beads as drug carriers

Assignment On An Extensive Review on Beads as Drug Carriers:

Assignment On An Extensive Review on Beads as Drug Carriers Presented By Manas Boxi , 1 st Sem M.Pharm Guided By Mrs. J. Sruti M.Pharm, Lecturer Department of Pharmaceutics Roland Institute of Pharmaceutical Sciences Berhampur, Ganjam-760010 2011

Contents:

Contents Introduction Materials used for preparation of beads Drug loading and drug release kinetics Methods of preparation Types of beads used in pharmaceutical industry Physiochemical evaluation of beads Application of beads Conclusion References 2

Introduction :

Introduction To obtain maximum therapeutic efficacy, it is necessary to deliver the agent to the target tissue in the optimal amount in the right period of time there by causing little toxicity and minimal side effects . There are various approaches in delivering a therapeutic substance to the target site in a sustained or controlled release fashion. One such approach is using beads as carriers for drugs . The term bead is defined as a spherical particle with a size varying from 50 nm to 2mm, containing a core substance . The term beads is used synonymously with microspheres or microcapsules. 3

Slide 4:

When discussing drug delivery by beads, topics related to the method of drug incorporation, size and density of the bead, extent and nature of the cross linking, physicochemical properties of the drug, interactions between the drug and the matrix material, and concentration of the matrix material and release environment, such as the presence of enzymes, are of the utmost importance. 4

Slide 5:

Prerequisites for ideal microparticulate carrier Longer duration of action Control of content release Increase of therapeutic efficiency Protection of drug. Reduction of toxicity Biocompatibility Relative stability Water solubility or dispersibility Bioresorbability Targeability 5

Slide 6:

Advantages Target specificity Prolonged release Drug targeting for pathogens Blood flow determination: Relatively large beads (10-15 μm in diameter) are useful for regional blood flow studies in tissues and organs. In most cases the beads are injected at desired locations in the circulatory system and eventually lodge in the capillaries. 6

Slide 7:

Controlled Drug Release Diffusion through a rate-controlling membrane or matrix, osmosis, ion exchange, and matrix degradation are all means of controlling drug release. Surface (heterogeneous) and bulk (homogeneous throughout) degradation are two different modes of biodegradation based on the site of polymer breakdown. In bulk polymer degradation, drug diffusion occurs prior to or concurrent with matrix degradation. In surface polymer degradation, drug release is determined by the relative contributions of drug diffusion and matrix degradation. Dual drug loaded beads. 7

Materials Used For Preparation of Beads :

Materials Used For Preparation of Beads Beads used usually are polymers. They are classified into two types: 1. Synthetic Polymers 2. Natural polymers 1 . Synthetic polymers are divided into two types. a. Non-biodegradable polymers: e.g . Poly methyl methacrylate (PMMA) , Acrolein , Glycidyl methacrylate Epoxy polymers. b. Biodegradable polymers: e.g . Lactides , Glycolides & their co-polymers ,Poly alkyl cyano acrylates Poly anhydrides 2 . Natural polymers obtained from different sources like proteins, carbohydrates and chemically modified carbohydrates. Proteins : Albumin, Gelatin, and Collagen Carbohydrates : Agarose , Carrageenan , Chitosan, Starch Chemically modified carbohydrates : Poly dextran, Poly starch. 8

Drug Loading and Drug Release Kinetics :

Drug Loading and Drug Release Kinetics The active components are loaded over the beads principally using two methods, i.e.. During the preparation of the beads or After the formation of the beads by incubating them with the drug/protein . 9 Fig: Drug release from microparticulate systems 9

Slide 10:

The drugs could be released through the beads by any of the three methods The osmotically driven burst mechanism. Pore diffusion mechanism. Erosion or the degradation of the polymer. The geometry of the carrier, i.e. whether it is reservoir type where the drug is present as core, or matrix type in which drug is dispersed throughout the carrier, governs overall release profile of the drug or active ingredients.

Methods of Preparation:

Methods of Preparation Preparation of beads should satisfy certain criteria: The ability to incorporate 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. Sustained release. Biocompatibility with a controllable biodegradability and Susceptibility to chemical modification. 11

Slide 12:

1.Single emulsion technique : The micro particulate carriers of natural polymers i.e. those of proteins and carbohydrates are prepared by single emulsion technique. 12

Slide 13:

2. Double emulsion technique : 13

Slide 14:

3. Polymerization techniques: Normal polymerization Interfacial polymerization Normal polymerization: Suspension polymerization also referred as bead or pearl polymerization. 14

Slide 15:

Interfacial Polymerization: It involves the reaction of various monomers at the interface between the two immiscible liquid phases to form a film of polymer that essentially envelops the dispersed phase. Two conditions arise depending upon the solubility of the formed polymer in the emulsion droplet. If the polymer is soluble in the droplet it will lead to the formation of the monolithic type of carrier If the polymer is insoluble in the monomer droplet, the formed carrier is of reservoir type . The interfacial polymerisation technique is not widely used because of certain drawbacks : Toxicity associated with unreacted monomer High permeation of the film High degradation of the drug during the polymerisation Fragility of microcapsules Non- biodegradibility of the microcapsules. 15

Slide 16:

4. 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. 16

Slide 17:

5. Coacervation and Phase separation technique: This process is based on the principle of decreasing the solubility of the polymer in organic phase to affect the formation of polymer rich phase called the coacervates . 17

Slide 18:

18

Slide 19:

6. Solvent extraction: Solvent evaporation method is used for the preparation of microparticles, involves removal of the organic phase by extraction of the organic solvent. The method involves water miscible organic solvents such as isopropanol. Organic phase is removed by extraction with water. 19

Types of Beads :

Types of Beads Albumin Beads Albumin microspheres being hydrophobic in nature are rapidly cleared from the body. Hydrophilic microspheres are considered to be good carriers because they carry large amount of drugs. If hydrophilicity of the microsphere increases they are advantageous in many ways because: They don’t require any surfactant . High concentration of drug can be incorporated after the preparation. The drug release from albumin microspheres depends upon the degree of cross linking. 20

Slide 21:

2. Alginate Beads These are prepared by ion- gelation method. If alginate with a higher proportion of D- mannuronic acid is chosen for production, a bead with a larger internal pore size is produced. As the concentration of alginate in the beads increases, so does their mechanical strength. The uncoated beads demonstrated faster drug release of drug in the medium of lower pH (i.e., 1.2) as compared to that in the medium of pH 6.8 and the release process was found to be diffusion controlled. 21

Slide 22:

3. Chitosan Beads Chitosan is a high molecular weight, polycationic polysaccharide derived from naturally occurring chitin by alkaline deacetylation Chemically, it is a poly ( N -glucosamine). The degree of swelling of a chitosan gel is controlled by both pH and ionic strength. Release of drug from chitosan microspheres is dependent upon the molecular weight of chitosan , concentration of chitosan , drug content and density of crosslinking . 22 Structure of Chitosan

Slide 23:

4. Casein–gelatin beads Casein-gelatin beads have been prepared by emulsification extraction method Casein emulsifying properties cause air bubble incorporation and the formation of large holes in the beads. The high porosity of the matrix influences the bead properties such as drug loading, drug release and floatation These cavities act as an air reservoir and enable beads to float. Therefore, casein seems to be a material suitable to the inexpensive formation of an air reservoir for floating systems. 23

Slide 24:

5. Dextran Beads Dextrans are a class of polysaccharides with a linear polymer backbone with mainly 1,6- α -D- glucopyranosidic linkages. The release from the hydrogel matrix is dependent upon the diffusion of the protein through the hydrogel matrix, if the protein diameter is smaller than the pore size of the matrix, it results in a typical first order release. However, when the protein diameter is larger than the pore diameter, the release tends to be dependent upon the degradation rate of the gel. The rate of degradation of dextran depends entirely upon the degree of substitution of dextran and the amount of dextranase enzyme incorporated. 24

Slide 25:

6. Starch Microspheres Calcium ions react with the hydroxyl groups on starch and the resultant cross-linking tightens the starch matrix. These microspheres are biocompatible and enzyme degradable. The starch microspheres when introduced into the body cavity undergo potential swelling , leading to the development of mucoadhesive character . Therefore, they are not cleared rapidly from the body. 25

Slide 26:

7. Cellulose Hydrogels The cellulose derivatives that are used in the pharmaceutical area are methylcellulose (MC), hydroxyl ethyl methyl cellulose (HEMC), hydroxyl propyl methyl cellulose (HPMC), ethyl hydroxyl ethyl cellulose (EHEC), hydroxyl ethyl cellulose (HEC), and hydroxyl propyl cellulose (HPC). The release of water-soluble drugs from crosslinked HPMC involves both diffusion and matrix dissolution. The factors that govern drug release are polymer type, its concentration, drug particle size, and type and concentration of different additives. 26

Slide 27:

8. Gellan Beads Gellan gum is composed of a linear structure of repeating tetra saccharide units of glucose, glucuronic acid, and rhamnose in a molar ratio of 2:1:1. Because of the presence of free carboxylate groups in gellan gum, it is anionic in nature and, consequently, exhibits the characteristic property of undergoing ionic gelation in the presence of mono- and divalent cations . Gellan gum is a useful carrier for the encapsulation of fragile drugs and provides new opportunities in the field of bioencapsulation . 27

Slide 28:

9. Guar Beads Guar gum derived from the seeds of Cyamopsis tetragonolobus is a naturally occuring galactomannan polysaccharide. Carboxymethyl guar gum (CMGG) has the ability to form microparticles for the gastrointestinal delivery of sensitive drugs such as proteins. 10. Polyanhydride microspheres Polyanhydrides are biodegradable and biocompatible polymers. They can be manufactured with desired features such as crystallinity , controlled degradation rate, degree of cross-linking, water uptake, etc. Polyanhydride microspheres can be prepared by solvent evaporation, solvent extraction, hot melt technique and spray drying techniques. 28

Slide 29:

11. Pectin Microspheres Pectin’s ability to form a gel by complexing with metal ions is dependent on both its molecular weight and degree of esterification . Low- methoxy pectin forms a gel matrix with Ca 2+ and can complex with chitosan These polysaccharides remain intact in the physiological environment of the stomach and the small intestine, but are degraded by the bacterial inhabitants of the human colon. 29

Slide 30:

12. Polyphosphazene Microspheres Polyphosphazene polymers have a long chain backbone of alternating nitrogen and phosphorous atom with two side group attached to each phosphorous atom. Polyphosphazene polymers form highly swellable ionotropic gels in presence of multivalent ions (such as Ca) in aqueous media. The microspheres (1-10 µm) are used to target Peyer’s Patch M cells and sub-epithelial macrophages. 30

Slide 31:

13. Floating Beads A variety of approaches to induce buoyancy in crosslinked beads exist, among them freeze drying, entrapment of gas, and use of entrapped oils. These approaches have several limitations , e.g., coalescence of oil droplets within the oil containing beads yielding beads of wider particle size distribution, volatilization, or leaching of the oil. Nevertheless, violent gas generation, disintegration of the dosage form, burst release, dose dumping, and alkaline microenvironment are limitations of these dosage forms. 31

Physicochemical Evaluation of Beads:

Physicochemical Evaluation of Beads Particle size and shape analysis Electron spectroscopy for chemical analysis (ESCA) Attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR) Density determination Isoelectric point Surface carboxylic acid residue(EDAC) Surface amino acid residue(EDAC) Capture efficiency Beaker method Dissolution studies In-vivo methods Animal models Buccal absorption test In-vitro In-vivo corelation 32

Applications of Beads:

Applications of Beads In vaccine delivery Targeting using microparticulate carriers Monoclonal antibody mediated targeting Chemoembolism Imaging For topical applications: porous beads As magnetic microspheres Surface modified beads to protect from phagocytic clearance. 33

Conclusion:

Conclusion In future by combining various other strategies, beads will find the central place in novel drug delivery, particularly in diseased cell sorting, diagnostics, gene & genetic materials, safe, targeted and effective in vivo delivery and supplements as miniature versions of diseased organ and tissues in the body. 34

References:

References Alagasundaram , M., et al, 2009, Microspheres as a novel drug delivery system,- a review, International Journal of ChemTech Research, 526-534. Benita. S. ,2006, Microencapsulation methods and industrial applications, Vol-158, 2 nd Edition, CRC Press, London Bulgarelli , E., Forni , F., and Bernabei , M. T. 2000. Effect of matrix composition and process conditions on casein-gelatin beads floating properties. Int. J. Pharm. 198:157–165. Gupta, P. K., and Hung, C. T. 1990. Albumin microspheres. Vs Evaluation of parameters controlling the efficacy of magnetic microspheres in the targeted delivery of adriamycin in rats. Int. J. Pharm. 59:57–67. Heller, J. 1980. Controlled release of biologically active compounds from bioerodible polymers. Biomaterials 1:51–57. Lee, V. H. L., and Mukkerjee , S. K. 2002. Drug delivery: oral colon-specific. In: Encyclopedia of Pharmaceutical Technology, vol. 1, 2nd ed , ed. J. Swarbrick , J. C. Boylan , pp. 871–885. New York: Marcel Dekker, Inc. Mehvar , R. 2000. Dextrans for targeted and sustained delivery of therapeutic and imaging agents. J. Contr. Rel. 69:1–25. Narisawa , S., Nagata, M., Ito, T., Yoshino, H., Hirakawa , Y., and Noda, K. 1995. Drug release behavior in gastrointestinal tract of beagle dogs from multiple unit type rate-controlled or time controlled release preparations coated with insoluble polymer-based film. J. Contr. Rel. 33: 253–260. 35

Slide 36:

Nussinovitch , A. 1997. Hydrocolloid Applications, Gum Technology in the Food and other Industries. London, UK: Blackie Academic & Professional. Onishi , H., Nagai, T., and Machida, Y. 1996. Application of chitin, chitosan , and their derivatives to drug carriers of microparticulated or conjugated drug delivery systems. In: Applications of Chitin and Chitosan, ed. M.F.A. Goosen , pp. 205–228. Boca Raton: CRC Press. Park, K., Shalaby , W. S. W., and Park, H. 1993. Biodegradable drug delivery systems. In: Biodegradable Hydrogels for Drug Delivery, pp. 189–232. Lancaster, Basel: Technomic Publishing Co., Inc. Shi, J., Alves , N. M., and Mano , J. F. 2007. Chitosan coated alginate beads containing poly( Nisopropylacrylamide ) for dual-stimuli-responsive drug release. J. Biomed. Mater. Res. B Appl. Biomater . 84:595–603. S.P. Vyas and R.K.Khar , Targeted and Controlled drug delivery, 07 th Edition, 418-457. Sinha , V.R., Kumria , R., 2001, Polysaccharides in colon specific drug delivery, International Journal of Pharmaceutics, 224: 19-38. Yonese , M. 2001. Sustained drug delivery by gels. In: Gels Handbook, vol. 3: Applications, ed. Y. Osada , K. Kajiwara , pp. 230–240. San Diego and San Francisco: Academic. Zhang, L., Guo , J., Peng , X., and Jin, Y. 2004. Preparation and release behaviour of carboxymethylated chitosan /alginate microspheres encapsulating bovine serum albumin. J. Appl. Polym. Sci. 92: 878–882. 36

Slide 37:

37 Thank you