Nanoparticle Drug Delivery Systems PDF

PHARM 131: LOREM IPSUM NANOPARTICLE DRUG DELIVERY SYSTEM Czarina Dominique R. Rodrguez, RPh M Eng | Reviewed: 12/12/24 | Last Edited: 12/12/24 OUTLINE NANOMATERIALS MEDICAL APPLICATION NANOPARTICLE MANUFACTURING TYPES LIPOSOMES POLYMERIC NANOPARTICLES...

PHARM 131: LOREM IPSUM NANOPARTICLE DRUG DELIVERY SYSTEM Czarina Dominique R. Rodrguez, RPh M Eng | Reviewed: 12/12/24 | Last Edited: 12/12/24 OUTLINE NANOMATERIALS MEDICAL APPLICATION NANOPARTICLE MANUFACTURING TYPES LIPOSOMES POLYMERIC NANOPARTICLES NANOPRECIPITATION Figure 2. Mechanism of Action of Nanoparticles EMULSION DIFFUSION OR SOLVENT EVAPORATION ​ ‘Active Targeting’ or ‘smart targeting’ is also possible for SALTING-OUT METHOD nanoparticles SOLID LIPID NANOPARTICLES ○​ Attachment of PEG to doxorubicin can self-assemble into micelles under the presence of curcumin HIGH-PRESSURE HOMOGENIZATION (pH-sensitive) CHALLENGES IN NANOPARTICLE MANUFACTURING ​ Other mechanisms employ temperature QUALITY BY DESIGN dependence QUALITY CONTROL ○​ Since the pH of tumor cells is lower, easily absorbed in tumors where it will be broken down NANOMATERIALS ​ Organic or inorganic structures with size ranging from 1-100 nanometers ○​ Can vary and is still considered as nanoparticle if within 100 nm to less than 1 micrometer; but in medical application, usually within the range ​ Promising application in the delivery of drugs, such as anticancer drugs ○​ Encapsulation or Matrix-type ​ Key issue ○​ Different to scale up to manufacture ​ Misconception: All nanoparticles are spheres. Not True ​ Disadvantage of Inorganic Nanoparticles: Figure 3. Mechanism of Smart Targeting (Zhang et al., 2024) ○​ Poor biodegradability in the body that might lead to toxic accumulation NANOPARTICLE MANUFACTURING ○​ Lower drug loading efficiency ​ Top-Down Approach ○​ Starts with a bulk material and then breaks it into smaller pieces using mechanical, chemical, or other forms of energy ○​ Disadvantage: More labor and time intensive (Application mostly in tech and microchip industry) ​ Bottom-Up Approach (Usual method) Figure 1. Types of Nanomaterial ○​ Production of nanomaterials from atomic or molecular species via chemical reactions or MEDICAL APPLICATION physicochemical interactions such as self-assembly ​ Leaky blood vessels in the tumor can accommodate the small size of nanoparticles without permeating to the TYPES nearby healthy cells LIPOSOMES ○​ Leads to enhanced permeation-retention (EPR) effect ​ Lipid vehicles ​ Phospholipids that self-assemble into bilayers, with lipid chains inside and polar groups outside ○​ Similar principle with surfactants and micelle formation ​ Has good biocompatibility and spontaneous self-assembly DATOON​ 1  ○​ Phase Ratio ○​ Stirring Rate ○​ Temperature ○​ Flow of Water SALTING-OUT METHOD ​ Polymer dissolved in water-miscible organic solvents, then emulsified with aqueous phase containing emulsifier and high salt concentration (1:3 polymer to salt ratio). Fast addition allows migration of organic phase to aqueous phase, inducing nanoparticle formation ​ Advantage against emulsion diffusion: Less emulsifier quantity ​ Parameters that affect size Figure 4. Formation of Liposomes ○​ Polymer concentration ○​ Molecular weight ​ Manufacturing Method through Ethanol Injection Method ○​ Stirring rate 1.​ Dissolution of lipid components in ethanol ○​ Time 2.​ Rapid injection of ethanol solution into agitated ○​ Nature and concentration of surfactant aqueous media, with tip under the surface ○​ Solvent 3.​ Removal of ethanol ○​ Liposome is formed here SOLID LIPID NANOPARTICLES 4.​ Concentration by evaporating water ​ Major component: Solid lipids such as glycerides of 5.​ Sterilization (autoclave) various fatty acids 6.​ Lyophilization (when needed; for stability) ​ Commonly implemented for hydrophobic drugs 7.​ Purification ​ Methods of production ○​ High-pressure homogenization POLYMERIC NANOPARTICLES ○​ Solvent emulsification/evaporation method ​ Synthetic polymers: ○​ Poly(lactic) acids (PLA) HIGH-PRESSURE HOMOGENIZATION ○​ Poly(lactideco-glycolide) (PLGA) ​ Two separate techniques, but all start by melting the lipid ○​ Poly(epsilon-caprolactone) (PCL) and dissolving/dispersing the drug in the lipid ​ Natural polymers: ​ Hot homogenization technique ○​ Albumin 1.​ Disperse drug-loaded lipid in hot surfactant aqueous ○​ Gelatin solution ○​ Alginate 2.​ Mix thoroughly using stirrer to form coarse ○​ Chitosan pre-emulsions ○​ Starch 3.​ High pressure homogenization at temperature above ​ Manufacturing methods: melting point of lipid to form o/w nanoemulsions ○​ Nanoprecipitation 4.​ Solidification of nanoemulsions by cooling down to ○​ Emulsion diffusion or solvent evaporation room temperature ○​ Salting-out method ​ Cold homogenization technique 1.​ Solidification of drug-loaded lipid in liquid nitrogen or NANOPRECIPITATION dry ice ​ Polymer and drug dissolved in appropriate organic 2.​ Grind in powder mill (to achieve 50 to 100 solvent, and then a non-solvent (solvent where API is micrometer) insoluble) is added to precipitate out the polymer and 3.​ Disperse powder in surfactant aqueous solution rind drugs in powder mill (to achieve 50 to 100 micrometers) ​ Size may vary according to the type and amount of 4.​ High pressure homogenization at room temperature polymer and amount of non-solvent added. Particles are or below then centrifuged and freeze-dried when needed CHALLENGES IN NANOPARTICLE MANUFACTURING EMULSION DIFFUSION OR SOLVENT EVAPORATION ​ Physicochemical Characterization ​ Polymer and hydrophobic drugs are dissolved in ○​ Not yet established what type of nanoparticle or partially-water miscible organic solvent, then organic process of manufacture to use phase is emulsified with aqueous medium with suitable ​ Biocompatibility & Nanotoxicology surfactant. Organic phase then diffuses out of the ​ Pharmacokinetics & Pharmacodynamics emulsion droplet and water diffuses in. Organic solvent is ○​ Still being studied then evaporated ​ Process Control & Scale-up Reproducibility ​ Parameters to control size ○​ Process controls in laboratory is very difficult to ○​ Polymer nature reproduce in manufacturing scale ○​ Polymer concentration ​ Difficult due to their unique properties ○​ Solvent nature ○​ Large surface area leads to high surface energy ○​ Surfactant Molecular Mass meaning that it is prone to agglomeration ○​ Viscosity DATOON​ 2 ​ Requires highly advanced tools/equipment and carefully ​ Drug loading and encapsulation efficiency clean environments (given that most are parenteral) ​ Drug release ○​ This is to control particle size, shape, size ​ Stability distribution, particle composition, and degree of agglomeration ​ For clinical applications, the nanomaterial should always have good biocompatibility or biodegradability QUALITY BY DESIGN ​ A pharmaceutical development approach used in the systematic evaluation and control of nanomedicines ​ Identification of Critical Quality Attributes (CQA) and relate it with relevant formulation and process parameters ○​ CQA: Drug parameters that manufacturer believes will significantly impact the product Figure 5. Risk Overview of Nanomedicines ​ Abbreviations in diagram: ○​ QTPP: Quality Target Product Parameters ○​ CQAs: Critical Quality Attributes ○​ CMAs: Critical Material Attributes (Raw Materials) ○​ CPPs: Critical Process Parameters Figure 6. Diagram of QbD Process QUALITY CONTROL ​ Particle size and size distribution/polydispersity; measured through: ○​ Dynamic light scattering (hydrodynamic diameter) ○​ Microscopy: Scanning Electron Microscope (SEM) or Transmission Electron Microscopy (TEM) ​ Surface charge and zeta potential ○​ Stability metrics (if neutral charge, more likely to agglomerate) DATOON​ 3