Nanoparticle for drug delivery system

nanoparticle drug delivery system ideal chararcters advantages application preparation evaluation

1. NANOPARTICLES Sujitha Mary Second Semester M Pharm Pharmaceutics 1

2. Contents Introduction Ideal characteristics Advantages and disadvantages Application Preparation of nanoparticles Evaluation Conclusion References 2

3. Introduction The prefix “nano” comes from the Greek word nanus meaning very small. Nanoparticles are solid colloidal particles ranging 1 to 100 nm in size, they consist of micro-molecular materials in which the active ingredients are dissolved, entrapped, or encapsulated, or adsorbed, or attached. 3

4. Nanotechnology is defined as design, characterization, production and applications of structures, devices and systems by controlling shape and size at nanometers scale. Depending on the method of preparation nanoparticles, nanospheres , or nanocapsules can be constructed to possess different properties and release characteristics for the best delivery or encapsulation of the drug. 4

5. The advantage of using nanoparticles for drug delivery are a result of two main basic properties : Small size Use of biodegradable materials. NPs can extravasate through the endothelium in inflammatory sites, epithelium , tumors, or penetrate micro capillaries. The nanosize of these particles allows for efficient uptake by a variety of cell types and selective drug accumulation at target sites. The use of biodegradable materials allows for sustained drug release within the target site over a period of days or even weeks. 5

6. Particle size and size distribution are the most important characteristics of nanoparticles. They determine the in-vivo distribution, biological fate, toxicity, and targeting ability of these delivery systems. In addition, they can influence drug loading, drug release, and stability of nanoparticles . 6

7. Advantage of NPs over microparticles Generally NPs have relatively high cell uptake when compared to microparticles. NPs have a wider range of cellular and intercellular targets due to their small size and mobility. NPs can cross BBB and provide sustained delivery of therapeutic agents 7

8. Surface properties of nanoparticles The association of a drug to conventional carriers leads to modification of the drug bio-distribution profile, as it mainly delivered to the mononuclear phagocyte system (MPS) such as liver, spleen, lungs and bone marrow. NPs can be recognized by the host immune system when intravenously administered and cleared by phagocytes from the circulation. Apart from the size, nanoparticle hydrophobicity determines the level of blood components (e.g., opsonins ) that bind this surface . 8

9. Hence, hydrophobicity influences the in vivo fate of NPs. Indeed, once in a blood stream, surface non-modified NPs are rapidly opsonized and massively cleared by the MPS. To increase the likelihood of success in drug targeting, it is necessary to minimize the opsonization and prolong the circulation of NPs in vivo. This can be achieved by coating NPs with biodegradable copolymers with hydrophilic characteristics, eg., PEG, Tween 80, polyethylene oxide. 9

10. Advantages Nanoparticles are control and sustain release form at the site of localization. They enhance bioavailability, therapeutic efficacy. They reduce side effects. Nanoparticles can be administered by various routes including oral, nasal, parenteral, intra-ocular etc. Nanoparticles shows better drug delivery as compare to other dosage forms and target to a particular cell type or receptor. 10

11. Due to the small particle size nanoparticles overcome resistance by physiological barriers in the body and easily penetrates to cell walls, blood vessels, stomach, epithelium and blood-brain barrier. They enhance the aqueous solubility of poorly soluble drug. Faster, smaller and highly sensitive diagnostic tool. Enhanced stability of ingredients Prolonged shelf life 11

12. Disadvantages High cost Productivity more difficult Reduced ability to adjust the dose Highly sophisticated technology Requires skills to manufacture Difficult to maintain stability of dosage form. E.g .: Resealed erythrocytes stored at 40C. 12

13. Ideal Characteristics It should be biochemical inert , non toxic and non-immunogenic . It should be stable both physically and chemically in in-vivo & in-vitro conditions. Restrict drug distribution to non-target cells or tissues or organs & should have uniform distribution. Controllable & Predictable rate of drug release . Drug release should not effect drug action 13

14. The preparation of the delivery system should be easy or reasonable Simple , reproducible & cost effective Carriers used must be biodegradable or readily eliminated from the body without any problem and no carrier induced modulation in disease state. 14

15. Applications Widely used in case of Cancer Therapy. In intracellular Targeting. Used for Prolonged Systemic Circulation. As a Vaccine Adjuvant. In Case of Ocular delivery. Used in DNA Delivery . It is used in case of Oligonucleotide delivery . Enzyme immunoassays. Radio-imaging and DNA sequencing 15

16. Nanotechnology based drug delivery in cancer HYDROGELS They are based on proprietary technology that uses hydrophobic polysaccharides for encapsulation and delivery of drug, therapeutic protein, or vaccine antigens. MICELLES AND LIPOSOMES Block-copolymer micelles are spherical super-molecular assemblies of amphiphilic copolymer. The core of micelles can accommodate hydrophobic drugs, and the shell is a hydrophilic brush-like corona that makes the micelle water soluble, thereby allowing delivery of the poorly soluble contents. 16

17. NANOSYSTEMS Novel nanosystems can be pre-programmed to alter their structure and properties during the drug delivery process , allowing for more effective extra and intra cellular delivery of encapsulated drug. This can be achieved by incorporation of molecular sensors that respond to physical or biological stimuli, including changes in ph, redox potential, or enzymes . 17

18. METAL BASED SYSTEMS The characteristic shine that is common with gold NPs and the ease of localization and visibility makes them a great tool for future research, both diagnostically and preventatively, in cancer therapy and treatment. Platinum based NPs have demonstrated increased efficacy of chemotherapeutic agents in the treatment of a variety of breast and ovarian cancer cell lines. The magnetic properties and biocompatibility of super paramagnetic iron oxide nanoparticles has facilitated their emergence into the field of biomedicine as a promising agent in medical therapeutics and diagnostic . 18

19. CARBON NANOTUBES CNTs consist of a hexagonal arrangement of carbon atoms consisting of one or more walls of graphene sheets. Drug formulations utilizing CNTs presented with increased total circulation time, sustained release and enhanced cytotoxicity of anticancer drugs. When coupled with their larger surface area and subsequent high loading capacity, these properties make them ideal candidates for new approaches to drug delivery. 19

20. QUANTUM DOTS QDs are described as basic semiconductors that exude electrical characteristics with a particle size distribution between 2 and 10nm. QDs in tissue specific targeting of tumor cells by tethering prostate specific antigen to QDs. PROTEIN BASED NANOPARTICLES These have been developed to aid the delivery of certain drugs to specific, localized compartments. Abraxane is an albumin-bound NP containing the chemotherapeutic agent paclitaxel which was approved by the FDA for use in relapsed and metastatic breast cancer. 20

21. Preparation of nanoparticles Solvent evaporation Double emulsification method Emulsions – diffusion method Nanoprecipitation method Coacervation method Salting out method Supercritical fluid technology 21

22. Solvent evaporation method In this method firstly nano -emulsion formulation was prepared. Polymer is dissolved in organic solvent. Drug is dispersed in solution. This mixture is emulsified in an aqueous phase containing surfactant and oil-in-water emulsion is made by using mechanical stirring, sonication, or micro fluidization. 22

23. After formation of emulsion the organic solvent is evaporated in a condition of increased temperature and reduced pressure with continuous stirring. 23

24. Double emulsification method Emulsification and evaporation method have limitation of poor entrapment of hydrophilic drugs. Firstly w/o emulsion is prepared by addition of aqueous drug solution to organic polymer solution with continuous stirring. To this prepared emulsion another aqueous phase is added with vigorous stirring, resulting in w/o/w emulsion. Then the organic solvent is removed by centrifugation. 24

25. BSA – bovine serum albumin PLA – poly lactic acid PVA – poly vinyl alcohol 25 centrifugation

26. Emulsion diffusion method Selection of an organic phase (oil phase) containing polymer solution which must be partially miscible in aqueous phase. The most important step is solvent diffusion, in which the organic phase diffuses from the oil phase to outer water phase and the formed particles become hardened. Polymer is dissolved in water miscible solvent (propyl carbonate, benzyl alcohol), this solution is saturated with water. 26

27. Polymer-water saturated solvent phase is emulsified in an aqueous solution containing a stabilizer. The solvent is removed by evaporation or filtration 27

28. Salting out method Firstly the polymer is dissolved into the organic solutions (oil phase) which are usually water miscible. Commonly used solvents are tetrahydrofuran and acetone. The aqueous phase consist of surfactants and saturated solution of electrolyte. The electrolytes should not be soluble in the organic solvent. The most commonly used salts are magnesium chloride hexahydrate or magnesium acetate tetrahydrate in a ratio of 1:3 (polymer to salt). 28

29. The oil phase is emulsified in an aqueous phase under strong shearing force by overhead mechanical stirrer. In order to decrease the ionic strength in the electrolyte, the distilled water is added into the formed o/w emulsion under magnetic stirrer. At the same time, the hydrophilic organic solvents migrate from the oil phase to aqueous phase which results in the formation of nanoparticles. 29

30. There is no solvent diffusion step in salting out method due to the existence of salts. 30

31. Nanoprecipitation method It is also called solvent displacement or interfacial deposition method. Nanoparticles are obtained in the colloidal suspension when the oil phase is slowly added to aqueous phase under moderate stirring Formation of nanoparticle is instantaneous and needs only one step so advantage of rapid and easy operation. The key parameters in the fabrication procedure are : Organic phase injection rate Aqueous phase agitation rate Oil phase/aqueous phase ratio 31

32. Particle size of narrow distribution can be synthesized due to absence of shearing stress. Mostly used for hydrophobic drug entrapment. Polymer and drug are dissolved in water miscible organic solvent (acetone or methanol). The solution is then added into an aqueous solution which contains surfactant in a drop-wise manner. Through rapid solvent diffusion, the NPs are formed immediately. Solvents are removed under reduced pressure. 32

33. 33

34. Coacervation method By using biodegradable hydrophilic polymers (chitosan, gelatin, sodium alginate) nanoparticles are prepared by coacervation method. First phase contain polymer like chitosan and the second phase contain polyanion sodium tripolyphosphate. Nanoparticles are formed based on the formation of complexation between positively charged amine group of chitosan and negatively charged polyanion such as TPP. Cationic solution of BSA-loaded chitosan was previously obtained by dissolving in diluted acetic acid, and anionic solution of TPP was obtained by dissolving it in distilled water. 34

35. TPP solution was added drop wise into the cationic solution of chitosan . NPs were formed instantly under mechanical stirring at room temperature. 35

36. Super critical fluid technology It is an alternative method because in this method organic solvents. Supercritical CO 2 is the most widely used supercritical fluid because of its mild condition, non toxicity, non-inflammability, and low price. Mainly supercritical fluid used in two main techniques: Supercritical anti-solvent (SAS) Rapid expansion of critical solution (RESS). In SAS process liquid solvents are used, which should completely miscible with the supercritical fluid. The extract of the liquid solvent by supercritical fluid leads to the instantaneous precipitation of the solute, resulting in nanoparticles. 36

37. In RESS high degree of super saturation occur by dissolving solute in a supercritical fluid to form a solution. It is followed by rapid expansion of the solution across an orifice or a capillary nozzle into ambient air. By the rapid pressure reduction in the expansion which results in homogenous nucleation and thereby, the formation of well-dispersed particles . 37

38. EVALUATION OF NANOPARTICLES 38

39. Particle size DYNAMIC LIGHT SCATTERING (DLS) The fastest and most popular method. Also known as photon correlation spectroscopy. 39

40. SCANNING ELECTRON MICROSCOPY SEM is giving morphological examination with direct visualization. They provide limited information about the size distribution 40

41. TRANSMISSION ELECTRON MICROSCOPY . TEM operates on different principle than SEM, yet it often brings same type of data. The sample preparation for TEM is complex and time consuming because of its requirement to be ultra thin for the electron transmittance. 41

42. ATOMIC FORCE SPECTROSCOPY AFM offers ultra-high resolution in particle size measurement and is based on a physical scanning of samples at sub-micron level using a probe tip of atomic scale. 42

43. Yield of nanoparticles The yield of nanoparticles was determined by comparing the whole weight of nanoparticles formed against the combined weight of copolymer and drug. 43  

44. Particle size and zeta potential Value of particle size and zeta potential of prepared nanoparticles were determined by using zetasizer. Samples were prepared by diluting with distilled water. Zeta potential was determined by measuring the electrophoretic mobility of NPs. Surface morphology Surface morphology study was carried using scanning electron microscope (SEM) of prepared nanoparticles. 44

45. Drug-excipient compatibility studies It was performed by using FT-IR spectrophotometer. The FT-IR spectra of drug, polymers, and formulations were analyzed separately and then correlated for incompatibility . Surface hydrophobicity Surface hydrophobicity can be determined by several techniques such as hydrophobic interaction, chromatography, biphasic partitioning, adsorption of probes, contact angle measurements etc . 45

46. DRUG ENTRAPMENT EFFICIENCY   Drug entrapment percentage = mass of drug in nanoparticle ×100 Mass of drug used in formulation SURFACE CHARGE AND ELECTRON MOBILITY   Surface charge of particle can be determined by measuring particle velocity in electrical field. Laser Doppler Anemometry tech. for determination of Nanoparticles velocities. Surface charge is also measured as electrical mobility. Charged composition critically decides bio-distribution of nanoparticle   46

47. Conclusion Nanoparticle formulations offer a highly feasible alternative in the realm of new drug development. The use of NPs in new formulation offers a promising alternative to side effect, risk reduction and overall patient safety and quality of life. Furthermore, it is important to understand the fate of the drugs once delivered to the nucleus and other sensitive cell organelles . 47

48. References Renu Tiwara. A review on nanoparticles – preparation and evaluation parameters. Indian J. Pharm. Biol. Res.2015; 4(2): 27-31. Wang. Y, Puwang Li, Tran. T. Manufacturing techniques and surface engineering of polymer based nanoparticles for targeted drug delivery to cancer. Nanomaterials 2016;6(26): 2-7. J. C. Rather, S. Tamizhrasi, A. Shukla, T. Shivkumar. Formulation and evaluation of lamivudine loaded polyacrylic acid nanoparticles. Int.J.PharmTech Res.2009;1(3): 411-415. 48