INTRODUCTION:

Microspheres are solid spherical particles ranging in size from 1-1000μm. They are spherical free flowing particles consisting of proteins or synthetic polymers. The microspheres are free flowing powders consisting of proteins or synthetic polymers, which are biodegradable in nature. There are two types of microspheres;

· Microcapsules.

· Micromatrices.

Microcapsules are those in which entrapped substance is distinctly surrounded by distinct capsule wall and micromatrices in which entrapped substance is dispersing throughout the microspheres matrix. Solid biodegradable microspheres incorporating a drug dispersed or dissolved through particle matrix have the potential for the controlled release of drug. They are made up of polymeric, waxy, or other protective materials, that is, biodegradable synthetic polymers and modified natural products^[1].

Advantages:

· Microspheres provide constant and prolonged therapeutic effect.

· Reduces the dosing frequency and thereby improve the patient compliance.

· They could be injected into the body due to the spherical shape and smaller size.

· Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects^[2].

Limitation:

Some of the disadvantages were found to be as follows.

· The costs of the materials and processing of the controlled release preparation, are substantially higher than those of standard formulations.

· The fate of polymer matrix and its effect on the environment.

· The fate of polymer additives such as plasticizers, stabilizers, antioxidants and fillers.

· Reproducibility is less.

· Process conditions like change in temperature, pH, solvent addition, and evaporation/agitation may influence the stability of core particles to be encapsulated.

The environmental impact of the degradation products of the polymer matrix produced in response to heat, hydrolysis, oxidation, solar radiation or biological agents^[3].

CRITERIA FOR MICROSPHERE PREPARATION:

Incorporation of solid, liquid or gases into one or more polymeric coatings can be done by micro encapsulation technique^[4]. The different methods used for various microspheres preparation depends on particle size, route of administration, duration of drug release and these above characters related to rpm, method of cross linking, drug of cross linking, evaporation time, co precipitation etc^[5]. Preparation of microspheres should satisfy certain criteria^[6]:

· The ability to incorporate reasonably high concentrations of the drug.

· Stability of the preparation after synthesis with a clinically acceptable shelf life.

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

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

· Biocompatibility with a controllable biodegradability and

· Susceptibility to chemical modification.

TYPES OF MICROSPHERES:

1. Bioadhesive Microspheres:

Adhesion can be defined as sticking of drug to the membrane by using the sticking property of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane such as buccal, ocular, rectal, nasal etc can be termed as bio adhesion. These kinds of microspheres exhibit a prolonged residence time at the site of application and causes intimate contact with the absorption site and produces better therapeutic action^[7].

2. Magnetic Microspheres:

This kind of delivery system is very much important which localizes 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. The different types are^[8]

Therapeutic magnetic microspheres: These are used to deliver chemotherapeutic agent to liver tumour. Drugs like proteins and peptides can also be targeted through this system.

Diagnostic microspheres: They can be used for imaging liver metastases and also can be used to distinguish bowel loops from other abdominal structures by forming nano size particles supramagnetic iron oxides^[9].

3. Floating microspheres:

In floating types the bulk density is less than the gastric fluid and so remains buoyant in stomach without affecting gastric emptying rate. The drug is released slowly at the desired rate, if the system is floating on gastric content and increases gastric residence and increases fluctuation in plasma concentration. Moreover it also reduces chances of striking and dose dumping. One another way it produces prolonged therapeutic effect and therefore reduces dosing frequencies. Drug (ketoprofen) is given through this form^[10].

4. Radioactive microspheres:

Radio emobilisation therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they come across. They are injected to the arteries that lead to tumour of interest. So in all these conditions radioactive microspheres deliver high radiation dose to the targeted areas without damaging the normal surrounding tissues^[11]. It differs from drug delivery system, as radio activity is not released from microspheres but acts from within a radioisotope typical distance and the different kinds of radioactive microspheres are α emitters, β emitters, γ emitters^[12].

5. Polymeric microspheres:

The different types of polymeric microspheres can be classified as:

i) Biodegradable polymeric microspheres

Natural polymers such as starch are used with the concept that they are biodegradable, biocompatible, and also bio adhesive in nature. Biodegradable polymers prolongs the residence time when contact with mucous membrane due to its high degree of swelling property with aqueous medium, resulting in gel formation. The rate and extent of drug release is controlled by concentration of polymer and the release pattern in a sustained manner. The main drawback is, in clinical use drug loading efficiency of biodegradable microspheres is complex and is difficult to control the drug release. However they provide wide range of application in microsphere based treatment^[13].

ii) Synthetic polymeric microspheres

The interest of synthetic polymeric microspheres are widely used in clinical application, moreover they are also used as bulking agent, fillers, embolic particles, drug delivery vehicles etc and proved to be safe and biocompatible. But the main disadvantage of these kinds of microspheres is they tend to migrate away from injection site and lead to potential risk, embolism and further organ damage^[14].

METHOD OF PREPARATION:

Spray Drying Technique:

This was used to prepare polymeric blended microsphere loaded with ketoprofen drug. It involves dispersing the core material into liquefied coating material and then spraying the mixture in the environment for solidification of coating followed by rapid evaporation of solvent^[15]. Organic solution of poly (epsilon-caprolactone) (PCL) and cellulose acetate butyrate (CAB), in different weight ratios and ketoprofen were prepared and sprayed in different experimental condition achieving drug loaded microspheres. This is rapid but may loose crystalinity due to fast drying process.

Dig No. 1 Microspheres by Spray Drying Technique

Solvent Evaporation:

This process is carried out in a liquid manufacturing vehicle phase. The microcapsule coating is dispersed in a volatile solvent which is immiscible with the liquid manufacturing vehicle phase. A core material to be microencapsulated is dissolved or dispersed in the coating polymer solution. With agitation the core material mixture is dispersed in the liquid manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then heated if necessary to evaporate the solvent for the polymer of the core material is disperse in the polymer solution, polymer shrinks around the core. If the core material is dissolved in the coating polymer solution, matrix – type microcapsules are formed. The core materials may be either water soluble or water in soluble materials. Solvent evaporation involves the formation of an emulsion between polymer solution and an immiscible continuous^{[16, 17]}.

Single emulsion technique:^[18]

The micro particulate carriers of natural polymers i.e. those of proteins and carbohydrates are prepared by single emulsion technique. The natural polymers are dissolved or dispersed in aqueous medium followed by dispersion in non-aqueous medium like oil. In the next step, the cross linking of the dispersed globuleis carried out. The cross linking can be achieved either by means of heat or by using the chemical cross linkers. The chemical cross linking agents used are glutar aldehydes, formaldehyde, acid chloride etc. Heat denaturation is not suitable for the molabile substances. Chemical cross linking suffers the disadvantage of excessive exposure of active ingredient to chemicals if added at the time of preparation and then subjected to centrifugation, washing, separation3 The nature of the surfactants used to stabilize the emulsion phase scan greatly influence the size, size distribution, surface morphology, loading, drug release, and bio performance of the final multi particulate product.

Dig No. 2 Microspheres by Single Emulsion Technique

Double emulsion technique:

Double emulsion method of microspheres preparation involves the formation of the multiple emulsions or the double emulsion of type w/o/w and is best suited for water soluble drugs, peptides, proteins and the vaccines. This method can be used with both the natural as well as synthetic polymers. The aqueous protein solution is dispersed in a lipophilic organic continuous phase. This protein solution may contain the active constituents. The continuous phase is generally consisted of the polymer solution that eventually encapsulates of the protein contained in dispersed aqueous phase. The primary emulsion is subjected then to the homogenization or the sonication before addition to the aqueous solution of the poly vinyl alcohol (PVA). This results in the formation of a double emulsion. The emulsion is then subjected to solvent removal either by solvent evaporation or by solvent extraction. A number of hydrophilic drugs like luteinizing hormone releasing hormone (LH-RH) agonist, vaccines, proteins/peptides and conventional molecules are successfully incorporated into the microspheres using the method of double emulsion solvent evaporation/ extraction.

Dig No. 3 Microspheres by Double Emulsion Technique

Coacervation Method:

Co-acervation thermal change: Performed by weighed amount of ethyl cellulose was dissolved in cyclohexane with vigorous stirring at 800C by heating. Then the drug was finely pulverized and added with vigorous stirring on the above solution and phase separation was done by reducing temperature and using ice bath. Then above product was washed twicely with cyclohexane and air dried then passed through sieve (sieve no. 40) to obtain individual microcapsule. Coacervation non solvent addition: Developed by weighed amount of ethyl cellulose was dissolved in toluene containing propylisobutylene in closed beaker with magnetic stirring for 6 hr at 500 rpm and the drug is dispersed in it and stirring is continued for 15 mins. Then phase separation is done by petroleum benzoin 5 times with continuous stirring.1After that the microcapsules were washed with n-hexane and air dried for 2 hr and then in oven at 50oC for 4 hr ^[19].

Spray drying and spray congealing:

These methods are based on the drying of the mist of the polymer and drug in the air. Depending upon the removal of the solvent or cooling of the solution, the two processes are named spray drying and spray congealing respectively. The polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, acetone, etc. The drug in the solid form is then dispersed in the polymer solution under high speed homogenization. This 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 instantaneously leading the formation of the microspheres in a size range 1-100 μm. 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 spray drying process is used to encapsulate various penicillin’s. Thiamine mononitrate and sulpha ethyl thiadizole are encapsulated in a mixture of mono- and diglycerides of stearic acid and palmitic acid using spray congealing. Very rapid solvent evaporation, however leads to the formation of porous micro particles ^{[20, 21]}.

Solvent extraction:

Solvent evaporation method is used for manufacturing of micro particles, involves removal of the organic phase by extraction of the ornon aqueous solvent. This method involves water miscible organic solvents as isopropanol. Organic phase can be removed by extraction with water. This process decreases the hardening time for the microspheres. One variation of the process involves direct incorporation of the drug or protein to polymer organic solution. Rate of solvent removal by extraction method depends on the temperature of water, ratio of emulsion volume to the water and solubility profile of polymer ^{[22, 23, 24]}.

Quassi Emulsion Solvent Diffusion:

A novel quasi-emulsion solvent diffusion method to manufacture the controlled release microspheres of drugs with acrylic polymers has been reported in the literature. Micro sponges can be manufactured by a quasi-emulsion solvent diffusion method using an external phase containing distilled water and polyvinyl alcohol. The internal phase is consisting of drug, ethanol and polymer is added at an amount of 20% of the polymer in order to enhance plasticity. At first, the internal phase is manufactured at 60ºC and then added to the external phase at room temperature. After emulsification process, the mixture is continuously stirred for 2 hours. Then the mixture can be filtered to separate the micro sponges. The product is then washed and dried by vacuum oven at 40ºC for a day ^[25].

Ionic gelation:

Alginate/chitosan particulate system for diclofenac sodium release was prepared using this technique. 25% (w/v) of diclofenac sodium was added to 1.2% (w/v) aqueous solution of sodium alginate. In order to get the complete solution stirring is continued and after that it was added drop wise to a solution containing Ca2+ /Al3+ and chitosan solution in acetic acid. Microspheres which were formed were kept in original solution for 24 hr for internal

Gellification followed by filtration for separation. The complete release was obtained at pH 6.4-7.2 but the drug did not release in acidic pH ^[26].

Hydroxyl appetite (HAP) microspheres in sphere morphology:

This was used to prepare microspheres with peculiar spheres in sphere morphology microspheres were prepared by o/w emulsion followed by solvent evaporation. At first o/w emulsion was prepared by dispersing the organic phase (Diclofenac sodium containing 5% w/w of EVA and appropriate amount of HAP) in aqueous phase of surfactant. The organic phase was dispersed in the form of tiny droplets which were surrounded by surfactant molecules this prevented the droplets from co-solvencing and helped them to stay individual droplets .While stirring the DCM was slowly evaporated and the droplets solidify individual to become microspheres ^[27].

FACTORS AFFECTING PARTICLE SIZE, ENTRAPAMENT EFFICIENCY AND RELEASE CHARACTEISTICS:

The drug release is strongly influenced by a various parameters including the drug content, the nature of polymer, the physical state of the drug, the molecular weight of polymer, the density of cross linking the copolymer concentration, the type of any excipients included in the micro particles preparation, and the microsphere size.

i) Drug content:

The amount of drug that present in the micro particle determines the release kinetics of the drugs from the matrix devices; the release proportionately increases with increase in drug content in the micro particles.

ii) Nature of polymer:

The nature of polymer present in micro particles and the type of polymer erosion clearly determine the drug delivery rate. Polymers are generally classified into two types: surface erosion and bulk-erosion. In bulk-eroding polymers, the matrix degrades by diffusion of water molecules. While, in surface-leaching polymers, water repelling monomers resist penetration of water molecules therefore degradation takes place from the surface of the particle.

iii) Physical state of the drug:

The physical state of a drug affects the drug release kinetics from a dosage form. The presence of the drug inside the micro particles may vary from molecular dispersion to well defined crystalline structures.

iv) Molecular weight of polymer:

Molecular weight of polymer plays a major role in polymer degradation as well as drug delivery rates. This indicates that, higher the molecular weight lower the diffusivity and decreased drug delivery rate. In addition, drug delivery takes place by diffusion through water filled pore. The decrease in delivery rates reported for small molecules such as drugs, and macromolecules with increasing molecular weight of polymer.

v) Density of cross linking:

The cross linking density plays a major role on the release kinetics of drugs from the micro particles. It was observed from the results that drug delivery rates become slower when micro particles preparation utilizes polymer at higher concentration and polymer with higher molecular weight and/or a lower drug concentration.

vi) Copolymer concentration:

The concentration of co-monomer presence in copolymers has a strong effect on release rates. Normally, the release rate increases with increasing the concentration of polymer that degrades faster. Likewise, when polymer erosion controls the drug delivery, release rate is usually increased by higher concentration of more soluble and/or the smaller monomer.

vii) Type of excipients:

To maintain stability of the drug a range of excipients might be included to micro particle preparations during manufacture and/or release. Decreased delivery rate may be due to interaction with the excipients and forming chelation, complexation, polymerization, is omerisation, racemisation etc.

viii) Micro particle size:

Largely, the rate of drug release will be strongly influenced by micro particles size. The surface area-to-volume ratio of the particle increases when size decreases. Therefore, drug diffusion and the release rate will increase with declining particle size. In addition, the smaller radius of the micro particle the higher the water penetration.

Evaluation of Microspheres:

Particle size analyzer:

Microsphere (50 mg) are 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 is expressed as volume mean diameter in micrometer^[28].

Optical microscopy:

This method is used to determine particle size by using optical microscope (Meizer OPTIK) The measurement i done under 450x (10x eye piece and 45x objective) and100 particles are calculated^[29].

Scanning electron microscopy (SEM):

Surface morphology is determined by the method SEM. In this microcapsule are mounted directly on the SEM sample slab with the help of double sided sticking tape and coated with gold film under reduced pressure and analyzed^[30].

Swelling index:

This technique is used for characterization of sodium alginate microspheres. Different solution (100mL) is taken such as [distilled water, buffer solution of Ph (1.2, 4.5, and 7.4) and alginate microspheres (100mg) are placed in a wire basket and kept on the above solution and swelling is allowed at 37oC. Thus, changes in weight variation between initial weight of microspheres and weight due to swelling is measured by taking weight periodically and soaking with filter paper^[31].

Entrapment efficiency:

Microspheres containing of drug (5mg) are crushed and then dissolved in distilled water with the help of ultrasonic stirrer for 3 hr, filtered then assayed by uv-vis spectroscopy. Entrapment efficiency is equal to ratio of actual drug content to theoretical drug content.

X-ray diffraction:

Change in crystalinity of drug can be determined by this technique. Micro particles and its individual components are analysed by the help of XRD Instrument ^[32]. Scanning range angle between 80^oC - 70^oC.

Thermal analysis:

Thermal analysis of microcapsule and its component can be done by using Differential scanning calorimetry (DSC) Thermo gravimetric analysis (TGA)

Differential thermometric analysis (DTA) Accurately the sample is weighed and heated on alumina pan at constant rate of 10oc/min under nitrogen flow of 40 ml/min.

FTTR:

The drug polymer interaction and also degradation of drug while processing for microencapsulation can be determined by FTIR^[33].

Stability studies:

Stability Studies are done by placing the microspheres in screw capped glass container and storing them at following conditions:

· Ambient humid condition

· Room temperature (27+/-2 ^oC)

· Oven temperature (40+/-2 ^oC)

· Refrigerator (5 0+/-8 ^oC).

It was carried out of for 60 days and the drug content of the microsphere is analysed^[34].

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^[35].

APPLICATION OF MICROSPHERES:

1. Gene delivery

2. Ophthalmic Drug Delivery

3. Intratumoral and local drug delivery

4. Oral drug delivery

5. Nasal drug delivery

6. Buccal drug delivery

7. Gastrointestinal drug delivery

8. Peroral drug delivery

9. Vaginal drug delivery

10. Transdermal drug delivery

11. Colonic drug delivery

12. Multiparticulate delivery system

CONCLUSION:

Microsphere is a short term but it is having wide applications in drug delivery systems. Most important are the targeted drug delivery (Bioadhesive microspheres-nasal, ocular, buccal, rectal etc., Magnetic microspheres and radioactive microspheres – For tumours), Controlled and sustained drug delivery (Polymeric microspheres, Floating microspheres). By combining various strategies, microspheres will find central place in novel drug delivery mainly particularly in cell sorting, diagnostics and Genetic engineering. From the study it is proved that Microspheres act as effective carriers for the novel drug delivery system.

ACKNOWLEDGEMENT:

Authors are highly Acknowledge the help of teaching staff of Sahyadri College of Pharmacy, Methwade. For providing necessary information required for research work. Also we are highly Acknowledge the help and guidance of Dr. Manojkumar S. Patil.

REFERENCE

1. Chaudhari A, Jadhav K. R, Kadam VJ. An Overview: Microspheres as a Nasal Drug Delivery System. Int. J. of Pharmaceutical Sciences Review and Res. 2010; 5.

2. Vyas SP, Khar RK. Targeted and Controlled drug delivery; 7th Edition; Vallabh Prakashan, New Delhi India, 420-445.

3. Sree Giri Prasad B., Gupta V. R. M., Devanna N., Jayasurya K., Microspheres as drug delivery system – A review, JGTPS. 2014; 5(3): 1961 -72.

4. Ghulam M., Mahmood A., Naveed A., Fatima R.A., Comparative study of various microencapsulation techniques. Effect of polymer viscosity on microcapsule characteristics, Pak. J. Sci. 22 (3), 2009, 291-300.

5. Li, S.P., Kowalski C.R., Feld K.M., Grim W.M., Recent Advances in Microencapsulation Technology and Equipment, Drug DevInd Pharm. 14, 1988, 353-376.

6. Alagusundaram. M, MadhuSudana Chetty. C, Umashankari. K, Attuluri Venkata Badarinath, Lavanya. C and Ramkanth. S. Microspheres as a novel drug delivery system – A Review. International Journal of Chem Tech Research. 1(3), 2009, 526-534.

7. Patel JK, Patel RP, Amin AF, Patel MM, 4(6).

8. Li S.P, Kowalski C.R, Feld K.M, Grim W.M. 1988. Recent Advances in Microencapsulation Technology and Equipment, Drug Dev, Ind Pharm. 14: 353-376.

9. Shanthi N.C, Gupta R, Mahato K.A. 2010 Traditional and Emerging Applications of Microspheres: A Review, International Journal of Pharm Tech Research; 2(1):675-681.

10. Najmuddin M, Ahmed A, Shelar S, Patel V, Khan T. 2010. Floating Microspheres Of Ketoprofen: Formulation and Evaluation, International Journal Of Pharmacy and Pharmaceutical sciences. 2(2):83-87.

11. Hafeli U, 2002, Physics and Chemistry Basic of Biotechnology. Focus on biotechnology. Review. Radioactive Microspheres for Medical Application, 7:213-248.

12. Yadav AV, Mote HH. 2008. Development of Biodegradable Starch Microspheres for Intranasal Delivery, Indian Journal of pharmaceutical Sciences. 70 (2):170-174.

13. Saralidze K, Leo H, Koole, Menno L, Knetsch W. 2010. Polymeric Microspheres for Medical Applicatio, Materials; 3:3357-3564.

14. Trivedi P, Verma L, Garud N. 2008.Preparation and Characterization of Acclofenac Microspheres, Asian Journal of pharmaceutics. 2(2): 110-115.

15. Mathew Sam T., Devi Gayathri S., Prasanth V.V., Vinod B; NSAIDs as microspheres, The Internet Journal of Pharmacology. 6(1), 2008, 67 – 73.

16. Ramteke K.H., Jadhav V.B., Dhole S.N., Microspheres: As carrieres used for novel drug delivery system, IOSRPHR. 2012; 2(4):44-48.

17. Patel B., Modi V., Patel K., Patel M., Preparation and evaluation of ethyl cellulose microspheres prepared by emulsification emulsification - solvent evaporation method, International Journal For Research In Management And Pharmacy. 2012; 1(1):83-91.

18. Patel N. R., Patel D. A., Bharadia P.D., Pandya V., Modi D., Microsphere as a novel drug delivery, Int. j. pharm. life sci. 2011;2(8):992-7

19. Ghulam M., Mahmood A., Naveed A., Fatima R.A., Comparative study of various microencapsulation techniques. Effect of polymer viscosity on microcapsule charecterestics, .J. Sci. 22 (3), 2009, 291-300.

20. Bansal H., kaur S. P., Gupta A. K., Microsphere: Methods of preparation and applications; a comparative study, Int J Pharm Sci Rev Res. 2011; 10(1):69-78.

21. Alagusundaram M., Chetty. C. M. S., Umashankari. K, Badarinath A. V., Lavanya. C., Ramkanth. S., Microspheres as a novel drug delivery system - A review, Int J Chem Tech Res. 2009;1(3):526-34.

22. Patel N. R., Patel D. A., Bharadia P.D., Pandya V., Modi D., Microsphere as a novel drug delivery, Int. j. pharm. life sci. 2011;2(8):992-7.

23. Bansal H., kaur S. P., Gupta A. K., Microsphere: Methods of preparation and applications; a comparative study, Int J Pharm Sci Rev Res. 2011; 10(1):69-78.

24. Alagusundaram M., Chetty. C. M. S., Umashankari. K, Badarinath A. V., Lavanya. C., Ramkanth. S., Microspheres as a novel drug delivery system- A review, Int J Chem Tech Res. 2009;1(3):526-34.

25. Davis S.S. and Illum L. (1989). Microspheres as drug carrier in drug carrier system, F.H Roerdink and A.M. Kron (Eds), John Wiley and sons Ltd., 1-6

26. Mathew Sam T, Devi Gayathri S, Prasanthv VV, Vinod B. NSAIDs as microspheres, The Internet Journal of Pharmacology. 2008; 6: 11-15.

27. Pradesh TS, Sunny M., Varma KH, Ramesh P. Preparation of micro structured hydroxy apatite microspheres using oil in water emulsion, Bull Matter. Sci. 2005; 28(5):383- 90.

28. Kannan. K., Karar. K.P., Manavalan. R., Formulation and Evaluation of Sustained Release Microspheres of Acetazolamide by Solvent Evaporation Technique, J. Pharm. Sci& Res. 2009; 1 (1):36-39.

29. Shaji J., Poddar A., Iyer S., Brain-Targeted Nasal Clonazepam Microspheres, Indian Journal ofpharmaceutical Sciences. 2009; 71(6): 715–718.

30. Chowdary K.P.R., Suri B.J., Permeability of Ethylene Vinyl Accetate Copolymer Microcapsules: Effect of Solvents, Indian Journal of pharmaceutical Sciences. 2003; 65(1):62 66.

31. Soni L.M., Kumar M., Namdeo P.K., Sodium alginate Microspheres for extending drug release: formulation and in vitro evaluation, International Journal of Drug Delivery. 2010; 2(1):64-68.

32. Ghulam M., Mahmood A., Naveed A., Fatima R.A., Comparative study of various microencapsulation techniques. Effect of polymer viscosity on microcapsule charecterestics, Pak.J.Sci.2009; 22 (3):291-300.

33. Surini S., Anggriani V., Anwar E., Study of Mucoadhesive Microspheres Based on Pregelatinsed Cassava Starch Succinate as a New Carrier for Drug Delivery, J. Med. Sci. 2009; 9(6):249-256

34. Tamizharsi S., Rathi C.J., Rathi. Formulation and Evaluation of Pentoxy fylline-Loaded Poly (ε-caprolactone) Microspheres, Indian Journal of pharmaceutical Sciences. 2008; 70(3):333- 337.

35. Fischer S., Foreg C., Merkle P.H., Gander B., Chitosan Coated Plga-Microspheres-A Modular System for Targetting Drug Delivery, European Cells and Materials. 2004; 7:11-12

Received on 27.02.2019 Accepted on 21.03.2019

Asian J. Pharm. Res. 2019; 9(2): 123-129.

DOI: 10.5958/2231-5691.2019.00020.0