogenous monolithic drug release systems for various routes of administration. One very attractive type of such dosage from is microspheres.The considerable interest in using polymer based micro spheres as drug carrier is due to variety of reasons.
- Flexibility in design and development.
- Attractive in appearance.
- Better, improve the safety and efficiency of bio-active agents.
- Desired release pattern can be engineered.
Micro spheres are defined as solid spherical particles containing dispersed drug in either solution or micro-crystalline form.
- They are ranging in size a 1 to 100 mm.
- They are made of polymeric waxy or other protective material like biodegradable and non-biodegradable polymer and modified natural products such as starches gum, proteins and fats.
In microsphers of biodegradable and non polymer have been investigated for sustained release depending on final application.
The understanding of these two terms biodegradable carries which degrade in the body to non- toxic degradation products  do not pose the problem of carrier toxicity and are more suited for parenteral application.
Non-bridgeable drug carries, when administered parentrally, the carries remaining in the body after the drug is completely release poses the possibility of carrier toxicity over a long period of time.
Type of micro spheres :-
Two types of micro sphere
(1) Microcapsule:-where the entrapped substance is completely surrounded by distinct capsule wall.
(2) Micro matrices:-where the entrapped substance is dispersed throughout the polymer matrix.
Methods of preparation :-
The preparation of micro spheres should satisfy certain criteria they are.
(1) The ability to incorporate reasonably high concentration of the drug.
(2) Stability of the preparation after synthesis with a clinically acceptable shelf life.
(3) Controllable particle size and dispensability in aqueous vehicles for injection.
(4) Release of active agent with good controller over a wide time scale.
(5) Bio-compatibility with a controllable biodegradability.
(6) Susceptibility to chemical modification.
The preparation of microspheres from natural polymers involves three steps.
Steps
First step :-the solution of the polymer is dispersed in a continuous medium such as vegetable oil or an organic solvent using a suitable stabilizing agent. Dispersion is accomplished using mechanical stirring or by ultrasonication or by high speed homogenization depending on the particle size required.
Second step :-involves the hardening of polymer droplets either by heat denaturation [in case of proteins] or by chemical cross-linking using suitable cross-linking agent like formaldehyde, glutaraladehyde or by using diacid chlorides such as terephthaloy chloride.
Now a days, the protein micro spheres are prepared by heat denaturation.Thermal treatment of proteins such as albumin causes formation of intermolecular disulphide linkage between free-SH gps.
Third step :- involves separation of solid microsphered formed, purification& drying.
Cure temperature is a key factor in determining the aqueous swelling behavior of protein micro spheres and biological life.
As the temperature is increases for the thermal determining the swelling ability of the resultant micro spheres preparation is found to be decrease.
The heat denaturation method is not suitable for drugs such as adriamycion which have love thermal stability.
Now, in case of chemical cross linking agents.
For example, glutaraldehyde interests with salbutamol and methotrexate and formaldehyde interacts with epinephrine.
Hydrophilicity of the micro spheres preparation was found to be increased by addition of the cross-linking agents through the org medium which presumably limits the cross-linking predominantly to the surface.
As above described two method head denaturation and chemical cross-linking method. There are various other following techniques are also used.
Technology related factors as mentioned below :-
(1) The particle size requirement.
(2) The drug or the protein should not be adversely affected by the process.
(3) Reproducibility of the release and the method.
(4) No stability problem.
(5) There should be no toxic products(s) associated with the final product.
Emulsion technique:-There are two technique (1) Single emulsion technique and (2) Double emulsion technique.

Polymerization techniques:-
The polymerization techniques conventionally used for the preparation of the micro spheres are mainly classified as:
Normal polymerization
Interfacial polymerization

(a) Normal polymerization :-
The two processes are carried out in a liquid phase. Normal polymerization proceeds and carried out using different technique as bulk suspension precipitation, emulsion and micelle polymerization process. In bulk polymerization, a monomer or a mixture of monomer along with the initiator is usually heated to initiate the polymerization and carry out the process. One catalyst or the initiator is added to the reaction mixture to facilitate or accelerate the rate of the reaction. The polymer so obtained may be molded or fragmented as micro spheres. For loading of drug, adsorptive drug loading or adding drug during the process of polymerization may be opted. The scheme of the bulk polymerization is represented in the Figure-2.

The Suspension polymerization, which is also referred to as the bead or pearl polymerization is carried out by heating the monomer or mixture of monomers with active principles (drugs) as droplets dispersion in a continuous aqueous phase. The droplets may also contain an initiator and other additives. The schemes for the suspension polymerization are given in the Figure-3.The Emulsion polymerization, however, differs from the suspension polymerization as due to presence of the initiator in the aqueous phase, which later on diffuses to the surface of the micelles or the emulsion globules. The bulk polymerization has an advantage of formation of the pure polymer, but it also suffers a disadvantage, as it is very difficult to dissipate the heat of reaction, which can adversely. Affect the thermo labile active ingredients. On the other hand the suspension and emulsion polymerization can be carried out at lower temperature, since continuous external phase is normally water through which heat can easily dissipate. The two processes also lead to the formation of the higher molecular weight polymer at relatively faster rate. The major disadvantage of suspension of polymer with the unreacted monomer and other additives.
(b) Interfacial polymerization :-
Interfacial polymerization essentially proceeds involving reaction of various monomer at the interface between the two immiscible liquid phased to form a film of polymer that essentially envelops the dispersed phase. In this technique two reacting monomers are employed, one of which is dissolved in the continuous phase while the other being dispersed in the continuous phase. The contininuous phase is generally aqueous in nature through which the second monomer is emulsified. The monomers present in either phase diffuse rapidly and polymerize rapidly at the interface. Two conditions arise depending upon the solubility of formed polymer in emulsion droplet. If the polymer is soluble in the droplet it will lead to the formatting of the monolithic type of the carried on the other hand if the polymer insoluble in the monomer droplet, the formed carried is of capsular (reservoir) type.
The degree of polymerization can be controlled by the reactivity of the monomer chosen, their concentration, the composition of the vehicle of either phases and by the temperature of the system. The particle size can be controlled by controlling thermopile or globules size of the disperse phase. The polymerization reaction can be controlled by maintaining concentration of the monomers, which can be achieved by addition of an excess of the continuous phase. The interfacial polymerization is not widely used in the preparation of the micropaticles because of certain drawbacks, which are associated with the process such as;
*    Toxicity associated with the unreacted monomer 
*     High permeability of the film
*     High degradation of the drug during the polymerization 
*     Fragility of microcapsules 
*     Non-biodegradability of the microparticale
Phase Separation Coacervation Technique(s) :-
Phase separation method is specially designed for preparing the reservoir type of the system, i.e. to encapsulate water soluble drug e.g. peptides, proteins, however, some of the preparation are of matrix type particularly, when the drug is hydrophobic in nature e.g. steroids. In matrix type device, the drug or the protein is soluble in the polymer phase. The process in based on the principal of decreasing the solubility of the polymer in the organic phase to affect the formation of the polymer rich phase called the coacervates. The Coacervation be through about by addition of the third component to the system which results in there formation of the two phase one rich in the polymer, while the other,i.e.supernatant related to the polymer. There are various means and methods, which are effectively employed for coacervate phase separation. The method choice is large dependent upon the polymer and set of conditions. The methods are passed on salt addition non-solvent addition, addition of the incompatible polymer of change in pH.
In the Phase separation technique, the polymer is first dissolved in a suitable solvent and then drug is dispersed by making its aqueous solution, if hydrophilic, dissolved in the polymer solution it self, if hydrophobic, Phase separation is then accomplished by changing the conditions by using any of the method mentioned above. The process is carried out under continuous stirring to control the size of the micro paricles. The process variables are very important since the rate of achieving the coacervate determines the distribution of the polymer film, the particle size and agglomeration of the formed particles. The agglomeration must be avoided by stirring the suspension using a suitable speed stirrer since as the process of micro spheres formation begins the formed polymerize globules start to stick and form the agglomerates. Therefore, the process variables are critical as they control the kinetic of the formed particles since there is no defined state of equilibrium attainment.

Spray drying and spray congealing :-
Spray drying and spray congealing methods are based on the drying of the polymer and drug in the air. Depending upon the removal of the solvent or the cooling of the solution the two processes are named spray drying and the spray congealing respectively. The polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, acetone, etc. the drug in the solution form is then dispersion is then atomized in a stream of hot air. The atomization leads to the formation of the small droplets or the fine mist from which the solvent evaporates      leading the formation of the micro spheres in a size range1-100in. Micro particles are separated from the hot air by means of the cyclone separator while the traces of solvent are removed by vacuum drying. One of the major advantages of the process is feasibility of operation under aseptic conditions. The two processes are rapid, requiring single stage operation, suitable for both batch and bulk manufacturing. These techniques have been used to encapsulate a large number of the drugs. The spray drying process is used to encapsulate various penicillin. The amine mononitrate and sulpha ethylthiadizole are encapsulated in a mixture of mono-and diglycerides of stearic and palmitic and using spray congealing the rate of solvent removal by evaporation strongly influences the characteristics of the formed micro spheres and it depends on the temperature, pressures, and the solubility parameter of the polymer, the solvent and the dispersion media. Very rapid solvent evaporation however leads to the formation of porous micro particles.   

Solvent extraction :-
Solvent extraction method used for the preparation of micro particles, involves removal of the organic phase by extraction on the organic solvent. The method involves water miscible organic solvents such as is propanolol. Organic phase if removed by extraction with water these process decreases the hardening time for the micro spheres. One variation of the process involved direct addition of the drug or protein to polymer organic solutions. The rate of solvent removal by extraction method depends on the temperature and or water ratio of emulsion volume to the water and the solubility profile of the polymer.
Material used in the preparation of micro spheres :-
(A) The material utilized for the preparation of micro spheres should ideally fulfill the following prerequisites
- Longer duration of action.
- Control of content release.
- Increase the therapeutic efficiency
- Protection of drug.
- Reduction of toxicity.
- Biocompatibility.
- Sterilizability 
- Relative stability  
- Water solubility or dispersability.
- Bio-reabsorbability
- Targetability
- Polyvalent.
The no of different subject used for the preparation of micro spheres as above
Biodegradable  
Non biodegradable
These materials include the polymers of natural and synthetic origin and also modified natural substance.
Synthetic material employed as a carrier materials are methyl methcrylate, acrolein lactide,  glycolide and their co- polymer, ethylene vinyl acetate copolymer, poly anhydride etc.
The natural polymers used for the purpose are albumin, gelatin, and starch. Carrageen etc.
(B) Classification :-
The material used are as following.
-Synthetic polymer
-Non –biodegradable.
- PMMA 
-Acrolein
-Glycidyl methacrylate
-Epoxy polymers
Biodegradable :-
Lactides and glycolides and these copolymers 
Poly-alkyl cyano acrylates, poly-anhydrides
Natural materials :- 
Protein      albumins 
Gelatin 
Collagen

Carbohydrates                  Starch
Agarose 
Carrageenan
Chitosan
Chemically modified carbohydrates
DEAE cellulose
Poly (acryl) dextran
Poly (acryl) starch
Characterization of micro spheres:-
(A) Polymer characterization:
(a) Molecular weight :-
gel permeation 
viscosity 
Collgative properties ( Vapour pressure, boiling point, elevation, freezing point depression )
Refractrometry 
Light scattering measurements.
(b) Purity :-
(a) Gas chromatography (for residual monomer and solvent)
(b) Karl Fischer and thermo gravimetric analysis. 
(c) Fourier transform remain spectroscopy. 
(d) Differential photoelectron spectroscopy.
(e) X-ray photoelectron spectroscopy.
Attenuated total reflectance Fourier transform-infrared spectroscopy.
FTIR is used to determine the degradation of the polymeric matrix of the carrier system. The surface of the micro spheres is investigated measuring alternated total reflectance (ATR) The IR beam passing through the ATR cell reflected many times through the sample to provide IR spectra mainly or surface material. The ATR-FTIR provides information about the surface composition of the micro spheres depending upon manufacturing procedure and conditions.
(c) Miscellaneous :-
Density, Crystallinity and film forming properties.
(B) Microsphere characterization:-
(a)  Particle size and size distribution
(1) Sieving
(2) Microscopy
(3) Resistance blockage analysis (Coulter analysis )
(4) Light blockage techniques.
(5) Recent techniques such as photon correlation spectroscopy
(For particles less than I m) and for diffraction analysis.
(b)  Surface Characterization:
(1) Electron microscopy
(2) Scanning electron microscopy 
(3) Scanning tangeling microscopy.
Electron spectroscopy for chemical analysis
The surface chemistry of the micro spheres can be determined using the electron spectroscopy for chemical analysis (ESCA). ESCA provides a means for the determination of the atomic composition of the surface. The spectra obtained using ESCA can be used to determine the surface degradation of the biodegradable micro spheres.
(c)  Surface Charge Analysis :- (1) Micro electrophoresis (2) Laser droppler anemometry 
(d)  Hydrophobicity   
(1) Contact angle measurements
Angle of Contact 
The angle of contact is measured to determine the wetting property of a micro particulate carrier. It determines the nature of micro spheres in terms of hydrophilicity or hydrophobicity. This thermodynamic property is specific to solid and affected by the presence of the adsorbed component. The angle of contact is measured at the solid/air/water interface. The method for the determination of the angle of contact is given by Nutt who proposed that the particle floating at interface is subjected to number of forces such as gravitational, Archimedean thrust, etc. these forces affect the angle of contact. The advancing and receding angle of contact are measured by placing a droplet in a circular cell mounted above objective of inverted microscope. Contact angle is measured at 20 C within a minute of deposition of micro spheres.
(e) Density
(1) Bulk density
(2) Tapped density
(f) Surface area
(g) Porosity
(h) Hardness and friability
(i) Flow properties
Angle of repose
Housner ratio
(j) Drug contact
(k) Drug release profiler
in-vivo
in-vitro
Loading of drug :-
The active components are loaded over the micro spheres principally using two methods.
During the preparation of micro spheres.
After the formation of the micro spheres by incubating them with the drug or protein.
The active component can be loaded by means of physical entrapment, chemical linkage and surface adsorption
(1) Entrapment :- These are largely depends on the method of preparation on the method of preparation on the method of preparation and nature of the drug or polymer.
Maximum loading can be achieving by incorporating the drug during the time of preparation.
The factor which affect the process variables such as,
Method of preparation
Presence of additives
Such as cross linking agent, surfactant, stabilizers etc.
Heat of polymerization
Agitation intensity
-  Now a days, the incorporation in pre-formed microspheres is relatively less, but the major advantage of the leading method being there no effect of process variables.
These loading processes is carried out in pre-formed microspheres by incubating them with high concentration of drug in a suitable solvent.
The drug in these microspheres is loaded via penetration or diffusion of the drug through the pores in the microspheres as well as adsorption on this surface. The solvent is them removed, leaving drug loaded microspheres.
Adsorption :- These are depends on the nature of polymers applied to determine the adsorption of the drugs. The Freud lick equation is: X/M=kcp eq 
Where k=constant related to the capacity of the adsorbent for the adsorb ate.
P= constant related to the affinity of the adsorbent for the adsorb.
Although this equation was first employed empirically, it can be derived with the assumption of a continuously varying heat of adsorption. The freundlich model unfortunately predicts both infinite adsorption at infinite concentration and are infinite heat of adsorption at zero average.
Drug- polymer binding :- 
The binding force that holds the drugs to the microspheres matrix can either be physical or chemical. In addition to this, hydrophobic and interaction may also exit. Depending on the force of attachment, drug release from the matrix also varies. The drug release is expected to be faster in only physical entrapment is achieved Drug release in such cases is modulated by a diffusion controlled mechanism.
Slow release can be achieved by chemically binding the drug to the microspheres matrix the polymeric matrix should have reactive functionalities to which the drug can be bound through a functionality, available on the drug. Drug with M NH2-group can be attached to the matrix containing either COOH-OH or CHO groups. There are various methods for attaching drug to the matrix.In some cases, activity of the drug is compromised. For example, daunonycion attached to N-hydroxypropyl,methacrylamide was also ineffective against L1210 lukemia. Polvglutamic acid-adriamycin conjugated was also totally ineffective against the same tumour using spacer such as Gly-Gly-Gly-leu-adr and Gly-Glu-Adr enhances drug activity as evidenced by the mean survival time of mice with L1210 leukemia cells implanted intra peritonially. Drug can be either attached onto the performed microspheres or a polymer-drug conjugate prepared by attaching the drug to the polymer chain can be fabricated further functionalities so that to which drug is released form. The linkage should be susceptible matrix. High loading is possible if sufficient functionalities to which drug can be bound exist on polymer matrix. The drug release in this case will depend on the rate of cleavage of the bond linking the drug to the to the matrix.
In the case of protein microspheres, certain drug bind strongly to the matrix without covalent attachment. The exact nature of this binding is not known at present albumin and casein microspheres were found to show this behavior with creation cytotoxic drugs such as methotrexate, mitoxanthrone, 5 fluorouracil (5-FU), etc Sugubayashi (et al. 1979a) observed that 5FU release from heat denatured albumin microspheres prepare at 100c is about 35% 2 DAYS, no significant amount was released form the matrix even after 7 days. In over studies on glutaraldehyde cross-linked album and casein microspheres with methotrexate and 5-FU, we observed that most of the drug incorporated is strongly bond to the matrix. Around 30to 40 %of the methotrexate was released from both albumin and casein microspheres in about 2 h and no further release was observed even after 24 h release of 5-FU from glycine-quenched and unquenched casein microspheres was only about 10-20% after 7 days which suggested that presences of free aldehyde had effect on drug building. The physically entrapped portion of the drug is released in a rapid in a fashion, but complete release occur only on degradation of the matrix. Drug release in this case is usually slow in the absence of proteolytic enzymes. Thus, slow release is possible form microspheres without chemical attachment for certain.
Route of administration :-
Micro spheres can be used for the delivery of drugs via different routes.  Route of administration is selected depending on the drug properties, disease state being treated and the condition of the patient. Desirable properties of the microspheres used for the delivery will also change depending on the route of administration.
(A) Oral Delivery :-
Oral delivery is the simplest way of drug administration. In oral drug delivery, the microspheres have to pass through frequently changing environments in the GI tract. There is also patent variation in GI content, so much emptying time and peristaltic activity. Although constrains of the oral route are numbers, on the whole, it less potential danger than the pretrial route. The relatively brief transit time of about 12 h through the GI tract limits the duration of action that can be expected via the oral route. Recently, it has been reported that microspheres of lass than 10 un in size are taken up by the payer’s patches and may increase the retention time in the stomach. Eldrige  el al. (1990) found that oral administration of poly-lactide co-glycodine microspheres containing staphylococcal enter toxin B is effective in including disseminated muccal Iga antibody response. Also microspheres made from polymers with mucoadhesive properties get attached to the stomach and prolong the residence time in the stomach. Bioavailability of drugs with limited solubility in this stomach or intestine and small absorption rate constant can be increased by increasing the retention time in the stomach. Longer et al al. (1985) studied chlorothiazide release form albumin microspheres by oral administration by mixing it with poly-carbophill, a bioadhesive polymer. Improved drug delivery was observed compared to the micro spheres administered alone.
(B) Parentral delivery :-
Most of the micro spheres based controlled delivery system are developed was the aim of using them for parental administration. Drug released is completely absorbed in this case. Micro spheres used for parental delivery should be sterile and should be dispersible in a suitable vehicle for injection hydrophilic micro spheres have the potential advantage of aqueous dispensability surfactants in small concentrations are often necessary for reconstituting hydrophobic particles for injection is aqueous vehicles which are reported to case adverse tissue reactions and affect the incorporated drug.
Mechanism of drug release :-
Theoretically, the release of drug from biodegradable micro spheres can he classified into four different categories. But actual, the mechanism is more complex and interplay of different mechanism may operate.
(A) For biodegradable: - 
Degradation controlled monolith system :- 
In degradation controlled monolithic microspheres system, the drug is dissolved in the matrix is in degradation controlled monolithic microspheres system, the dissolved and is released only on degradation of the matrix. The diffusion of the drug is slow compared with the degradation of the matrix. When degradation as by homogeneous bulk mechanism, drug release is show initially and increase rapidly when repaid bulk degradation starts. Drug release from such type of device in independent of the geometry of the device if the degradation is by homogeneous mechanism, degradation is confined to the surface. Hence rate of release is affected by the geometry of the device. If the degradation by the geometry of the device.   Release from a sphere is governed by the education, where M is the amount of the agent released at time t. m-is the amount at time—and t—is the for total erosion. Progesterone release from poly (glycolic-co-lactic acid) polymer films containing 10wt% steroid is an example of this of release (pitt) et al.1981b 
Diffusion controlled monolith system :-
Here the active is released by diffusion prior to or concurrent with the degradation of the polymer matrix. Degeneration of the polymer matrix affects the rate of release and to be taker into account. Rate of release also depends on whether the polymer degrades by homogeneous or heterogeneous mechanism.
Diffusion controlled reservoir systems :-
Here the active is encapsulated by rare controlling membrane in which the agent diffuses & membrane erodes only after its delivery is completed. In this case drug released is unaffected by the degradation of matrix. Polymers that remains as such till complete release of drug & they degraded by homogeneous mechanism so that the device is removed from the body is better for this type of delivery.
Erodable polyagent system :-
In this case the active agent is chemically attach to matrix & the rate of biodegradation of matrix is slow compared to the rate of hydrolysis of drug-polymer bond. Assuming that the rate of diffusion of active agent from the matrix to the surrounding is rapid, the rate limiting step is the rate of cleavage of bond attaching drug to polymer matrix. This type of delivery is obtained in the release of norethindrone-17-chlorofirmate which is then attached to the –OH group of polymer. In vitro studies in rats using labeled drug polymer conjugate showed that a fairly constant release is obtained during the time of observation which was 5 months.

(B) Non- Biodegradable type :-
Drug release from non-biodegradable type of polymer can be understood by considering the geometry of carrier,i.e. whether it is reservoir type where the drug is present as core, or matrix type in which drug is dispersed throughout the carrier, governs overall release profile of the drug or active ingredients.

(1) Reservoir type system :-
Release from the reservoir type system with rate controlling membrane proceeds by first penetration of the water through the membrane followed by dissolution  fluid. The dissolved drug after partitioning through the membrane diffuses across the stagnant diffusion layer. The release is essentially governed by the Fick’s first law of diff
J= - D (dc/dx)

Where, j is flux per unit is, D is diffusion coefficient, and dc/dx is concentration gradient.
Diffusion across the membrane determines the effectiveness of the carrier, system. The cumulative amount of drug that is released through the unit area, Qt at any time‘t’ is given by equation;
Qt =  Cs K Dm Dd t /K Dm Im + Dd Id
Where, Cs represents Saturation solubility of drug in dispersion medium, Dm is diffusion coefficient of drug in membrane of thickness Im, Dd is diffusion-coefficient of drug in static diffusion layer of thickness. Id, k is partition-coefficient of drug between membrane and reservoir compartments.
The release rate from the carrier can be modified by changing both the composition and the thickness of the polymeric membrane.
(2) Matrix type system :- Release profile of the drug from the matrix type of the device critically depends on the state of drug whether it is dissolved in the polymer matrix, amount of drug, and the nature of the polymer (whether hydrophobic or hydrophilic) affect the release profile.
In case of dug dissolved in the polymeric matrix, the amount of drug appearing in the receptor phase at time ‘t’ is approximately by two separate equations. The first equation determines the initial 60 percent of the drug release while the second shows the release profile at later stage.
dMt/dt = 2 Mg  (DI²t/ ∏ )½
dMt/dt = 8DMg/I² exp ∏²Dt/I²
Where 1 is thickness of polymer slab, D is diffusion coefficient, Mx is the total amount of drug present in the matrix and Mt is the amount of drug released in time t. when the drug is dispersed throughout the polymer matrix then the release. Profile follows higuchi’s equation
dMt/dt = A/2  (2DCsCo)½/t
Where, A is area of matrix, cs is solubility of the drug in the matrix and cs represents total concentration in the matrix. 
dMt/dt = [ε/τ Dm(2Co – ε Cs)Cs t]
Tacking porosity (ε) and tortuosity (τ) of matrix into the consideration the above equation can be rewritten as
(C) Factors affecting drug release :-
Factors affecting the release of the drug from the particular system in relation to drug, micro spheres and bioenvironmental;
Drug
Position in micro spheres
Molecular weight 
Physicochemical properties 
Concentration
Interaction with matrix
Micro spheres 
Type and amount of the matrix polymer 
Size and density of the micro spheres
Extant of cross linking, denaturation or polymerization 
Adjuvant 
Environment
PH
Polarity
Pressure of enzyme.
Targeting of micro spheres :-
Targeting is achieved by exploiting the natural distribution pattern of a drug passive targeting or by changing the natural distribution pattern of the carrier by some means thereby directing the drug to the specific organ or tissue. This is called active targeting.
(1) Passive Targeting :- Particles administered into the body intravenously will distribute itself in different organs depending on the size of the particle. The administered particles pass through the heart with little or no uptake to the lungs where particles > 7um get entrapped in the capillary bodes particles with mean diameter 280 nm and micro spheres with a mean diameter 14.9 um in the body and fund that most of the  particles were in the organs of reticuloendothelial system while 95.4  of the micro spheres were found in the lungs. Since bigger particles may cause toxicity, particles of size 10-15 particles in the systemic circulation are removed rapidly or slowly. Particles in the systemic circulation ate removed rapidly or slowly. Particles of 60-150 nm size coated with a polymer such as poloxamer are taker up to a considerable extent by the bone marrow. It has been proposed that particles>250 nm can be used for spleen targeting.
(2) Active targeting :- Active targeting includes containing the micro spheres with hydrophilic agents which surprises opsonization. When colloidal particles are administered into the blood stream, they may be coated with proteins such as albumin, globulin etc. 0depending on the nature of the material, surface change and hydrophilicity of the particle. This is called opzonization. By coating the particles with certain polymers like poloxamer, opzonization and removal of particles by microphage can be reduced. It is thus possible to direct particles within the body to sites as the ling, the liver, and the bone marrow or to retain them for longer periods within the systemic circulation. Blockage of kupffer cells of the liver by giving placebo spheres, change the in vivo distribution. Thus 5-FU loaded albumin micro spheres, sugibayshi et al. (1979b) have shown that mice pretreated with placedo spheres, there was a reduced uptake of drug in the liver and the spleen. Attaching sprecige ligands to the drug can also direct it to the specific cells. Much attention has been focused on the on the drug to the target site by attaching antibodies. Direct linking of the antibody to the drug molecule has some limitations. The number of drug molecules that can be linked to the antibody is limited and the linking process may inactivate the drug or the antibody. Biodegradable micro spheres with large drug carrying capacity have been proposed overcome some of these problems. Antibodies ate attached to the micro spheres matrix containing the drug to enhance the efficiency. Monoclonal antibodies have been employed in achieving target specificity for drugs incorporated into microspheres.If attached irreversibly to the micro spheres Via. The Fc portion which has affinity for hydrophobic surface, targate specificity can be achived.Davis & Illum (1983) studied the binding capacity of monoclonal-Ab attached polycynoacrylate particles to antigenic tumor cells in vitro.The microspheres-Ab conjugates showed strong interaction with the antigenic cells. Such approaches hold considerable promise in cancer chemotherapy
(3) Targeting using magnetic Micro spheres :-
Another approach is this area is by using magnetic microspheres.In this method magnetic loaded microspheres is infused into an artery supplying a given targeting site. A magnet is placed externally over the target area which restrict the microspheres to that area.Widder et al.(1983) studied the targeting of adriamycin to the tail of Sparauge-Dawley rats using magnetite loaded albumin microspheres containing adriamycin.Efficiency of localization was found to increase with the strength of of the magnetic field.At 8000 Oe magnetic field 3.9 ug adriamycin was obtained in the target.No drug is detected in non targeting tail segment or liver.Sugihayshi et al.(1982) studied the anti cancer effect of magnetic albumin microspheres containg adriamycin in a rat model & found that the particles could be guided to the target site by magnetic means & a sustained release was observe.Magnetically controlled release of proteins & macromolecules has also been attempted.                                                                   
(4) Intracellular targeting
Certain cytotoxic drugs are active intracellularly, but are normally discarded  due  to  their  poor intracellular  influx. Intracellular  pathogens  are usually  protected from the immune  and the chemotherapeutic  agents  the  poor  efficacy of  many  therapeutic substances for intracellular bacterial & parasitic  therapy is well known. Commonly Phagocytics cells are the sites of intracellular infection. Intracellular delivery of druge by suitable means can obviate these problems. Hoffman et al.(1984) demonstrated that albumin microspheres were avidly taken up by marophages.They have also observed that biologically active streptomycin was released from albumin microspheres inside the phagocytic cells after ingestion & intra cellular degradation of microspheres.Mannose residues were found to increase the endocytic uptake of glucoproteins by macrophages. In a still unpublished study,Quigg et al.(1995)have demonstrated that the uptake of albumin microspores by rat alveolar  macrophages was enchanted by the incorporation of mannose  in the microspheres.We have recently demonstrated that  fluorrescein labeled casein & casein & albumin microspheres of less then 5 µm in size are taken up by the mouse myleomonocyte leukemia cells, a macrophages like cells line in culture. Resistance encountered by methotrexate in the treatment of cancer is reported to be due to the membrane transport of the drug.Tumort cells display high uptake of protein microspheres & after internalization drug is released on digestion of matrix by enzyme.Polymericmicrospheres, therefore have the potential for intracellular targeting.

(5) Micro spheres based on natural polymers
Protein & polysaccharide microspheres have been extensively investigated for targeted drug delivery. Natural polymers have the advantage that they have less toxicity problems of their own. Majority of the natural polymers are susceptible to biodegradation & are generally biocompatible. A major problem with biopolymers is the presence of antigenic determinants in them.Biopolymer also differ in their molecular  weight & their physical & chemical properties to varying extents depending on the source & method of isolation & purification. 
   
Different form of Polymeric Micro spheres :-( 3)      
(1) Albumin Micro spheres:-
The albumin is a widely distributed natural protein. The particulate or the colloidal form of albumin is considered as the potential carrier of drug for either there site specific  localization or their local application into anatomical discrete sites. Much of earlier use of  serum albumin microspheres was limited to the diagnostic purpose as the microsphere of different size range locate themselves differentially at selected sites to facilitate the imaging.Now because of selected uptake of protein carrier by tumour cells, the micro spheres of albumin are being widely used for targeted drug delivery to the tumour cells.
The preparation of the albumin micropheres is easy & particles of size range 15 mm to 150 µm diameter are easy to prepare. There are numerous methods available for preparation of the albumin microsphers,which involve the drug incorporation either during the preparation or after the formation of the particles as the conditions may be on the basis of  the changes in process variables at the time of preparation the degradation can be varied.Albumin micro particle are mainly prepared by emulsion polymerization ,using either heat denaturation of the particles at elevated temprature(100-180°c) or chemical cross linking. The albumin microspheres can also be prepared by denaturation of protein aerosol in gas medium or an aerosol step followed by denaturation in oil.
The microspheres prepared by above method are hydrophobic in nature,& therefore small amount of surface-active agent is needed to disperse them in parental preparation. Hydrophobic microspheres are rapidly cleared from the body. The hydrophilic microspheres are considered to be good carriers as they can carry large amount of druge.Microspheres with increased hydrophilicity are advantages beacause(1)They may exhibit enhanced surface physical & chemical properties in vivo(2)They do not required surfactant currently needed to prepare aqueous dispersions which may influence tissue interaction,drug released,& activity(3)Hydrophilicity facilitates aqueous chemical modification(4)High concentration of drug can be incorporated after preparation.In order to make hydrophilic,a method was proposed by Long et al.1982.In this method lbumin droplets are stabilized using high molecular weight polymer solution followed be cross linking with glutaraldehyde introduced through organic phase ,e.g. toluene.Thise in turn to produces high cross-linking density at or near the surface accompanied by high concentration of mono reacted aldehyde.This process increases the anionic character & leads to incorporation of greater hydrophilicity. The drug release from albumin microspheres depends on the degree of cross-linking.The surface free aldehyde & carboxyl groups can be used for further surface & bulk chemical modification.The reactive -CHO group readily quencned or capped with compounds containing primary amino groups such as amino alcohol or amino acids e.g.glycine.Glycine conjugation  leads to an increased anionic charcter & hence hydrophilicity.
The albumin micropheres were evaluated for the chemotherapeutic  agents.Albumin microspheres loaded wih anticancer  drug such as mitomycin-C were found to be more effective than the drug alone. Burger et al.,1985 observed that cisplatin- loaded micropheres are 10 times more potent in targeting the drug to the patient with hypervascular liver carcinoma.Albumin  microspheres can also be targeted to the various organ & cell lines & they are found to decrease the toxicity  of the incorporated drugs.Intarvenous injection can provide  efficient targeting of albumin microspheres  either to the lung or liver. Their location will depend on the wide range of the microspheres.Microspheres of particles size range 15-30 µm or larger will pass through the hearts & deposited in the capillary bed of lung with 99% efficiency.The microspheres of 1-3 µm size will pass into reticuloendothelial system where they deposit with 90% efficiency in the liver.Microspheres with particel size less then 1 µm,when injected intravenously,lead to about 80-90% deposition in drug about 5-8% in spleen & about 1-2% in bone marrow.The releases of drug from heat stabilized albumin microspheres is frequently biphasic profile is dependent to some degree on the water solubility on the entrapped drug.Highly water-soluble drug exhibits very noticeable biphasic release characteristics.Relatively water insoluble drug such as steroids,exhibit less prounounced biphasic release properties. Theconcentration of drug incorporated in the microspheres also plays a major role in governing the biphasic character of the drug release.
(2)  Gelatin Microspheres:-
It is a biodegradable polymer obtaind from the partial hydrolysis of the collagen derived from the skin,connective tissue & bones of animals.The acid treated collagen is called type-A & the alkali treated is refered as type-B.Gelatin microspheres are extensively studied because they are prone to strong ionization.Figure-6 represants minor details of macrophage morphology which on activation of macrophages translated into multifold membranes as pseudopodes.
Thus gelatin microspheres of suitable size range can be used as an efficient carrier system capable of delivering the drug or biological response modifiers such as interferon to the phagocytes.Sustain release with the glutaraldehyde cross-linkined microspheres, while zero order release in case of the ethyl cellulose coated microspheres.
Gelatin microspheres are reported to be taken up by some of the tumour cells,which do not take albumin. Gelatin microspheres is prepared by cross-linking gelatin microspheres are also prepared by similar method by dispersing gelatin having IFN-αA/D in oil followed by cross-linking with glutaraldehyde.The shape of microspheres prepared by this method is spherical & size of microspheres can be reduced to average dimeter of about 1.5 µm by sonicating the emulsion.This size is suitable for macrophagic phagocytosis.The size & surface charecteristics of gelatin microspheres have great influence on the macrophage uptake.Gelatin microspheres are found to be more opsonic than immunoglobulins & affinity towards the proteins so in presence of the serum proteins leading to an increased opsonization
The gelatin microspheres being succeptible for the macrophages recognition,can be used as carrier for the antigens.The antigens from microspheres are released within the macrophages upon their degradation leading to enhanced production of antigen specific antibody.Thus this can be used as immunoadjuants.A number of different drug have been studied for their targeting using gelatin based microparticulate carriers, such as sulphanilamide for GIT;bleomycin for liver & joints; & daunorubicin & fluoouracil for liver tumours etc.

(3)  Starch Microspheres:-
Starch is one of the most biodegradable  polymers that belong to carbohydrate class.It consist of  the principle glucopyranose unit,which undergoes hydrolysis to yield D-glucose.Starch being a polysaccharieds,consists of larger number of the free hydroxyl groups.By means of these free hydroxyl groups a larger number of active ingradient can be incorporated within as well as active on surface of microspheres.The starch microspheres when introduced into the body cavity undergo potential swelling,leading to the development of mucoadhesive character.Therefore,they are not cleared rapidly from the body cavity.Intranasally administered insulin starch microspheres are cleared slowly & offer a delivery mode for protein & small molecules.

(4)Dextran Microspheres :-
Dextran,a carbohydrate use to prepare hydrogel type of biodegradable & biocompatible systems.It can be chemically modify that provide higher percentage of drug or proteins incorporation.Simple method of incorporating aldehyde group to dextran is by oxidation using sodium iodate.
Protein loaded dextran microspheres are prepared by water in water emulsion technique.In the method an aqueous solution of the methacylated dextran is emulsified in aqueous solution  of PEG.The dispersed methacrylated phase is then crossed-linked by using radical polymerization of the dextran bound methacrylate groups.This leads to formulation of the dextran microspheres with hydrogen charecters.The method is based on the phenomenon that the phase seperation occurs in aqueous solution of the dextran & PEG.The microspheres were rendered biodegradable by the co-entrapment of the dextranase.By using water & water emulsion technology it is possible to encapsulated IgG with very high entrapment or loading efficiency(more then 88%). The release from hydrogel matrix is dependent on the diffusion of the protein through the hydrogel matrix,if the protein dimeter is smaller then the pore size of the matrix,it result in the typical first order release.When the protein dimeter is larger then the pore the dimeter,the release tend to be dependent on the degradation rate of the gel.The rate of degradation of dextran microspheres depends entirely on the degree of substitution of dextran & the amount of dextranase enzyme incorporated. The optimization of water content reduces the episode of brust effect to less then 10%.Similarly,incorporation of dextranase helps in tailoring  the release of microspheres.A linear relationship between the amount of the dextranase & the initial degradationis generally recorded.The major advantage of dextran water in water emulsion technique is that no organic solvent is used, which might have adverse effect on the stability  of drug or protein & second.Protein is largely allowed to release the water filled pores.
(5) Polylactide & polyglycolide Microspheres:
Polylactoicacid(PLA),polyglycolic acid (PGA) there co-polymer poly(lactide co polyglycolide) (PLGA) represent the grup of synthetic biodegradable polymers. They were used earlier as absorbable sutures,implant materiels & recently as the carrier for the drug.L-PLA has been recorded as suitable carrier for sustain release of narcotic antagonist 7 anticancer agent cisplastin,cyclophosphamide,doxorubicin.Anderson et al.1976 used PLA for sustained release of norethisteron in fertility control.Sustained release preparation for antimalerial drug as well as for many other drugs have been formulated by using a copolymer of PLA & PGA.
Microspheres from PLA &PGA may beprepared by any of the microparticles preparation techniques like single & double emulsion techniques,phase separation-coaservation,spray drying,etc.The PLGA microspheres are successfully prepared by double emulsion techniqes & phase separetion methods.In the phase separation method product agglomerated microspheres in case of large scale production while double emulsion methods required a lengthy & cumbersum procedure & it is difficult to incorporate the procedure & it is difficult to incorporate the hydrophilic drug.In contrast to these,spray drying method is fast & by controlling the different process variable desired type of microspheres can be obtained.
Double walled microspheres in size range 4-22 µm can be obtained in order to protect antigen(e.g.hepatitis)from the harmfull effects of solvent.The method involves prior production of core microparticles by mixing hepatitis B antigen wlth hydroxy propyl cellulose(HPC) followed by spray drying.These core microparticles are then suspended in the PLGA/ethyl acetate solution & spray dried to yield double walled microspheres.

To improve patient acceptance and to overcome drawbcks of traditional methods as
(1) requirements of reconstitution before administration in the body cavity 
(2)Presence of residual solvent & 
(3)Hazard of using organic solvents.
A novel implant system has been developed, which after administration (in liquid form ) solidifies in situ.This method is reported by a number of scientists to deliver a number of antigen  & variety of therapeutic & classes.Fig-8 represent the method of preparation of this novel microspheres.
After  injection,protein release occurs from biodegradable microspheres,as the protein diffuses from the interior of the microspheres through pores more void is created by polymer degradation or dissolution of encapsulated solids. 
The duration of release,which can range from days to months,is determined by polymer molecular wt.lactide:glycolide ratio & the presence of hydrophobic end-groups.Excipients,such as zinc salts,can be included to stabilized the protein.


(6) Polyhydride Microspheres:-
Polyhydrides are biodegradable & biocompatible polymers.They were first prepared using aromatic monomers.The first aliphatic polyanhydride was prepared as a raw material for the textile purposes.In 1980 the polyanhydride were discovered as they can be used for the erosion controlled devices in the area of drug delivery.
The polyanhydride can be manufactured with desired features(such as  crystallinity,controlled degradation rate, degree of cross linking,water uptake etc.)by employing different monomers & controling the polymerization process variables. It can be prepared by solvent evaporation,solvent extraction, hot melt technique & spray drying technique.For hot melt encapsulation procedure,polyanhydrides were melted,& drug was dispersed in melted polymer.This suspension was then transformed into microspheres by addition to or of a non-solvent such as silicone or olive oil,at 5°c above the melting point of polymer.The sphere solidified on subsequent colling & were washed with petroleum ether.The temperature of the preparation is a limiting step of the method.Apart from these the double wallied polyanhydride microsphere having two different polymer layers can be using one partial or complete.The first method is based on the partial or complete insolubility of one polymer into other.The co-solution of the 2 polymers is then added to poly vinyl alcohol(PVA)aqueous solution followed by evaporation of the solvent.on evaporation of solvent,The polymers separates polymer while coat the other.The second method (FIG-8) is based on modified double emulsion technique.In this method the microspheres is aqueous phase dispersed in apolymer solution in organic phase to form W/O emulsion.This is then added to the aqueous from W/O emulsion.This is then added to the aqueous PVA solution to form the double walled microspheres instantaneously.    
(7) Polyphosphazene Microspheres:-
It have a long chain backbone of alternating nitrogen & phosphorus atom with 2 side group atteched to each phosphorus atom.Polyphosphazene polymers from highly swollen ionotropic gel in the presence of the multivelent ions in aqueous media,such as calcium. Because of this properties the polyphosphozene microspheres can be prepared under very mild condition of low temperature & in absence of the organic solvents.The microspheres are prepared by using a droplet apparatus,which produces sphericles gel particle of size range 0.5-1.5 µm.In this method a 2.5% W/V Phosphazene solution  is added in the form of the droplet to a7.5% W/V aqueous solution of calcium chloride.The microspheres (1-10 µm) have been used to target peyer’s patch-M cells & sub epithelial macrophages.The method describe the preparation of microspheres where Polyphosphazene polymer solution at pressure(10psi) is sprayed through & ultrasonic spray nozzle,which produces a spray could having micro droplets of the polymer solution This could when collide with calcium chloride solution,instantaneously get to from the microspheres.The nature of the substrate & gelation condition determine the encapsulation efficiency & bioavaibility & bioactivity of the substrate.Using this the entrapment of B-galectosidase enzyme was reported to be about 80%.Hydroma cells were encapsulated up to 30%with recorded viability of about 70%.The polyphosphazene microspheres are sensitive to the ionic environment of the surroundings.They can be stabilized by coating with +ve charged polyelectrolytes such as poly(L-lysine).The hydrophobicity of the polyphosphazene can be manipulated by subsequent reaction of PLA surface with the polycation solution.The formation of the inter polymer complex at the surface & within provides stability to the microspheres in saline solution.

(8) Chitosan Microspheres:-
Recently,natural polymers such as polysaccharides & proteins have received much attention in the pharmaceuticle field owing to their good biocompatibility & biodegradability.Among polysaccharides,Chitosion,the deacetylated product of chitin,is one of the most usefull natural polymers from the view of possible exploitation of natural resoures.Chitosan is insoluble at neutral & alkaline pH values,but forms salts with inorganic & organic acids such as HCL.Upon dissolution,the amine groups of chitosan get protonated & the resultant polymer becomes +ve charged.Since chitosan exhibits net +ve charged,it has been recently introduction the market as an aid for Wt loss & as cholesterol-lowering agent.The mechanisum behind chitosan may be it’s effect on lipid transport in the gut,where the +ve charged chitosan can bind the free fatty acids & bile salts components & hence disrupts overall lipid abosrption.
The effect of chitosan has been considered mainly because of its +ve charge,however,the adsorption process could also be the result are forces that might exit between molecules,such as hydrogen bonding or vander waal`s force.These interaction might have a strong impact on the absorption & bioavibility of pharmaceutical compounds,especially drugs that are potent & have low water solubility.
Yao et al. 1995 high lighted the preparation & properties of microcapsules & microspheres of chitosion.Due to attractive properties & wider application of chitosan based microspheres,They are used as carrier for the application in controlled drug release.Morever,microcapsules & microspheres have an edge over other forms in regard to their handalling & administration.

(9) Polysaccharide or lipid cross-linked chitosan microspheres:-
Ohya & Takei,1993 studied 5-fluorouracil (5-FU) and its aminoderivatives, loaded cross linked chitosan microsphere coated with polysaccharide or lipid for controlled and target drug delivery. The microsphere were prepared  with an inverse emulsion of 5-fu or its salt solution with chitosion containing a aqueous phase while toulene containing span-80 served as dispersion phase.Chitosion was cross-linking with schiff`s salt formation on addition of glutaraldehyde toluenme solution.At the same time,of the amino derivatives of the 5-fu were immobilised,obviously resulting in a drug content within the microspheres.The microspheres were furthuer coated with anionic polysaccharides (e.g. carboxymethylchitin)throgh a polyion complexion reaction.Inthe case of lipid coated microspheres along with dipalmitoyl phosphatidyl choline(DPPC) were dispersed in chloroform.After evaporation of the solvent,chloroform,microspheres were obtained coated with DPPC lipid multilayers,which exhibited a transition temperature of a liquid crystal phase at 41.4°c.The dimeter range of microspheres was 250-300 mm with a narrow size distribution.Improvment in stability of the dispersion was recorded following coating of the microspheres with anionic polysaccharides or a lipid multilayer.
A comparative study of the release of a 5-FU & it’s derivatives from polysaccharides coated microspheres was carried out in physiological saline at 37°c. Data indicated that the 5-FU release rate decreased in the order free 5-FU >carboxymethyl type 5-FU>ester type 5-FU.The result revealed that the coating imposed the effective barriers to 5-FU release.The lipid multilayers with a homogeneous composition generally show a transition of gel-liquid crystal.When the temperature raises to 42°c,i.e.above the phase transition temperature(41.4°c),the amount of 5-FU released is increased.In contrast the amount of drug delivered decreased at 37°c or at temperature below the transition temperature.Due to the improved recognition function of poly-saccharide chains for animal cells,it is resionable to develop targeted delivery system using polysaccharides of a coating of the microspheres.
Chitosion/Gelatin polymers based microspheres are reported for controlled release of cimetidine.The drug loaded microspheres were prepared by dissolving chitosion,gelatin & cimetidine in 5% acetic acid.A certain amount of Tween-80 & liquid paraffin at a water to oil ratio 1:10 was added to the chitosion/Gelatin mixture under agitation 650 rpm at 30°c. A suitable amount of 25% W/V aqueous glutaraldehyde solution was added to the inverse emulsion & maintained for 2 hr. Finally,the liquid paraffin was vaporized under vaccum to obtain microspheres.The drug release studies were performed in 0.1N HCL solution(PH-1) & potassium dihydrogen phosphate buffer(PH-7.8,ionic strength 0.1m/l) A pH dependent pulesd-released behaviour of the HPN matrix was observed. Morever,the release rate can be controlled via the composition of the HPN & degree of deacetylation of chitosion.Gohel et. Al. 1994 reported the preparation of chitosion microspheres containing diclofenac sodium by co-acervation phase separation method.Chitosion & glutaraldehyde were used as coating & cross-linking agent respectively.Moreover,the microspheres were found to be stable at 42°c for 30 days.

(10)Carrageenan  Microspheres:-
Carrageenan is an anionic polymer of hemisulphate galactose & 3-4 anhydrogalactose residue alternatively linked by α1-34 & β 1-4 glycosidic linkage.Hemisulphate ester groups impart –ve charge to the polymer.Based on the sulphate esterification pattern,the polymer is graded as the L,k,& δ.L-carrageenan has been proved to be a better canditate for the preparation of the microspheres using aqueous microencapsulation process that avoids the use of the organic solvents,which may alter the biological properties.
Patil & Speaker,2000 uses carrageenan for the formulation of model protein horseadish peroxide in the water based microspheres delivery systems.Patil & Speaker,1997 have described the method for carrageenan microspheres preparation(FIG-9).They pumped mixture of mM L-carrageenan(9ml) & 1mg/ml horseradish peroxide at the flow rate of the 1ml/min throgh a 76 µm orifice to produce a continuous jet.Against the side of the capillary,sonic pulsing was applied to produce uniform droplets.The formed droplets were lowed to fall into a magnatically stirred amine the concentration of amine is varied & tested for stable microspheres.Prepared microspheres were separated by the centrifugation(1000gm) & washed twice with 10 ml distilled water.

(11) Alginate Microspheres:-
Many of present controlled release devices in their-preparation involve hazardous chemicals such as organic solvent or extreme condition such as high temperature,which can adversly affect the drug or the proteins.Alginate microspheres are suggested for such sensitive drugs.Sodium alginate(NaALg) ,a water soluble salts of alginic acid,is a natural polysaccharides extracted from marine brown alge.It contain 2 uronic acids,β-D-mannuronic acids(M) & α-L-glucouronic acids (G),& it is composed to homopolymeric blocks MM Or GG,&blocks with an alternating sequence(M blocks).NaALg has been used as matrix for entrapment of drug & macromolecules.Some of the applications of NaALg relate to it’s particular properties.It can form hydrophilic gels by interaction in aqueous medium gel,beads are commonly obtained by dropping solution of NaALg into solution of calcium chloride.Many grades of NaALg are avilable & are selected upon the purpose,e.g. high L-glucouronic content gives high gel strength.Most of the alginicacid contain a homopolymeric blocks of D-mannouronic acid & L-glucouronic acid.Enzymatic degradation using a poly(L-glucouronate)lyase to leave the polymannouronic blocks intact,has shown that these blocks have a uniform chain length of 24 residues.
The alginate microspheres are prepared by suspending the protein in NaALg solution & spraying this solution 1.3 % W/V buffer & (HEPES BUFFER)calcium chloride to form cross-linked microcapsules.Poor formation of capsule occurs due to strong protein alginate interaction.As a result,diffusion technique is employed for the incorporation of drug & proteins.In this technique the plain alginate microsphere are produced using the previous technique.Protein is subsequently loded by allowing its step wise diffusion from solution of incresing concentration.In all,3 polycation coating are used,i.e.two prior loading one after loading.The first coating influences the size,integrity,& loading capacity of microcapsules.The first coat also influences duration of drug release,size & burst effect.The second coat to influences drug loading & release characteristics.The final coat however,has little effect on the drug release profile.

(12) Poly alkyl cynoacrylate (PAC) Microspheres:-
It is a potential colloidal drug carrier for parentral administration as well as through other alternative routes(opthalmic,oral).The microspheres of PAC are prepared by simple polymerization techniques.Several polymerization system can be used for the preparation of the PAC microspheres,which leads to the microspheres production with different particle size ranges.The general method of preparation of PAC microspheres involves addition of the monomer(1%v/v) to the rapidly stirred aqueous phase.The pH of the system is criticle in deciding the polymerization of alkyl cyanoacrylate monomers.The pH of system is normally adjusted to 2-4 for optimum polymerization while in case of pH less then 2,the rate of the polymerization tends to be slow.In body PAC microspheres degrade by reverse Knovenagel reaction resulting in the production of al 2-cynoacrylate & formaldehyde.The rate of degradation rise with the ester chain length & pH the media.The choice of monomer & polymerization condition also effect the degradation rate of the microspheres.PAC microspheres loaded with anticancerous agents are extensively studied for the purpose of tumours targeting.PAC microspheres natural affinity towards the tumours & they also possess inherant antitumours activity.These are found to have her tumours uptake.The studies indicate that anti-tumour effect of cytotoxic drug increased when they are administerd contained the PAV microspheres.Monoclonal antibody may be used to target PACmicrospheres.This monoclonal antibody may be atteched to either via spacer groups or simple absorption.This particles are specially taken by the tumour cells.PACmicrospheres are also used for targeting liver diseases.The tissue toxicity of PAC microspheres decreases with decreases in the rate of degradation & increases in the homologous series.PACwas found to be more toxic in the series because of rapid degradation of polymer.LD50 value for the isobutyl & butyl microspheres was found to be 196 mg & 230 mg/kg following the intravenous injection,which shows an increases in toxicity within the homologous series.The rate of administration also determines the toxicity of the polymer.

(13) Polyacrolein Microspheres:-
This microspheres are functional type of the microspheres.These microspheres do not require any activation step since the surfacial free aldehyde groups over the polyacrolein can react with amine group of the protein to form Schiff’s base.Polyacrolein microspheres remain active for more then a month when stored at 4°c.The hydrophilicity can be generated by co-polymerizing the acrolein monomer with hydroxy ethyl methylacrylate,styrene or methyl methacrylate.The polyacrolein microspheres are prepared by alkaline polymerization of acrolein monomer(FIG-10)or by co-polymerization of acrolein monomer with other monomers.

Acrolein microspheres can be prepared by simple radiation polymerization using COBALT-60.Acrolein molecules have two functionality one is carboxyl while other is vinyl.Studies have shown that acrolein polymerizes through its vinyl groups.The resultant polymer exists in equilibrium with the acetal isomers.Polyacroleinmicrospheres where successfully prepared by aqueous polymerization surfactant under alkaline condition.Agarose polyacrolein micro beads can be prepared by encapsulating polyacrolein microspheres in agarose gel matrix.The cross-linking is affected using divinyl sulphone.This sytem acts as an efficient immunoadsorbent.     

Fate of Microspheres in Body :-[3]
Microparticulate carrier system can be administered throgh different routes such as i.v,ocular,i.m,oral,intra arterial.etc.Each routes has it’s own biological significance,limitation & pharmaceuticle feasibility.The microparticles are intended to be administration through differents routes to achieve desired activity of either sustained action or targeting or both.Throgh different routes different mechanisms of uptake,transport & fate of translocated particles have been proposed.
Biodegradable microparticulate carriers are of intrest for oral delivery of drugs to improve bioavailability,to enhance drug absorption,to target particular organ 7 to reduce toxicity to improve gastric tolerence of gastric irritant to stomach & as a carrier for antigen.The polystyrene microspheres administered orally are reported to be taken up by Peyer’s Patch.They are subsequently translocated to discrete anatomical compartments such as mecentric lymph vessels,lymh nodes & to alesser extent in liver & spleen.The particulates matters gain entry into follicle associated epithelium through Peyer`s patches.
After the uptake of particulate carriers via different mechanism their fate become more important.Some uptake mechanism avoids the lysosomal system of the enterocytes.The particles following uptake by enterocytes are transported to the mecentric lymph,followed by systemic circulation & subsecuently phagocyosized by the Kupffer cells of liver.However,after uptake by enterocytes,some particulate carriers may be taken up into vacuoles & discharged back into gut lumen.

Microsperes can also be designed for the controlled release to the gastrointestinal tract.The release of drug contents depends on the size of microparticles & the drug contet within microspheres.The release of the drug could be regulated by selecting an appropriate hydrophilic/lipophilic balance of the matrix such as in case of matrix of polyglycerol,ester of fatty acids.Microparticles of mucoadhesives polymers get atteched to the mucous layer in GIT & hence, prolong the gastric residence time & functionally offer a sustained release.The microspheres of partical size less then 0.87 µm are taken to the general circulation.The fluid environment of the GIT can affect the number & rate of particles translocation.
Microspheres given by parentral routes(i.v)distribute themselves according to their size range.The microparticulate carriers are rapidly cleared from the circulation mainly by means of reticuloendothelial system(FIG-11).
After i.v administration the particulates carriers distributed themselves passively or ifsutably designed,then actively.This distribution is refferred to as passive mode of the site specificdelivery of the microparticulates.

Application of microspheres :-
(1)Insustained &  controlled release
Microspherescanbe designed to release their ingredient at specific rate. This is most  resent addition to oral prolonged release as well as SR Dosage  forms ofdrugs such as theophylline, indomethacin, aspirin, diclofenac sodium, riboflavin, antimicrobial agent(nitrofurantoin) & steroid like progesterone, testosterone etc.can be incorporated in microspheresto control their release.

(2) In enteric release dosage form.
Drugs which are irritant to thestomach & other side effects like aspirin, pancrelipase & erythromycin, salbutamol sulphate can be incorporated in microspheres for tjeir selective release in intestine.

(3) To protect reactive materials against environment.
It is useful for drugs vitamins.aspirin which aresensitiveto oxygen & water.

(4) To mask bitter of unpleasant taste of the drug
E.g. for drugs such as quinidine,nitrofurantion, paracitamol prednisolone, metronidazole,fish oils,sulpha drugs, clofibrate, alkaloids & salts.

(5) For drug targeting.
E.g. casein & gelatin microspheres containing adriamycin & iterferons respectively were magnetically delivered to tumour site. Albumin microspheres used for anti-inflammatory  agents  for directing against knee joints.

(6)   To alter the residence time & to improve the bio-availability.
E.g.Albumin & gelation microspheres containing pilocarpine nitrate (opthal drug delivery to eye increase residence time of drug in the eye & provide improved bioavailability. Also the delivery ofn nonabsorbed of p[oorly absorbed drugs by the mechanism of transcellular passage across the GIT alter the gastrointestinal transit time of a drug through their mucoadhasive properties & for improving flow properties of drugs.

(7)   As a topical drug delivery system.
E.g.Microspheres of benzoyl peroxide for their bactericiday activity against acne.

(8) As drug carriers.
Albumin as a carrier has been used to protect/ target enzymes within circulation.By using it different enzymesare protected against proteolytic digestion, immunologically  tolerated or remain in thecirculation for long times.

(9) As an antidote in the poisoning of heavy metals.
E.g Polymercaptal microspheres as an antidote against mercury poisoning.

(10) As antigen carrier.
E.g.PLA & PLGA microspheres of vayring composition have used to improve the ability of the antigens to provoke a mucosal immune response.

(11) For liver cell immobilization.
Microspheres has been investigated as artificial cells as a means to immobilize liver cell such as liver,kidney & red blood cell substitutes & can be targeted to the site.

(12) As an absorption promoting system.
E.g Degabadle starch microspheres (DSM) for increasing the drug or peptide absortion across the nasal epithelium.

(13) To separate incompatible substances .
E.g the stability of incompatible drug aspirin, Chlorpheniramine maleate mixture was increase by microspheres individulal componants 

(14) For isolation from tissues.
E.gKCL aspirin.

(15) For administration in solid &   dry handling.
Liquids such as eprazine can be converted to a pseudo-solid by microsperes as an aid to handaling & storage.

(16) To facilitate handaling of toxic materials.
Microspheres has been used to decrese potentialdangerous handaling toxic substances like pesticides,fertilizers & certain pharmaceuticals.
(17) To reduce gastric irritation. 
Hard gelatin capsule containig microspheres liberate in stomach & spred in the overall GIT,thus ensuring more reproducible drug absorption with less local irritation.

(18) Miscellaneous Application.
Use as carrier for vaccine,as a diagnostic tool & for drug follicular targeting.

EVALUATION OF MICROSPHERES :-
(1) Size & shape of microspheres
The size of microspheres was determined using microscope(Olympus NWF 10x,Educational scientific Stores,india)fitted with an occular mirometer & stage micrometer.Scaning elrctron microscopy(SEM)(Leo 430 Leo electrone microscopy Ltd,Cambridge,England) was performed to characterize the surface of the formed microspheres.Microspheres weremounted directly onto sample stub & coated with gold film(~200nm)under reduced pressure(0.133pa).

(2) Flow properties 
The Flow propertis of microspheres were characterized in terms of angle f repose,carr index & hausner ratio(θ),the microsphere were poured through the walls of a funnel,which was fixed at a position suh that its lower tips was at a height of exectly 2.0 cm above hard surface.The microspheres were poured till the time when upper tip of pile surface touched the lower tip of funnel.The tan^(-1)⁡0f the height of the pile/radius of its base gave the angle of repose.
Microspheres were poured gently through a glass funnel into a graduated cylinder cut exectly to 10ml mark.Excess microspheres were removed using a spatula & the weight of the cylinder with pellets required for filling the cylinder volume was calculated.The cylinder was tapped from a height of 2.0 cm until the time when there was no more decrease in the volume.Bulk density(ρb) & tapped density(ρt) were calculated.Hausner ratio (Hr) & carrs index(Ic)were calculated according to the two equation given below:
Hr=ρt/ρb
Ic=(ρt℅ρb)/ρt

(3) In vitro buoyancy
Microspheres (300mg) were spread over the surface of USPXXIV dissolution apparatus type II filled with 900ml of 0.1 N HCL containing 0.02% tween 80.The medium was agitated with a paddle rotating at 100 rpm for 12hr.The floating microspheres & setteld portions were removed separately.The microspheres were dried & weighed.Buoyancy % was calculated as the ratio of the mass of the microspheres that remained floating & the total mass of the microspheres.

(4) In vivo floating behaviour
Healthy beagle dogs weighing approx.15 kg was used to asses in vivo floating behaviour.Ethical clearance for handaling o experimental animals was obtained from the institutional ethical committee(IAEC)constitutd for the purpose.The animal were fasted for 12hr & first X-ray photographed to ensure absence of radio opaque materials in stomach.Dogs were made to swallow barrium sulphate loaded cellulose acetatemicrospheres with 100ml of water.During the experiment dogs were not allowed to eat but water was provided ad libitum.At predetermined time intervals the radiograph of the abdomen was taken using an x-ray machine.

(5) In corporation efficiency (IE)
To determine incorporation efficiency floating microspheres were dissolving in a minimal amount of dichloromethane & the drug was extracted into a suitable aqueous media(0.1N HCL)by evaporating dichloromethane.The solution was filtered through 0.45 m membrane,diluted suitably & analyzed for drug content sprectrophotometrically at 278 nm using 0.1 N HCL as blank.

(6) In vitro drug release studies
The drug was studied using a USP24 dissolution apparatus type I(veego Scientific,Mumbai) at 100rpm in 0.1N HCL as dissolution medium(900ml) maintained at 37±1°c.A sample(ml)of the solution was withdrawn from the dissolution apparatus hourly & the samples were replaced with fresh dissolution medium.The sample were filterd through a 0.45 µ membrane filter & diluted to a suitable concentration with 0.1 N HCL.Absorbance of this solutions was measured at 278 nm using a Thermospectronic -1 UV/Visdouble beam spectrophotometer.Cumulative % drug release was calculated using an equation obtained from a standard curve.

RESULT AND DISCUSSION
The floating microspheres of verapamil HCL were prepared by solvent diffusion-evaporation method.The results of physico chemical characterization are shown in table 1.
Code Mean particle size(µm) Angle of repose(θ) Hausner ratio(Hr) Carr index(Ic) Buoyancy
(%) Incorporation
efficiency(%)
F1 350.75±5.30 24.42°±0.03 1.152±0.045 0.141±0.017 69.92±1.27 84.62±4.05
F2 307.85±9.63 29.46°±o.28 1.180±0.051 0.153±0.010 46.19±1.62 64.31±3.61
F3 251.80±7.27 28.29°±0.11 1.165±0.022 0.149±0.015 60.04±1.41 72.29±1.07

The prepared floating microspheres were found to be discrete,Spherical & free flowing.The mean arithmatic diameter varied between 251.80 to 350.75 um;eudragit S100 microspheres representing the least size & cellulose acetate microspheres the larget size.Surface morphology characteristics were studied using SEM(Figure 1).SEM  indicated that the prepared microspheres are spherical with smooth surface; distinct pores are evident on the surface of microspheres,which will be responsible for the release. The photomicrographs also showed presence of loose crystals of drug on the surface of few microspheres.
Angle of repose,hausner ratio,& carr index were determine to predict flowability.A higher Hausner ratio indicates greater cohesion between particles while a high carr index is indicative of the tendency to form bridges. The prepared microspheres exhibited good floow proparties & can be arranged as:F1> F3> F2. The percentage yield of floating microspheres was found to be 68.90,63.60 & 70.51% for F1,f2&f3respectively.Percentage incorporation efficiency was in the range of 64.31%to 84.62%,cellulose acetate microspheres entrapped maximum amount of the drug.
To assess the floating properties,the microspheres were placed in 0.1N HCL containing surfactanttween 80(0.02%v/v),to stimulate gastric condition.The use of tween 80 was to account for the wetting effect of the natural surface-active agent in GIT.The microsperes floated for prolonged time over the surface of dissolution medium without any apparent gelation.Buoyancy % of the microspheres was in the range of 46.19 to 69.59% at the end of 12hr.The nature of the polymer influenced the floating behaviour of the microspheres.The in vivo floating behaviour of cellulose acetate microspheres loaded with barium sulphate was investigated by radiographic image(X-ray photograph) of dog stomach at periodic time intervals.to make the microspheres X-ray opaque barium sulphate was incorporated into the microspheres.The amount of X-ray opaque materials in these microspheres was sufficient to ensure visibility by X-ray but at the same time the amount of barium sulphate(10mg per g of microspheres)was low enough to enable the microsphers to float.The duration of floating in vitro was more then 8hr.The microspheres did not adhere to the gastric mucosa & floated on the gastric fluid of about 3.2±0.05hr(fig-2)
The drug release from floating microspheres wasfound to be 95.52,83.51 & 72.76% at the end of 12hr for F1,F2,& F3 respectively(fig-3).The data obtained from in vitro dissolution studies were fitted to zero order,first order & Korsemeyer-Peppas equation(table-2).

Code Zero-order
K0(mg/hr) R*R First order
K1(1/hr)  R*R Korsemeyer-pepps
n         R*R
F1 8.003     0.989 -0.224  0.860 0.876  0.994
F2 7.034      0.981 -0.128  0.856 0.830  0.987
F3 6.269      0.985 -0.119  0.875 0.714  0.990

The zero order plots were found to be fairly linear as indicated by their high regression values of 0.989,0.981 & 0.985 for F1,F2 & F3 respectively.To conform the exactmechanisum of drug releas,the data were fitted according to Korsemeyer-pepps equation.It is used as simple emperical equation to describe general solute releasebehaviour from controlled release matrix:
Mt/mT=K tn
Were,mt/mT=fraction of drug release
K=kinetic constant
T=time
N=diffusional exponent for drug release
Pepps stated that above equation could adequetly describe the release of solutes from slabs,spheres,cylinders & discs,regardless of release character.The valueb of n gies an indication of releasemechanism;when n=1,the release rateis independent of time(zero orer)(case-2 transport),n=0.5 for fickian diffusion & 0.5<n<1,diffusion & non-Fickian transport are implicated.Lastly,when n>1super casetransport is apparent.’n’is the slope value of log mt/mT vs log time curve.
Regrassion analysis was performed & regrassion values ‘R*R’were 0.990 to 0.994for different formulation.Slope values suggest that the release ofverapami HCL from floating microspheres was followed non-fickian diffusion mechanism.There is significant difference in the release rate from formulations prepared from different polymers(p<0.01).The type of polymer significantly influenced the drug release rate,in the order:Cellulose acetate>AcrycoatS100>Eudragit S100.

CONCLUSION
Floating microspheres of verapamil HCL were prepared by a solvent evaporation method.The nature of polymer influenced the physical characteristics as well as floating behaviour of the microspheres In vitro buoyancy & in vivo studies conformed the exellent floating properties of cellulose acetate microspheres.The drug release fromsufficiently sustained & non-fickian transport of drug from floaing microspheres aws conformed.Hence the floating microspheres of verapamil HCL prepared with cellulose acetate,may providee a convenient dosage form for achieving best performance regarding flow,release & flow properties.Further,their potential to improve verapamil HCL bioavailability in humans need to be investigated in further studies.

SUMMARY
In the study of microspheres have the potential application in controlled drug delivery system.The polymer used in these preparation,biodegradable & non-bio degradable.Development have been great achieve & by help of these possible to synthesize polymer with wide range of biodegradability.The no.of method have been desired to prepare desired size,shape & surface properties of microspheres.The targeting to the pathogensmay prove to be potentially useful in the tretment of macrophage associated diseases.Infuture responses,by combining various other strategies,microspheres will find the central place in novel drug delivery,particularly in diseased cell sorting,diagnostics,gene & genatic materials,safe targeting & effective in-vivo delivery.


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Advances in controlled & novel drug delivery system.
1st edition – 2001
Encyclopaedia of pharmaceutical Technology
James Swarbrick & James C.Boylan 2nd edition vol – 2
Thesis of L.M. College of Pharmacy & A.P.M.C. College of Pharmacy
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