INTRODUCTION:

Site-specific drug delivery system signifies importance in drug delivery systems. Targeting of dug under controlled, burst or modulated release using biophysical approach in new way to achieve site specific targeting ^[1]. This dosage form overcomes a problem which exits such as cost-efficient treatment, patient compliance, optimum drug delivery and bioavailability. There are various routes of administration of novel drug delivery system like oral, parenteral, transdermal; inhalation etc^[2].Advantage of being efficient in allowing high local concentration of therapeutic agent. Magnetic drug delivery by particulate carriers is a very efficient method of delivering a drug to a controlled disease site. Targeting the drug by using magnetic carrier is very efficient in delivering the drug by incorporating magnetite inside the polymer by using an external magnet application to target the microsphere to the specific site for drug delivery.

Magnetic particles are well tolerated in our body they are harmless and adaptable in the body. Magnetic microsphere were developed to minimize renal clearance and to increase target site specificity. Microspheres constitute an important part of this particulate drug delivery system by virtue of their small size and efficient carrier characteristics. However, the success of this novel drug delivery system is limited due to their short residence time at the site of absorption. It would therefore be advantageous to have means for providing an intimate contact of the drug delivery system with absorbing gastric mucosal membranes. Microspheres are characteristically free powders consisting of proteins or synthetic polymers that are biodegradable in nature and ideally having a particle size less than 200µm ^[3,4]. It have been widely accepted for drug delivery, fabrication of biosensors as well as delivery of both hydrophilic and lipophillic drugs. Many conventional drug delivery systems for treating the colonic disorders fail, as the drugs do not reach the site of action in appropriate concentration. Drugs with less therapeutic index causes serious problem when reached the site in an excess amount. Magnetic microsphere can help reach the drug with magnetic carrier to the site of action to avoid systemic toxicity and to treat colonic disorders such as IBD, colon cancer etc ^[4]. Magnetic field helps force the magnetic carrier into the targeted area. The monitoring of the carrier to the localization is an important part of magnetic targeting that avoids normal tissue injury. Due to this mechanism large amounts of drugs are targeted magnetically to restricted disease site, reaching successfully up to numerous increased drug levels.(Figure 1) This work gives an overview of the size, properties, mechanism, benefits, drawbacks, preparation and applications of magnetic microspheres.

Figure 1.Principal of magnetic drug targeting to RES (Reticulo-endothelial system)

PREPARATION OF MAGNETITE

PREPARATION OF MAGNETITE FROM A-FEOOH (GOETHITE) OR FEO.

The nitrogen gas was flushed through a500 ml, two-necked round-bottom flask fitted with a condenser. The flask was charged with 8.9g (0.1mol) ofgoethite, 9.94g (0.05mol) ofFeCl2.4H2O along with 250 ml deionized water and then 50ml of 2M NaOH was added while stirring vigorously. The reaction mixture was heated to reflux for 12h.During the transformation of the pH, its pH fellfrom14 (orange) in to 8–9 (black precipitates) particles were washed with distilled water, filtered and dried under vacuum at room temperature ^[5].

WHAT IS FERROFLUID?

Ferro fluid (FF) is a colloidal suspension of single-domain magnetic particles, with dimensions of about 10 nm, dispersed in a liquid carrier ^[6].

PREPARATION OF MAGNETIC FLUID

Magnetic fluid was synthesized as follows: a 35% (w/v) ferrous sulfate solution, 54% (w/v) ferric chloride solution and 36% (w/v) sodium hydroxide solution were prepared using distilled water. Then the ferric salt and ferrous salt were mixed, stirred and heated. When the temperature reached 55˚C, the alkaline solution was added. The mixture was stirred for 30 min, and then 5 g of polyethylene glycol-10000 (PEG-10000) was added. The temperature was raised to 80˚C and maintained for 30 min. The mixture was then neutralized while cooling, and the magnetic fluid was prepared ^[7,8].

Different sort of drugs encapsulated with magnetite or magnetic fluid (ferro fluid) are produced using different preparation method having magnetic property, which are targeted to specific diseased sites using external magnetic field are mentioned (Figure2).

Figure 2. Drugs encapsulated by Magnetite and Magnetic Field

METHODS OF PREPARATION

Preparation of microspheres should satisfy certain criteria:

1. Ability to incorporate reasonably high concentration of drug.

2. Stability of preparations after synthesis with clinically acceptable shelf life.

3. Controlled particle size and dispersability in aqueous vehicles for injection.

4. Release of active reagent with good control over a wide time scale.

5. Biocompatibility with a controllable biodegradability and susceptibility to chemical modification.

Different materials are used for magnetic microsphere preparation for better delivery of drugs some carriers used widely in the preparation of magnetic microsphere are mentioned(Figure 3),these polymers are used for enhanced drug delivery system using magnetic energy for site specific delivery.

Figure 3. Materials Used In Magnetic Microsphere

MECHANISM OF ACTION

Site-specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects. Magnetic drug delivery technique is based on the fact that the drug can be either encapsulated into a magnetic microsphere (or microparticle) or conjugated on the surface of the micro/nanosphere^[9]. When the magnetic carrier is intravenously or orally administered, the accumulations take place within area to which the magnetic field is applied & often improved by magnetic agglomeration (Figure 4). The accumulations of the carrier at the target site allow them to deliver the drug locally. Efficiency of magnetic carrier on physiological carrier depends on parameters like particle size, surface characteristic, field strength, & blood flow rate etc.

Figure 4.Magnetic Drug Targeting

Advantages of Magnetic Microsphere:

1. Increased duration of action.

2. First pass effect can be avoided.

3. Good patient compliance.

4. Improved protein and peptide drug delivery.

5. Therapeutic responses in target organs at only one tenth of the free drug dose.

6. Controlled drug release within target tissues for intervals of 30 min to 30 hours, as desired.

7. Simple Method of preparation.

7. Avoidance of acute drug toxicity.

Disadvantages of Magnetic Microsphere

1. It is an expensive, technical approach and requires specialized manufacture and quality control system.

2. It needs specialized magnet for targeting, for monitoring, and trained personnel to perform procedures.

3. A large fraction (40-60%) of the magnetite, which is entrapped in carriers, is deposited permanently in tissue

PROPERTIES OF MAGNETIC MICROSPHERES

· PARTICLE SIZE ANALYSIS: Microsphere (50 mg) was suspended in distilled water (5mL) containing 2%w/v of tween 80, To prevent microsphere aggregation, the above suspension is sonicated in water bath and the particle size was expressed as volume mean diameter in micrometer.

· FLOW PROPERTIES:

· BULK DENSITY

BD = M / Vo

Where, BD = Bulk density

M = Mass of sample in g

Vo = Bulk volume of powder in cc

· TAPPED DENSITY

TD = M / Va

Where, TD = Tapped density

M = Mass of powder in g

Va = Tapped density of powder in cc

· COMPRESSIBILITY INDEX OR CARR’S INDEX

% Compressibility = (TD-BD) / TDx 100

Where, TD = Tapped density

BD = Bulk density

· HAUSNER’S RATIO

Hausner’s ratio = TD / BD

Where, TD = Tapped density

BD = Bulk density

· ANGLE OF REPOSE

θ = tan-1 h/r

Where, θ = Angle of repose

h = height of cone

r = radius of cone base

· SWELLING INDEX: This technique was used for characterization of sodium alginate microspheres were performed with swelling index technique different solution(100ml) were taken such as (distilled water, buffer solution of ph (1.2, 4.5, 7.4) were taken and Alginate microspheres (100mg) were placed in a wire basket and kept on the above solution and swelling was allowed at 37˚c and changes in weight variation between initial weight of microspheres and weight due to swelling was measured by taking weight periodically and soaking with filter paper.^[10,11]

BENEFITS OF MAGNETIC MICROSPHERES

· Magnetic microspheres are site specific and by localization of these microspheres in the target area, the problem of their rapid clearance by RES is also prevailing.

· Linear blood velocity in capillaries is 300 times less as compared to arteries, so much smaller magnetic field is sufficient to retain them in the capillary network of the target area^{[12] .}

· Avoidance of acute toxicity directed against endothelium and normal parenchyma cell, controlled release within target tissue for intervals of 30 minutes to 30 hrs.

· As desired, adaptable to any part of body. In case of tumor targeting, microsphere can internalize by tumors cells due to its much increased phagocytic activity as compared to normal cells.

· Problem of drug resistance due to inability of drugs to be transported across the cell membrane can be surmounted.

Comparative study of magnetic and non-magnetic carriers has been mentioned (Figure 5). Properties of magnetic and Non-magnetic microspheres are differentiated as following.

Figure 5. Comparison of Magnetic and Non-Magnetic Microspheres

EVALUATION OF MAGNETIC MICROSPHERES

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 ^[13,14].

THIN LAYER CHROMATOGRAPHIC STUDIES

The drug stability in the prepared microspheres can also be tested by the TLC method. The Rf values of the prepared microspheres can be compared with the Rf value of the pure drug. The values indicate the drug stability^[15,16].

SURFACE TOPOGRAPHY BY SCANNING ELECTRON MICROSCOPY (SEM)

SEM of the microspheres shows the surface morphology of the microspheres like their shape and size[^17].

PARTICLE SIZE DISTRIBUTION OF MAGNETIC MICROSPHERES

The size of the prepared microspheres can be measured by the optical microscopy method using a calibrated stage micrometer for randomly selected samples of all the formulations^[18].

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, r-radius^[19].

DRUG ENTRAPMENT CAPACITY

Efficiency of drug entrapment for each batch can be calculated in terms of percentage drug entrapment (PDE) as per the following formula: Theoretical drug content can be determined by calculation assuming that the entire drug present in the polymer solution used gets entrapped in microspheres and no loss occurs at any stage of preparation of microspheres^[20].

In vitro RELEASE STUDIES

In-vitro release studies can be performed according to USP XXII type I dissolution apparatus at suitable pH conditions. The temperature should be maintained at 37±0.5°C and the rotation speed of 100 rpm. Then 5 ml of sample should be withdrawn at various time intervals and replenished with an equal volume of fresh dissolution media. The drug content in the sample can be analyzed spectrophotometrically at specific wavelength (nm) ^[21].

PERCENTAGE MAGNETITE CONTENT

Higher strength of HCl (1N) was used along with the definite stirring and ultra-sonication conditions. The stirring at 50 rpm and 40ºC during the dissolution ensured complete solubilization of magnetite. One hundred mg of magnetite-containing microspheres was added to a 100 mL volumetric flask containing 100 mL of 1N HCL and incubated for two days at 50 rpm, 40°C in a water bath shaker. The contents of the flasks were sonicated (Hielscher Ultrasound Technology, amplitude 80 for 2 min) thrice with a 5 min interval, and the incubation was continued for another eight days. Then the content was cooled, filtered and made up to 100 ml with distilled water. 10 ml of the resulting solution was diluted to 100 ml with distilled water; 5 ml of the diluted solution was transferred into a 25 mL volumetric flask containing 750 μL of 10% w/v sulfosalicylic acid (SAS) and stirred for 2 min. Then, 750 μL of 25% w/v ammonia solution was added before the flask was topped up to volume with distilled water. The absorbance of total iron complex was measured using a spectrophotometer at given nm against the reagent blank ^[22].

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)⁰C; 3. Oven temperature (40±2)⁰C; 4. Refrigerator (50-80) ⁰C. It is carried out for 60 d and the drug content of the microsphere is analyzed ^[23].

APPLICATIONS OF MAGNETIC MICROSPHERES:

1. Magnetic microsphere carriers have received considerable attention, because of their wide applications in the fields of biomedicine and bioengineering, biological and biomedical developments and trends such as enzyme immobilization, cell isolation, protein purification, and target drugs^[24].

2. Magnetic vehicles are very attractive for delivery of therapeutic agents as they can be targeted to specific locations in the body through the application of a magnetic field gradient. The magnetic localization of a therapeutic agent results in the concentration of the therapy at the target site consequently reducing or eliminating the systemic drug side effects^[25,26].

3. Drug discovery, molecular targeting, DNA analysis, proteomics, and understanding the pathways of cell cycle regulation.

4. Also used as a chemotherapeutic agent.

5. These are used in the fields of biomedicine and bioengineering.

6. These can be targeted to specific locations in the body with magnetic field gradient.

7. They can be used for molecular targeting, DNA analysis, proteomics.

8. It is used in MRI, cell isolation, radiotherapy and protein purification.

Used in Bacteria Detection and magnetic bioseparation.^[27]

Various marketed products of magnetic microsphere with their including names have been mention below (Table 1).

Table 1. Marketed Products on Magnetic Microsphere with Their Including Names

SL NO	TRADE NAME	INCL NAME
1	EA-209	Ethylene/acrylic acid copolymer
2	Flo-beads SE-3207 B(Soft beads B)	Ethylene/Methacrylate copolymer
3	Flo- beads SE-3107A(soft beads A)	Ethylene/Methacrylate copolymer
4	BPD-800	HDl/trimethylol hexyllactyl cross polymer (AND silica)
5	SUNPMMA-H	Methyl methacrylate crosspolymer
6	MSP-822	Polymethyl methacrylate

Patent works done on various magnetic microspheres are mentioned below (Figure 6)

Figure 6.Patent Work Done On Magnetic Microsphere

CONCLUSION:

Targeted Drug delivery is an effective method to assist the drug molecule to reach preferably to the desired site. Microspheres containing anti neoplastic drugs, steroid hormones, vaccines, proteins and peptide antiviral, antifungal and antibiotic drugs, anti-diabetic drugs and anti inflammatory drugs are investigated extensively for controlled release by various routes and for targeting. Magnetically modulated drug release from implants, successfully compensate any decay in drug release against time. Moreover, it minimizes the cost, size and complexity of implanted devices. Magnetic targeting also offers advantage of magnetic capture and retention to endothelium of microvasculature.

FUTURE PERESPECTIVES:

Magnetic microspheres look bright particularly in the area of medicinal field because of its wide spectrum of application in site-specific drug delivery. Microspheres are used to advanced way in delivery of vaccines and proteins. The magnetic targeted chemotherapy has better tumor targeting, therapeutic efficacy & lower toxicity. 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.

REFERENCES:

1. Vyas S.P, Kakkar R.K. Targeted and controlled drug delivery novel carrier system.CBS Publishers and distributors 2002; 1: 458-01.

2. Hassan Rasool. Overview on Drug Delivery System. Pharm Anal Acta 2012; 3: 1.

3. Jain N.K. Controlled and Novel drug delivery. In: Advanced in pulmonary drug delivery, 4th Edition. CBS Publisher and Distributor, New Delhi. 2008; 236-237.

4. Kreuter J et al. Investigations on the toxicity of nanoparticles. J Pharm Sci 1983; 72:1146.

5. Deepa Batra et al Magnetic microspheres as a targeted drug delivery system: An overview. Journal of Drug Delivery Research. 2012;1(3)189-195.

6. Gowda DV et al. Development and evaluation of phosphated cross-linked guar gum microspheres for improved delivery of anticancer drug to colon. Polym-Plast Technol Eng 2012; 51: 1395–1402.

7. Amit Chandna et al. A review on target drug delivery: magnetic microspheres. Journal of Acute Disease 2013;189-195.

8. Mohamed K. Nasra et al. Preparation of biocompatible magnetic microspheres with chitosan. Journal of Biomaterials and Nanobiotechnology, 2011, 2, 194-200.

9. K Smita Magnetic drug delivery: A versatile system. Deccan J. Pharmaceutics and Cosmetology 2010;1(2).

10. Shah S et al. Formulation and evaluation of microsphere based dispersible tablets of oroitopride HCl. J Pharma Sci 2012; 20: 24.

11. Jagadeesh HG et al. Tamoxifen loaded poly (εCaprolactone) based injectable microsphere for breast cancer. Int. J. Pharm Pharm Sci 2010; 2: 189-195.

12. Fenandez A et al. Tamoxifen-loaded microspheres based on mixtures of poly (D,L-lactide-co-glycolide) and poly(D,L-lactide) polymers: effect of polymeric composition on drug release and in vitro antitumoral activity. J Appl Polym Sci 2012; 124: 2987–2998.

13. Dhananjay S Ghodke et al. Optimization of spray drying parameters for preparation of chitosan microspheres of oxidizing pharmaceutical active. J Pharm Res 2010; 3(8): 1752-1755.

14. Seema Badhana et al. Colon specific drug delivery of mesalamine using eudragit S100-coated chitosan microspheres for the treatment of ulcerative colitis. Int Curr Pharm J 2013; 2(3): 42-48.

15. Vyas MB et al. Design and characterization of cisplatin magnetic microspheres. Int J Biopharm 2013; 4(2): 66-72.

16. B K Jain. Preparation and in vitro characterization of mucoadhesive norethisterone - egg albumin microspheres for nasal administration. Asian J Biomed Pharm Sci 2012; 2(15): 49-57.

17. Sussan Ghassabian et al. Dexamethasone-loaded magnetic ethyl cellulose microspheres: Preparation and in vitro release. Int J Pharm 1996; 130: 49-55.

18. Anupama Singh et al. Formulation development and evaluation of magnetic microspheres containing caffeine as model drug. International Journal of Pharmaceutical Research and Technology2011;1 (3), pp. 1-4

19. The European Agency for the evaluation of medicinal products. Stability testing guidelines: stability testing of new drug substances and products. London: ICH-Technical Coordination, EMEA. [Online]. 2003 [cited 2003 Feb 20].

20. Philippova O et al. Magnetic polymer beads: Recent trends and developments in synthetic design and applications. Eur Polym J 2011; 47: 542–559.

21. Satinder kakar et al. Preparation of magnetic microsphere of mesalamine by phase separation emulsion polymerization technique. African Journal of Pharmacy and Pharmacology 2014;8 (9): 246-258.

22. Yadav N et al. Synthesis and characterization of sustained release atenolol microspheres by solvent evaporation technique. J Pharm Sci Tech 2011; 3: 559-562.

23. Schutt W et al. Applications of magnetic targeting in diagnosis and therapy possibilities and limitations: A Mini-Review. Hybridoma 1997; 16: 109-117.

24. Zhang B et al. Preparation and application of magnetic microsphere carriers. Front. Chem. Eng. China 2007; 1: 96–101.

25. Xianqiao Liu et al. Immobilization of lipase onto micron-size magnetic beads. J Chromatogr Sci 2005; 822: 91–97.

26. Kenneth J. Widder et al. Tumor remission in Yoshida sarcoma-bearing rats by selective targeting of magnetic albumin microspheres containing doxorubicin. Proc Natl Acad Sci 1981; 78(1): 579-581.

27. Toshihiko Wakabayashi et al. Preparation of tumor-specific magnetoliposomes and their application for hyperthermia. J Chem Eng JPN 2001; 34: 66-72.

Received on 12.11.2015 Modified on 21.11.2015

Research J. Pharm. and Tech. 9(3): Mar., 2016; Page 281-286

DOI: 10.5958/0974-360X.2016.00052.4