FORMULATION AND EVALUATION OF MICROSPHERES

1. FORMULATION AND EVALUATION OF MICROSPHERES PRESENTED BY GEETHA.R M.PHARM II - SEMISTER DEPARTMENT OF PHARMACEUTICS UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCE KAKATIYA UNIVERSITY, WARANGAL .

2. CONTENTS • INTRODUCTION • CLASSIFICATION OF POLYMERS. • METHODS OF PREPARATION. • CHARACTERIZATION. • APPLICATIONS. • CONCLUSION. • REFERENCES

3. INTRODUCTION POWDERS AND GRANULATES • Free-flowing powders and granulates are needed for a variety of industrial processes. These, however, do not always meet the exacting standards which modern manufacturing demands of them, due to their varying grain size distribution and odd shapes. • These properties are detrimental to efficient processing and lead to agglomeration, inexact dosage, abrading with loss of material, or low reproducibility of castings. • Pharmaceutical applications require highly reproducible dosage and the controlled release of active agents, which can not be achieved with conventional powders and Granulates.

4. Contd., • The use of small and perfectly round Microspheres with exactly the same size circumvents all of the disadvantages that are encountered while using powders and granulates. • These Microspheres are free-flowing and roll with practically no friction, that means there is no abrasion, guaranteeing a dust-free environment. Pharmaceuticals embedded in the Microsphere matrix are released continuously and at a constant rate.

5. Contd., • Administration of drugs in the form of microspheres usually improves the treatment by providing the localization of the active substances at the site of action & by prolonging the release of drugs.

6. Definition of microspheres • Microparticles or microspheres are defined as small, insoluble, free flowing spherical particles consisting of a polymer matrix and drug. and sized from about 50 nm to about 2 mm. • The term nanospheres is often applied to the smaller spheres (sized 10 to 500 nm) to distinguish them from larger microspheres

7. Ideally, microspheres are completely spherical and homogeneous in size

8. Microspheres are made from polymeric , waxy or protective materials that is biodegradable synthetic polymers and modified natural products. Microspheres are manufactured in both solid and hollow form. Hollow microspheres are used as additives to lower the density of a material. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of the drug. These carriers received much attention not only for prolonged release but also for the targeting anti cancer drugs to the tumour.

9. Advantages • Controlled release for longer period of time (like 1-3 months). • Frequency is reduced and hence patient compliance is increased. • Constant release and hence no peaks and troughs in concentration of drug. • Low dose and hence toxic effect is less. • Targeting the tissue is possible. • Other organ toxicity is less. • No distribution through out the body (no dilution effect)

10. Disadvantages • Intended mainly for parenteral route which causes pain. • Forms a depot in tissue or muscle for longer period and hence may produce pain when muscle activities are done. • Once administered, it is difficult to take back the dose. • Polymer may produce toxic effects. • High cost.

11. Potential use of microspheres in the pharmaceutical industry • Taste and odor masking. • Conversion of oils and other liquids to solids for ease of handling. • Protection of drugs against the environment (moisture, light etc.). • Separation of incompatible materials (other drugs or excipients). • Improvement of flow of powders. • Aid in dispersion of water-insoluble substances in aqueous media, and Production of SR, CR, and targeted medications.

12. Polymers used in the Microsphere preparation Synthetic Polymers • Non-biodegradable • PMMA • Acrolein • Epoxy polymers • Biodegradable • Lactides and Glycolides copolymers • Polyalkyl cyanoacrylates • Polyanhydrides

13. Natural Materials • Proteins • Albumins • Gelatin • Collagen • Carbohydrates • Starch agarose • Carrageenan • Chitosan • Chemically modified carbohydrates • Poly(acryl)dextran • Poly(acryl)starch

14. Prerequisites for Ideal Microparticulate Carriers • Longer duration of action • Control of content release • Increase of therapeutic efficacy • Protection of drug • Reduction of toxicity • Biocompatibility • Sterilizability • Relative stability • Water solubility or dispersibility • Bioresorbability • Targetability • Polyvalent

15. Types of Microspheres Micromatrix Microcapsule Types of Microspheres • Microcapsule: consisting of an encapsulated core particle. Entrapped substance completely surrounded by a distinct capsule wall. • Micromatrix: Consisting of homogenous dispersion of active ingredient in particle.

16. MICROSPHERE MANUFACTURE • Most important physicochemical characteristics that may be controlled in microsphere manufacture are: • Particle size and distribution • Polymer molecular weight • Ratio of drug to polymer • Total mass of drug and polymer

17. GENERAL METHODS OF PREPARATION • Single Emulsion techniques • Double emulsion techniques • Polymerization techniques - Normal polymerization. - Interfacial polymerization • Coacervation phase separation techniques • Emulsification-solvent evaporation method • Spray drying and spray congealing • Brace process

18. SINGLE EMULSION BASED METHOD Aq.Solution/suspension of polymer Stirring, Sonication Dispersion in organic phase (Oil/Chloroform) Chemical cross linking (Glutaraldehyde/Formaldehyde/Butanol Heat denaturation CROSS LINKING Microspheres in organic phase Microspheres in organic phase Centrifugation, Washing, Separation MICROSPHERES

19. DOUBLE EMULSION BASED METHOD Aq.Solution of protein/polymer Dispersion in oil/organic phase Homogenization First emulsion (W/O) Addition of aq. Solution of PVA Multiple emulsion Addition to large aq. Phase Denaturation/hardening Microspheres in solution Separation, Washing, Drying MICROSPHERES

20. Interfacial Polymerization technique • When two reactive monomers are dissolved in immiscible solvents, the monomers diffuse to the oil- water interface where they react to form a polymeric membrane that envelopes dispersed phase. • Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the nanoparticles after polymerization completed. • The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re- suspending the particles in an isotonic surfactant-free medium.

22. PHASE SEPARATION METHOD Aqueous/Organic.Solution of polymer Drug Drug dispersed or dissolved in polymer solution Polymer rich globules Hardening Microspheres in aq./organic phase Separation, Washing, Drying MICROSPHERES

23. Salting-out process • An aqueous phase saturated with electrolytes (e.g., magnesium acetate, magnesium chloride) and containing PVA as a stabilizing and viscosity increasing agent is added under vigorous stirring to an acetone solution of polymer. • In this system, the miscibility of both phases is prevented by the saturation of the aqueous phase with electrolytes, according to a salting-out phenomenon. • The addition of the aqueous phase is continued until a phase inversion occurs and an o/w emulsion is formed

25. Emulsification-Solvent evaporation method

26. Spray drying and spray congealing method • These methods are based on drying of the mist of polymer and drug in air. Depending on the removal of solvent or cooling the solution are named as “drying” and “congealing”, respectively. • The polymer dissolved in a suitable volatile organic solvent (dichloromethane,acetone,etc) • The drug in the solid form is then dissolved in polymer solution under high speed homogenization. • This dispersion is atomized in a stream of hot air. • This leads to formation of small droplets from which solvent evaporates leading to the formation of microspheres. • These are then separated from hot air by means of cyclone separator. • Spray congealing involves the formation of microspheres by solidifying the melted mass of drug and polymer in the form of minute particles.

27. The BRACE-Process • Ultra Spherical Microspheres • Microspheres with a monodisperse grain size distribution and the smallest divergence are manufactured by BRACE. • perfectly spherical Microspheres • monodisperse grain size, narrow size distribution with diameters between 50µm and 5000µm • nonabrading, therefore dust-free • free flowing, porous, large surface area,soft or rigid

28. The BRACE-Process • A liquid is gently pumped through a vibrating nozzle system whereupon exiting the fluid stream breaks up into uniform droplets. • The surface tension of these droplets moulds them into perfect spheres in which gelation is induced during a short period of free fall. • Solidification can be induced in a gaseous and/or liquid medium through cooling, drying, or chemical reaction. • There are no constraints on the type of liquid—molten materials, solutions, dispersions, sols, or suspensions can be used to manufacture perfectly spherical Microspheres.

30. DRUG LOADING • During the preparation of microspheres or after the formation of microspheres by incubating. • Loading into preformed microspheres has an advantage of removing all impurities from microsphere preparation before the drug is incorporated. • High loading can be achieved by insitu loading.

31. ROUTE OF ADMINISTRATION • ORAL DELIVERY • PARENTERAL DELIVERY

32. CHARACTERIZATION • PARTICLE SIZE. • PARTICLE SHAPE. • DENSITY DETERMINATION. • ISOELECTRIC POINT. • CAPTURE EFFICIENCY. • RELEASE STUDIES. • ANGLE OF CONTACT.

33. Particle size and distribution can be determined by conventional light microscopy scanning electron microscopy Confocal laser scanning microscopy Confocal fluorescence microscopy Laser light scattering and multisize coulter counter PARTICLE SIZE AND SHAPE

34. PARTICLE SIZE

35. PARTICLE SHAPE

36. DENSITY DETERMINATION • Measured by using a Multivolume psychnometer. ISOELECTRIC POINT • The microelectrophoresis is an apparatus used to measure the electophoretic mobility of microspheres from which isoelectric point can be determined.

37. CAPTURE EFFICIENCY

38. RELEASE STUDIES • Rotating paddle apparatus • Dialysis method ANGLE OF CONTACT • Determine wetting property of microparticulate carrier.

39. APPLICATIONS • MICROSPHERES IN VACCINE DELIVERY. Eg ; Diphtheria toxoid , Tetanus toxoid. • TARGETED DRUG DELIVERY. Eg ; ocular, eye (cornea).etc • CONTROLLED RELEASE. Eg ; GI tumors, Bone tumors. • CHEMOEMBOLIZATION. • IMMUNO MICROSPHERES

40. Contd.,

41. OTHER APPLICATIONS • Microcapsules are also extensively used as diagnostics, for example, temperature-sensitive microcapsules for thermographic detection of tumors. • In the biotechnology industry microencapsulated microbial cells are being used for the production of recombinant proteins and peptides. • Encapsulation of microbial cells can also increase the cell-loading capacity and the rate of production in bioreactors. • A feline breast tumor line, which was difficult to grow in conventional culture, has been successfully grown in microcapsules. • Microencapsulated activated charcoal has been used for hemoperfusion.

42. Modified release microspheres of indomethacin were prepared by the emulsion solvent diffusion technique using a synthetic polymer, Acrycoat s100. • Microspheres of diltiazem hydrochloride were formulated using combination of polyethylene glycol 6000 and Eudragit RS 100 and Eudragit RS 100 alone by solvent evaporation and non-solvent addition methods with an aim to prolong its release

44. New applications for microspheres are discovered everyday, below are just a few: • Assay- Coated microspheres provide meassuring tool in biology and drug research • Ceramics - Used to create porous ceramics used for filters (microspheres melt out during firing, polyetheylene) • Cosmetics - Opaque microspheres used to hide wrinkles and give color, Clear microspheres provide "smooth ball bearing" texture during application (polyethylene) • Drug Delivery - Miniture time release drug capsule (polymer) • Electronic paper - Dual Functional microspheres used in Gyriconelectronic paper • Personal Care - Added to Scrubs as an exfoilating agent (Polyethylene) • Spacers - Used in LCD screens to provide a precision spacing between glass panels (glass) • Standards - monodispere microspheres are used to calibrate particle sieves, and particle counting apparatus. • Thickening Agent - Added to paints and epoxies to modify viscosity.

45. Cancer research • One useful discovery made from the research of microspheres is a way to fight cancer on a molecular level. According to Wake Oncologists, "SIR-Spheres microspheres are radioactive polymer spheres that emit beta radiation. Physicians insert a catheter through the groin into the hepatic artery and deliver millions of micropheres directly to the tumor site. The SIR-Spheres microspheres target the liver tumors and spare healthy liver tissue. Approximately 55 physicians in the United States use Sirtex’s SIR-Spheres microspheres in more than 60 medical centers.

46. MARKETED PRODUCTS

47. Nanomi technologies • Product examples • 1| Monodisperse biodegradable polymeric microspheres for drug delivery.2| Monodisperse fluorescent polymeric markers.3| Monodisperse PLGA microspheres with encapsulated fluorescent protein.4| Hollow biodegradable capsules.5| Monodisperse microspheres with vitamine B12.6| Monodisperse magnetic particles. Biodegradable polymeric microspheres fabricated by conventional technology (50 - 100 μm)

48. )  Monodisperse PLGA microspheres with encapsulated fluorescent protein Monodisperse fluorescent red polymeric markers (≈ 10μm) Hollow biodegradable capsules after core-liquid removal Monodisperse microspheres with vitamine B12

50. SEM Unexpanded to Expanded Microspsheres HEAT 75 – 200°C Expancel DU (Unexpanded ) Expancel DET (Expanded