INTRODUCTION:

The concept of the advanced drug delivery systems especially those offering a sustained and controlled action of drug to desired area of effect, attained great appeal for nearly half a century. However, prior to advent of improved alternate methods, drug delivery systems were considered only as a means of getting the drug into the patient’s body. Actual practice of controlled release began with advent of timed release coating to the pills or solid drug particles in order to mask their unacceptable taste or make them more palatable.¹

Microspheres can be described as small particles (1~1000µm) for use as carriers of drugs and other therapeutic agents. We can define microspheres as, “A monolithic spherical structure with the drug or therapeutic agent distributed throughout the matrix either as a molecular dispersion or as a dispersion of particles”. Microsphere based drug delivery systems have received considerable attention in recent years in pharmaceutical science.^2-5

Microspheres constitute an important part of drug delivery systems by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at site of absorption. It would, therefore, be advantageous to have means for providing an intimate contact of the drug delivery system with the absorbing membranes.^6-10

Different Polymers Used in Microsperes

A number of different substances both biodegradable as well as non-biodegradable have been investigated for the preparation of microsperes. These materials include the polymers of natural and synthetic origin and also modified natural substances. Synthetic polymers employed as carrier materials are methylmethacrylate, ¹¹ acrolein,¹²lactide, glycolide and their copolymers, ^13,14 ethylene vinylacetate copolymer,¹⁵ polyanhydrides. The natural polymers used for the purpose are albumin,^16-17 gelatin, collagen and carrageenan,^18,19 strach.^20,21

MAGNETIC MICROSPHERES

Targeting of drug under controlled, burst or modulated release using biophysical approaches is a new way to achieve site specific drug delivery. Although direct measurements of the magnetic susceptibility of magnetic microspheres can be made with a magnetic Faraday balance ^22-24as well as with MRI techniques,²⁵ the results only hint at the microspheres behavior in vivo, as for example after injection into a person's blood system. For such applications, magnetic susceptibilities only give an approximate indication of magnetic 'responsiveness' because magnetic microspheres, nanospheres and particles not only span a large range of sizes, but are also made from many different matrix materials incorporating different types and amounts of magnetic compounds.²⁶

Magnetic microspheres are super molecular particles that are small enough to circulate through capillaries without producing embolic occlusion (<4 μm) but are sufficiently susceptible (ferromagnetic) to be captured in microvessels and dragged in to the adjacent tissues by magnetic fields of 0.5-0.8 tesla (T).¹Magnetic microspheres were prepared by mainly two methods namely phase separation emulsion polymerization (PSEP) and continuous solvent evaporation (CSE). The amount and rate of drug delivery via magnetic responsive microspheres can be regulated by varying size of microspheres, drug content, magnetite content, hydration state and drug release characteristic of carrier.²⁷ The amount of drug and magnetite content of microspheres needs to be delicately balanced in order to design an efficient therapeutic system. magnetic microsphere are characterized for different attributes such as particle size analysis including size distribution, surface topography, and texture etc. using scanning electron microscopy (SEM), drug entrapment efficiency, percent magnetite content, and in vitro magnetic responsiveness and drug release.

Targeting by magnetic microspheres i.e. incorporation of magnetic particles in to drug carriers (polymers) and using an externally applied magnetic field is one way to physically direct this magnetic drug carriers to a desired site, Widder et al. first reported on the use of magnetic albumin microspheres. Widder et al. also shows that in the presence of a suitable magnetic field, the microspheres are internalized by the endothelial cells of target tissues in healthy as well as tumor bearing animals.²⁸ Gupta and Hung suggests that in presence of magnetic field, the microspheres demonstrated 16 fold increase in the maximum drug concentration, 6 fold increase in drug exposure and 6 fold increase in the drug targeting efficiency to rat tail target segments.²⁹Morimoto and Natsume studied the utilization of magnetic microparticulate system for cancer therapy by formulating a novel cationic delivery system based on magnetic aminodextran microspheres (MADM) and compared with the neutral magnetic dextran microspheres (MDM).³⁰ The magnetic microspheres were effectively used for drug targeting to tumor cells, cell separation, diagnosis of disease and magnetic targeting of radioactivity.¹

History of Magnetic Targeting

The earliest use of magnet for selective delivery of clinical agents involved treatment of arterial thrombosis by angiography and intravascular localization of carbonyl iron with guidance of catheters. Continuous efforts by researchers established that microparticles of carbonyl iron (1-3µm) are retained at selected intravascular sites in the presence of arterial flow, under the influence of strong magnetic fields . Little amount of iron remained at the site for 7 days suggesting migration of some of the particles to the arterial wall and tissues.¹

Magnetic drug targeting is a young field. The surgeon Gilchrist published a seminal paper in 1956 on the selective inductive heating of lymph nodes after injection of 20–100-nm-sized maghemite particles into the lymph nodes near surgically removed cancer.³¹ Turner and Rand combined then this radiofrequency heating method with embolization therapy.³² Gilchrist apparently did not, however, envision that his magnetic particles could be magnetically guided and delivered to the target area. In 1963, Meyers described how they were able to accumulate small iron particles intravenously injected into the leg veins of dogs, using a large, externally applied horse shoe magnet .³³ They imagined that it might be useful for lymph node targeting and as a contrast agent. Hilal then engineered catheters with magnetic ends, and described how they could be used to deposit and selectively embolize arterio-venous malformations with small magnets.³⁴ The use of magnetic particles for the embolization therapy of liver cancer followed and has recently found renewed interest.^35,36 More defined spherical magnetic microspheres were made for the first time at the end of the 1970s by.³⁷ Their magnetic albumin microspheres worked well in animal experiments for tumor therapy and as magnet resonance contrast agents, but were not explored in clinical trials.^38,39

Principle of Magnetic Targeting

Magnetic drug delivery by particulate carriers is a very efficient method of delivering a drug to a localized disease site. Very high concentrations of chemotherapeutic or radiological agents can be achieved near the target site, such as a tumor, without any toxic effects to normal surrounding tissue or to the whole body. 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. Depending on the type of drug, it is then slowly released from the magnetic carriers (e.g. release of chemotherapeutic drugs from magnetic microspheres) or confers a local effect (e.g. irradiation from radioactive microspheres; hyperthermia with magnetic nanoparticles). It is thus possible to replace large amounts of freely circulating drug with much lower amounts of drug targeted magnetically to localized disease sites, reaching effective and up to several-fold increased localized drug levels Magnetic carriers receive their magnetic responsiveness to a magnetic field from incorporated materials such as magnetite, iron, nickel, cobalt, neodymium– iron–boron or samarium–cobalt. Magnetic carriers are normally grouped according to size. At the lower end, we have the ferrofluids, which are colloidal iron oxide solutions. Encapsulated magnetite particles in the range of 10–500 nm are usually called magnetic nanospheres and any magnetic particles of just below 1–100µm are magnetic microspheres.^{29, 37 ,40}

Magnetic microspheres is based on the force exerted by external magnetic field over the magnetically susceptible microspheres. The equation determining force can be as

F=MΔH

Where,

F= force on particles

M= magnetic moment of particles

ΔH= magnetic field gradients

The monitoring of the carrier localization is an important part of magnetic targeting that avoid the normal tissue injury. Magnetic shielding is desirable to restrict the capture of the magnetic microspheres to the desired tissue and avoid adjacent tissue localization. The tissue carrier localization monitoring is also important in order to determine the free tissue level of drug at various times after targeting.¹

Advantages of Magnetic Targeting

In magnetically modulated delivery system has been magnetize the carriers so that particles can be retained at or guided to the targed site by the application of an external magnetic field of appropriate strength.⁴¹Magnetic targeting has several advantages, which include:

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

2. Rentention of magnetic carrier at target site will delay reticuloendothelial clearance, facilitate extravasation and thus prolong the systemic action of drug.

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

4. Avoidance of acute drug toxicity directed against endothelium and normal parenchymal cells.

5. Adaptable to any part of the body.

6. Magnetic field are believed to be harmless to biological systems and adaptable to any part of the body.

7. Up to 60% of an injected dose can be deposited and released in a controlled manner in selected non-reticuloendothelial organs.

Disadvantages of Magnetic Targeting

Magnetic drug targeting is likely to be approved only for very severe diseases that are refractory to other approaches. Such targeting is limited to specialized centers; and to antitumour, antifungal, transplantation, and CNS acting agents that are highly toxic or labile.⁴² However, this novel approach suffers from certain disadvantages:

1. Magnets must have relatively constant gradients, in order to avoid focal over-dosing with toxic drugs.

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

3. Magnetic targeting is an expensive, technical approach and requires specialized manufacture and quality control system.

4. A large fraction of the magnetite, which is entrapped in carriers, is deposited permanently in target tissues.¹

APPLICATIONS OF MAGNETIC MICROSPHERES SYSTEMS

Magnetic drug targeting: Tumor targeting

The first clinical cancer therapy trial using magnetic microspheres (MMS) was performed by Lubbe et al. in Germany for the treatment of advanced solid cancer in 14 patients. ^{43, 44} Their MMS were small, about 100 nm in diameter, and filled with 4`-epidoxorubicin. The phase I study clearly showed the low toxicity of the method and the accumulation of the MMS in the target area. However, MRI measurements indicated that more than 50% of the MMS had ended up in the liver. This was likely due to the particles’ small size and low magnetic susceptibility which limited the ability to hold them at the target organ.

The startup company FeRx in San Diego developed irregularly shaped carbon-coated iron particles of 0.5–5µm in diameter with very high magnetic susceptibility and used them in a clinical phase I trial for the treatment of inoperable liver cancer. ⁴⁵They have treated 32 patients to date and are able to super-selectively (i.e. well directed) infuse up to 60 mg of doxorubicin in 600 mg MMS with no treatment-related toxicity. ⁴⁶The firm recently started a large phase I/II trial for the treatment of hepatocellular carcinoma in China, Korea, and the US.⁴⁶ Current preclinical research is investigating the use of magnetic particles loaded with different chemotherapeutic drugs such as mitoxantrone,⁴⁷ mitomycin C, etoposide, paclitaxel or oxaliplatin.⁴⁶

In case of brain tumors, the therapeutic ineffectiveness of chemotherapy is mainly due to the impervious nature of the blood-brain barrier (BBB), presence of drug resistance and lack of tumor selectivity. Various novel biodegradable magnetic drug carriers are synthesized and their targeting to brain tumor is evaluated in vitro and in animal models. New cationic magnetic aminodextran micro spheres (MADM) have been synthesized. Its potentiality for drug targeting to brain tumor was studied. This particle were retained in brain tissue over a longer period of time.⁴⁴

Magnetic targeting of radioactivity

Magnetic targeting can also be used to deliver therapeutic radioisotopes. The advantage of this method over external beam therapy is that the dose can be increased, resulting in improved tumor cell eradication, without harm to nearby normal tissue. Different radioisotopes can treat different treatment ranges depending on the radioisotope used—the β-emitters ⁹⁰Y for example will irradiate up to a range of 12mm in tissue. Unlike chemotherapeutic drugs, the radioactivity is not released, but rather the entire radioactive microsphere is delivered to and held at the target site to irradiate the area within the specific treatment range of the isotope. Once they are not radioactive anymore, biodegradation of the microspheres occurs (and is desired).⁴⁸

Magnetic bioseparation

Bioseparation is an important phenomenon for the success of several biological processes. Therefore, prospective bioseparation techniques are increasingly gaining importance. Amongst the different bioseparation techniques, magnetic separation is the most promising. The development of magnetically responsive microspheres has brought an additional driving force into play. Particles that are bound to magnetic fluids can be used to remove cells and molecules by applying magnetic fields and-in vivo-to concentrate drugs at anatomical sites with restricted access. These possibilities form the basis for well-established biomedical applications in protein and cell separation. Additional modifications of the magnetic particles with monoclonal antibodies, lectins, peptides, or hormones make these applications more efficient and also highly specific.⁴⁹

The isolation of various macro molecules such as enzymes, enzyme inhibitors, DNA, RNA, antibodies and antigens etc. from different sources including nutrient media, fermentation broth, tissues extracts and body fluids, has been done by using magnetic absorbents. In case of enzyme separation, the appropriate affinity ligands are immobilized on polymer coated magnetic carrier or magnetizable particles.^50,51 Immobilized protein A or protein G on silanized magnetite and fine magnetotactic bacteria can be used for isolation and purification of IgG.⁵² Monosized super paramagnetic particles, Dynabeads, have been used in isolation of mRNA, genomic DNA and proteins.⁵³

Magnetic systems for the diagnosis of diseases

The most important diagnostic application of magnetic nanospheres is as contrast agents for magnetic resonance imaging (MRI). Saini et al. tested 0.5–1.0 µm sized ferrites in vivo for the first time in 1987. Since then, smaller superparamagnetic iron oxides (SPIOs) have been developed into unimodular nanometer sizes and have since 1994 been approved and used for the imaging of liver metastases (ferumoxide based Feridex I.V., or Endorem in Europe) or to distinguish loops of the bowel from other abdominal structures.⁵⁴

Miscellaneous Applications

The most important application of magnetic particles is as contrast agent for magnetic resonance imaging in diagnosis of diseases. The most commonly used super paramagnetic material is Fe₃O₄ with different coatings such as dextrans, polymers, and silicone. Supramagnetic iron oxide (SPIO) it has been mainly used as a liver-specific contrast agent for intravenous application. It may also be used for detection of metastases in non-enlarged lymph nodes.⁵⁰

Magnetic elements have been successfully used in gastrointestinal surgery for tissue fixation. Which form hermetic seal after surgery and possibility of the gastrointestinal tract is maintained and the patient can able to eat immediately after operation.⁵⁵

Apart from their application in drug delivery, magnetism have sound applications in biosciences and biotechnologies like immobilization, detection of biologically active compound and xenobiotic, detection, isolation and study of cells and cells organelles.⁵⁶

CONCLUSION:

Magnetic modulated microspheres are an attractive technology platform for the pharmaceutical formulators as it has particulate carriers to delivering a drug to a localized disease site. The role of magnetic modulated microspheres is of paramount importance in providing novel solutions drug delivery by particulate disease site. Microspheres constitute an important part of drug delivery systems by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at site of absorption.

REFERENCES:

1. Vyas SP and Khar RK. Targeted & Controlled Drug Delivery, CBC Publisher & distributors, New Delhi 417-57; 2004:459-63.

2. Utpal K K and Faysal M. “Diclofenac as microspheres,” Journal of Third World Medicine. 8 (1); 2009.

3. Jeffery H, Davis SS, and O’Hagan DT. The Preparation and Characterization of Poly(Lactide-Co-Glycolide) Microparticles. II. The Entrapment of A Model Protein Using A (Water-In-Oil)-In-Water Emulsion Solvent Evaporation Technique. Pharm. Res. 10; 1993:362–368.

4. Yan C, Resau LH, Hewhtson J, et al. Characterization and Morphological Analysis of Protein-Loaded Poly(Lactide-Co-Glycolide) Microparticles Prepared by Water-in-Oil-in-Water Emulsion Technique,” J. Control. Rel. 32; 1994: 231–241.

5. Chen L, Apte RN, and Cohen S. Characterization of PLGA Microspheres for the Controlled Delivery of Il-1a for Tumor Immunotherapy. J. Control. Rel. 43; 1997:261–272.

6. Ikeda K, Murata K, Kobayashi M, et al. Enhancement of Bioavailability of

7. Dopamine via Nasal Route in Beagle Dogs. Chem. Pharm. Bull 40; 1992:2155-58.

8. Nagai T, Nishimoto Y, Nambu N, et al. Powder Dosage Form of

9. Insulin for Nasal Administration. J. Control. Release. 1; 1984:15-22.

10. Illum L, Furraj NF, Critcheley H, et al. Nasal administration of

11. gentamycin using a novel microsphere delivery system. Int. J. Pharm. 46; 1988:261-265.

12. Schaefer MJ, and Singh J. Effect of Isopropyl Myristic Acid Ester on the Physical Characteristics and In-vitro Release of Etoposide from PLGA Microspheres. AAPS Pharm Sci Tech. 1 (4); 2000: article 32.

13. Hannah B. Novel bioadhesive formulation in drug delivery. The Drug Delivery Companies Report. 2004:16-19.

14. Kreuter J, Nefzger M, Liehl E, et al. Distribution and elimination of poly(methyl methacrylate) nanoparticles after subcutaneous administration to rats. J. Pharm. Sci. 72; 1983:1146- 1149.

15. Margel S and Wiesel E. Acrolein polymerization: Monodisperse, homo, and hybrido microspheres, synthesis, mechanism, and reactions. J. Polym. Sci. 22; 1998:4145.

16. Wakiyama N, Juni K and Nakano M. Preparation and evaluation in vito of polylactic acid microspheres containing local anesthetics. Chem. Pharm. Bull. 29,;1981:3363-68

17. Benita S, Benoit JP, Puisieux F, et al. Characterization of drug-loaded poly(d,l-lactide) microspheres. J Pharm Sci. 73(12); 1984:1721-4.

18. Stefon M, Brown L R, and Langer R S. Ethylene-vinyl acetate copolymer microspheres for controlled release of macromolecules. J. Pharm. Sci. 73; 1984:1859.

19. Sugibayashi K, Akimoto M, Moromoto Y, et al. Pharmacobiodyn. 23; 1979:50.

20. Lee TK, Sokoloksi TD, and Royer GP. Serum Albumin Beads: An injectable, biodegradable System for the Sustained Release of Drugs. Science. 213(10); 1981:233-35.

21. Yoshioka T, Hashida M, Muranishi S, et al. Specific delivery of mitomycin C to the liver, spleen and lung: nano- and microspherical carriers of gelatin. Int. J. Pharm. 8; 1981:131-41.

22. Yoshioka T, Ikeuchi K, Hashida M et al. Chem. Pharm. Bull. 39; 1982:1074.

23. G.F. Russel. Pharm. Int. 4; 1983:260.

24. Lindberg B, Lote K and Teder H. In: Microsphere and Drug Threapy, S. S. Davis, L. Illem, J. G. McVie and Tomlinson (Eds.), Elsevier science. 1984:153.

25. Gill SJ, Malone CP, and Downing M. Magnetic susceptibility measurements of single small particles. Rev. Sci. Instrum. 31; 1960: 1299-03.

26. Lindoy LF, Katovic V and Busch DH. A variable-temperature faraday magnetic balance J. Chem. Ed. 49; 1972:117-20.

27. Hafeli UO, Ciocan R, Dailey JP. Characterization of magnetic particles and microspheres and their magnetophoretic mobility using a digital microscopy method. European Cells and Materials. 3( 2); 2002:24-7.

28. Beuf O, Briguet A, Lissac M, et al., J. Magn. Resonance, Series B 112; 1996:111-18.

29. Arshady R. Microspheres, Microcapsules & Liposomes: Magneto and radio pharmaceuticals Citus Books, London, 2001:1st ed. vol. 3.

30. Shinoda, Kozo and Friberg S. Emulsions and Solubility. New York: Wiley and Sons, 1986.

31. Widder KJ, Senyei AE and Scarpelli DG. Proc. Soc. Exp. Biol. Med. 58; 1978: 141.

32. Gupta PK, and Hung CT. J. Pharm. Sci, 78 ; 1989:745.

33. Morimoto Y, Natsume H. Nippon Rinsho. 56; 1998:649.

34. Gilchrist RK, Medal R and Shorey WD. Selective Inductive Heating of Lymph Nodes. Ann. Surg. 146; 1957: 596–06.

35. Turner RD, Rand RW and Bentson JR. Ferromagnetic Silicone Necrosis of Hypernephromas by Selective Vascular Occlusion to the Tumor: A New Technique. J. Urol. 113; 1975:455–59.

36. Meyers PH, Cronic F, and Nice CM, Experimental Approach in the Use and Magnetic Control of Metallic Iron Particles in the Lymphatic and Vascular System of Dogs as a Contrast and Isotopic Agent. Am. J. Roentgenol. Radium Ther. Nucl. Med. 90; 1963: 1068–77.

37. Hilal SK, Michelsen WJ and Driller J. Magnetically Guided Devices for Vascular Exploration and Treatment. Radiology. 113; 1974: 529–540.

38. Wu CB, Wei SL, and He SM. Studies on Adriamycin Magnetic Gelatin Microspheres. J. Clin. Pharm. Sci. 4; 1995: 1–6.

39. Jones SK, and Winter JG. Experimental Examination of A Targeted Hyperthermia System Using Inductively Heated Ferromagnetic Microspheres in Rabbit Kidney. Phys. Med. Biol. 46; 2001: 385–98.

40. Widder KJ, Senyei AE and Ranney DF. Magnetically Responsive Microspheres and Other Carriers for the Biophysical Targeting of Antitumor Agents. Adv. Pharmacol. Chemother. 16; 1979: 213–71.

41. Widder KJ, Morris RM and Poore GA. Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin: total remission in Yoshida sarcoma-bearing rats. Eur. J. Cancer Clin. Oncol. 19; 1983:135–39.

42. Widder DJ, Greif WL and Widder KJ. Magnetite Albumin Microspheres: A New MR Contrast Material. AJR. 148; 1987: 399–04.

43. Hafeli U, Schutt W and Teller J. Scientific and Clinical Applications of Magnetic Carriers,” first ed. Plenum Press, New York, 1997.

44. Widder K, Senyei AE and Scarpelli DG. Proc. Soc. Exp. Biol. Med. 58; 1978.

45. Ranny DF. and Huffaker HH. Biological Approaches to the Controlled Delivery of Drugs, R. L. Juliano ed., The New York Academy of Science, New York, 104;1987.

46. Lubbe AS, Bergemann C and Riess H. Clinical experiences with magnetic drug targeting: A phase I study with 4`- epidoxorubicin in 14 patients with advanced solid tumors. Cancer Res. 56; 1996:4686–93.

47. Lubbe AS, Alexiou C, and Bergemann C. Clinical applications of Magnetic Drug Targeting. J. Surg. Res. 95; 2001: 200–06.

48. Goodwin S. Magnetic Targeted Carriers Offer Site-Specific Drug Delivery. Oncol. News Int. 9; 2000: 22.

49. Johnson J, Kent T and Koda J. The MTC Technology: A Platform Technology for the Site-Specific Delivery of Pharmaceutical Agents. Eur. Cells Mater. 3; 2002: 12–15.

50. Alexiou C, Arnold W, and Klein R.J. Locoregional Cancer Treatment with Magnetic Drug Targeting. Cancer Res. 60; 2000: 6641– 48.

51. Hafeli UO. Magnetically modulated therapeutic systems. Int. J. Pharmaceutics. 277 (1-2); 2004: 19-24.

52. Bahadur D, Giri and Sadhana J. 28; 2003:639-656.

53. Burns MA, and Graves DJ. Biotechnol. Progr. 1; 1985: 95–103.

54. Kobayashi H, and Matsunaga T. J. Colloid Interface Sci. 141; 1991: 505–11.

55. De Cuyper M, De Meulenaer B and Van Der Meeren P. J Biocatal. Biotransform.13, 1995: 77–87

56. Dynal AS, Cell separation and protein purification. Technical handbook, Dynal, Oslo 1996.

57. Saini S, Stark DD and Hahn P.F. Ferrite Particles: A Superparamagnetic MR Contrast Agent for the Reticuloendothelial System. Radiology. 162; 1987: 211–16.

58. Kuzentoztsov A.A., Kanshin N.N., Piruzyan, V.M. Chikov, G.S. Nechitalio, and O.A. Kuzentsov. 3 (2); 2002: 179.

59. Saiyed ZMZ, Sugita T, Shimose S. et al. Targeted systemic chemotherapy using magnetic liposomes with incorporated adriamycin for osteosarcoma in hamsters. Int. J. Oncol. 18(1); 2001:121.

Received on 05.12.2013 Accepted on 06.12.2013

Asian J. Pharm. Res. 3(4): Oct. - Dec.2013; Page 220-224