A review on target drug delivery: magnetic microspheres

Amit Chandna, Deepa Batra, Satinder Kakar*, Ramandeep Singh

1Department of Pharmacy, Doon Valley Institute of Pharmacy & Medicine, Karnal (Haryana), India

2Department of Pharmacy, Himachal Institute of Pharmacy, Paonta Sahib (H.P), India

A review on target drug delivery: magnetic microspheres

Amit Chandna1, Deepa Batra1, Satinder Kakar1*, Ramandeep Singh2

1Department of Pharmacy, Doon Valley Institute of Pharmacy & Medicine, Karnal (Haryana), India

2Department of Pharmacy, Himachal Institute of Pharmacy, Paonta Sahib (H.P), India

Magnetic

Micro carriers

Target

Ferrofluids

Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the body during the period of treatment, and target the active entity to the site of action. A number of novel drug delivery systems have emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery, magnetic micro carriers being one of them.

Magnetic microsphere is newer approach in pharmaceutical field. Magnetic microspheres as an alternative to traditional radiation methods which use highly penetrating radiation that is absorbed throughout the body. Its use is limited by toxicity and side effects. The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects. This kind of delivery system is very much important which localises the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. magnetic microspheres can be prepared from a variety of carrier material. One of the most utilized is serum albumin from human or other appropriate species. Drug release from albumin microspheres can be sustained or controlled by various stabilization procedures generally involving heat or chemical cross-linking of the protein carrier matrix.

1. Introduction

Magnetic microspheres are supramolecular particles that are small enough to circulate through capillaries without producing embolic occlusion (＜4 μm) but are sufficiently susceptible (ferromagnetic) to be captured in micro vessels and dragged in to the adjacent tissues by magnetic fields of 0.5-0.8 tesla. Magnetic drug delivery by particulate carriers is a very efficient method of delivering a drug to a localized disease site. In magnetic targeting, a drug or therapeutic radioisotope is bound to a magnetic compound, injected into a patient’s blood stream, and then stopped with a powerful magnetic field in the target area. Magnetic carriers receive their magnetic responsiveness to a magnetic field from incorporated materials such as magnetite, iron, nickel, cobalt, neodymium-iron-boron or samariumcobalt[1]. Magnetic microsphere were developed to minimize renal clearance and to increase target site specificity

2. History of magnetic targeting

3. What is ferrofluid?

Ferrofluid (FF), is a colloidal suspension of single-domain magnetic particles, with dimensions of about 10 nm, dispersed in a liquid carrier[8]

4. Factors related to ferrofluid

Factors: 1. Size of the particles in ferrofluid. 2. Surface characteristics of particles. 3. Concentration of the ferrofluid. 4. Volume of the ferrofluid. 5. Reversibility and strength of drug/ ferrofluid binding (desorption characteristics). 6. Access to the organism (infusion route). 7. Duration or rate of injection/ infusion. 8. Geometry, strength and duration of the magnetic field application[10]. 9. Ferro fluids are optically isotropic but, in the presence of an external magnetic field, exhibit induced birefringence[11].

Wetting of particular substrates can also induce birefringence in thin FF layers. In order to avoid agglomeration magneticparticles need coating. So they are classified in two ways: Classification of ferrofluids: 1. Surfacted ferrofluids: if the coating is a surfactant molecule. 2. Ionic ferrofluids: if it is an electric shell.

Table 1.History of magnetic carriers.

Table 2.Characteristics of ferrofluids[9].

Table 3.Depiction of differences in surfacted ferrofluids and ionic ferrofluids[12,13].

5. Classification of drug targeting

Classification I: First-order targeting, Second-order targeting, Third-order targeting. Classification II: Organ targeting, Cellular targeting, Sub cellular targeting. Classification III: Passive targeting, Active targeting, Physiochemical targeting. Classification IV: Site-directed targeting, Site-avoidance targeting. Classification V. Biochemical targeting, Biomechanical targeting, Biophysical targeting, Bioadhesive targeting. Classification VI: Carrier-dependent, Carrier-independent[26]

Considerable attention has been paid to the use of polymer microspheres for the sustained release of various drugs and the targeting of therapeutic agents to their site of action. Biodegradable poly-D, L-lactic acid (PDLLA) microspheres can be efficiently taken up by macrophages and M cells[27].

Figure 1. Principle of magnetic drug targeting.

Table 4.Drugs and their polymers used in drug delivery.

Sandia model and metric are used to predict the detection platform’s sensitivity and speed for several CONcepts of OPeration (CONOP): (1) agent detection (chemical or biological) in clinical samples, (2) botulinum toxin detection in milk, and (3) pathogen detection in airplane cabin air. Application of the model in these CONOPs indicates that the proposed platform can be optimized to reduce TTI, thereby minimizing the impact of Chem-bio events.

Figure 2. Magnetic targeting in drug and gene delivery.

Figure 3. Chem-bio-threat agent detection using "sandwich" immunoassays.

Each bead contains a magnetic core to permit trapping for sample cleanup and concentration. Bead surfaces are modified with Analyte Specific Reagents (ASRs). ASRs may be antibodies or oligonucleotides for selective analyte capture, while an internal quantum dot (QD) or chromophore dye facilitates bar coding.

6.2. Solvents used for solvent evaporation method

Solvent used should meet the following criteria: (1) Being able to dissolve the chosen polymer; (2) Being poorly soluble in the continuous phase; (3) Having a high volatility and a low boiling point; (4) Having low toxicity[28]. Polymer encapsulated microspheres are synthesized on the basis of a continuous solvent evaporation technique. A solution of polymer, drug and magnetite should be added to the volatile organic solvent, which forms Auxiliary solution on stirring. The resulting solution should be homogenized at stirring temperature (22-30 ℃) (Figure 5 & 6). The magnetic microspheres will be formed in the suspension and should be separated by centrifugation. The product should be Freeze dried & stored at 4 ℃[29,30]

Figure 4. Microspheres for bio detection.

Figure 5. Continuous solvent evaporation method.

Figure 6. Schematic diagram of preparation of magnetic microspheres by solvent evaporation method.

Table 5Solvents used for continuous solvent evaporation method.

Figure 7. Schematic representation of phase separation emulsion polymerization.

6.3. Phase separation emulsion polymerization

Polymer encapsulated microspheres are synthesized based on a modified phase separation emulsion polymerization technique. Briefly aqueous solution of polymer, drug and magnetite should be added to the vegetable oil and emulsified using a magnetic stirrer at 1 500 rpm for 2 min. The resultant should be stabilized by heating at the temperature (100-150℃). Then cross linking agent should be injected drop wise into the resultant emulsion under continuous stirring. (Figure 7). The magnetic microspheres will be formed in the oil suspension and then should be separated from oil by washing procedures. The product should be Freeze dried & stored at 4℃[31].

Figure 8. Factors affecting the properties of microspheres.

7. Evaluation parameters for magnetic microspheres

7.1. Percentage yield of microspheres

Thoroughly dried microspheres are collected and weighed accurately. The percentage yield can be calculated using formula given below: Percentage Yield = mass of microsphere obtained/ total weight of drug & polymer×100[32]

7.2. Particle size analysis and particle size distribution

a) Sieving; b) Microscopy: This method is used to determine particle size by using optical microscope (Meizer OPTIK) The measurement is done under 450× (10× eye piece and 45× objective) and100 particles are calculated; c) Coulter counter analysis; d) Laser Diffraction analysis. Size distribution plays an important role in determining the release characteristics of the microspheres[33].

7.3. Density

a) Bulk density: Bulk density (ρb) (g/cm3) = M/Vb; Where, M = mass of powder taken, Vb = bulk volume; b) Tapped density: Tapped density (ρt) (g/ cm3) = M/Vt; Where, M = weight of sample powder, Vt = tapped volume

7.4. Flow properties

Table 6Depiction of flow properties.

Angle of repose is determined by using funnel method. The accurately weighed microspheres are taken in a funnel and then height of funnel is adjusted in such as way that the tip of funnel just touches the apex of heap of blends. The blends are allowed to flow through funnel freely on to surface. The diameter of powder cone is measured and angle of repose is calculated by using following equation: tanθ = h/r; Where θ - Angle of repose, h -height of pile, r - Radius of base.

7.5. Shape and surface characterization

The microspheres are mounted directly on the SEM sample stub, using double-sided sticking tape and coated with gold film (thickness 200 nm) under reduced pressure (0.001 torr) and photographed.

7.6. Determination of drug content

Accurately weighed 100 mg microspheres are crushed in glass mortar and pestle, powder microspheres are suspended in 100 mL of suitable solvent. After 12 h the solution was filtered and the filtrate was analyzed for the drug content using UV-Visible spectrophotometer.

7.7. Encapsulation efficiency

Encapsulation efficiency was calculated using the following formula: E =Qp / Qt × 100; Where, E = percentageof encapsulation of microspheres; Qp = quantity of drug encapsulated in microspheres; Qt = quantity of the drug added for encapsulation[34].]

Table 7Marketed products of magnetic microspheres.

7.8. Interaction study by TLC/IR

7.8.1. IR spectroscopic studies

The IR spectra of the free drug and the microspheres were recorded. The identical peaks corresponding to the functional groups and albumin (BSA, Egg albumin, Human serum albumin) features confirm that neither the polymer nor the method of preparation has affected the drug stability.

7.8.2. Thin layer chromatographic studies

The drug stability in the prepared microspheres can also be tested by the TLC method. The Rfvalues of the prepared microspheres can be compared with the Rfvalue of the pure drug. The values indicate the drug stability[35]

7.9. Surface topography by scanning electron microscopy (SEM)

SEM of the microspheres shows the surface morphology of the microspheres like their shape and size

7.10. Zeta potential

The polyelectrolyte shell is prepared by incorporating chitosan of different molecular weight into the W2 phase and the resulting particles are determined by zeta potential measurement

7.11. Stability studies

By placing the microspheres in screw capped glass container and stored them at following conditions: 1. Ambient humid condition; 2. Room temperature (27±2)℃; 3. Oven temperature (40 ±2)℃; 4. Refrigerator (50-80℃). It is carried out for 60 d and the drug content of the microsphere is analyzed.

8. Conclusion

Over the years, magnetic microspheres have been investigated for targeted drug delivery especially magnetic targeted chemotherapy due to their better tumor targeting. Targeted Drug delivery is an effective method to assist the drug molecule to reach preferably to the desired site. The main advantage of this technique is the reduction in the dose & side effects of the drug. It is a challenging area for future research in the drug targeting so more researches, long term toxicity study, and characterization will ensure the improvement of magnetic drug delivery system. The future holds lot of promises in magnetic microspheres and by further study this will be developed as novel and efficient approach for targeted drug delivery system

Conflict of interest

We declare that we have no conflict of interest.

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ment heading

10.1016/S2221-6189(13)60125-0

14 April 2013

*Corresponding author: Satinder Kakar, Doon Valley Institute of Pharmacy & Medicine, Karnal (Haryana), India.

E-mail: satinder.kakkar5@gmail.com

ARTICLE INFO

Article history:

Received in revised form 29 April 2013

Accepted 30 April 2013

Available online 20 September 2013