3 Drug Formulations
3.11 Nanotechnology-Based Drug Delivery
3.11.2 Liposomes
Liposomes are stable microscopic vesicles formed by phospholipids and similar amphipathic lipids. Liposome properties vary substantially with lipid composition, size, surface charge, and the method of preparation. They are therefore divided into three classes based on their size and number of bilayers.
1. Small unilamellar vesicles are surrounded by a single lipid layer and are 25–50 nm in diameter.
2. Large unilamellar vesicles are a heterogeneous group of vesicles similar to small unilamellar vesicles and are surrounded by a single lipid layer.
3. Multilamellar vesicles consist of several lipid layers separated from each other by a layer of aqueous solution.
Lipid bilayers of liposomes are similar in structure to those found in living cell membranes and can carry lipophilic substances such as drugs within these layers in the same way as cell membranes. The pharmaceutical properties of the liposomes depend on the composition of the lipid bilayer and its permeability and fluidity.
Cholesterol, an important constituent of many cell membranes, is frequently included in liposome formulations because it reduces the permeability and increases the stability of the phospholipid bilayers.
Until recently, the use of liposomes as therapeutic vectors was hampered by their toxicity and lack of knowledge about their biochemical behavior. The simplest use of liposomes is as vehicles for drugs and antibodies targeted for the targeted deliv- ery of anticancer agents. The use of liposomes may be limited because of problems related to stability, the inability to deliver to the right site, and the inability to release the drug when it gets to the right site. However, liposome surfaces can be readily modified by attaching polyethylene glycol (PEG) units to the bilayer (producing what is known as stealth liposomes) to enhance their circulation time in the blood- stream. Furthermore, liposomes can be conjugated to antibodies or ligands to enhance target-specific drug therapy.
Polymer Nanoparticles
Biodegradable polymer nanoparticles are PEG-coated poly(lactic acid) (PLA) nanoparticles, chitosan (CS)-coated poly(lactic acid–glycolic acid) (PLGA) nano- particles, and chitosan (CS) nanoparticles. These nanoparticles can carry and
Table 1.9Nanomaterials and nanobiotechnologies used for drug delivery StructureSizeRole in drug delivery Bacteriophage NK97 (a virus that attacks bacteria)Emptied of its own genetic material, HK97, which is covered by 72 interlocking protein rings, can act as a nanocontainer to carry drugs and chemicals to targeted locations Canine parvovirus (CPV) particles26 nmTumor-targeted drug delivery: CPV binds to transferrin receptors, which are overexpressed by a variety of tumor cells Carbon magnetic nanoparticles40–50 nmFor drug delivery and targeted cell destruction Dendrimers1–20 nmHolding therapeutic substances such as DNA in their cavities Ceramic nanoparticles~ 35 nmAccumulate exclusively in the tumor tissue and allow the drug to act as sensitizer for PDT without being released HTCC nanoparticles110–180 nmEncapsulation efficiency is up to 90%. In vitro release studies show a burst, effect followed by a slow and continuous release Liposomes25–50 nmIncorporate fullerenes to deliver drugs that are not water-soluble, that tend to have large molecules Micelle/Nanopill25–200 nmMade from 2 polymer molecules – one water-repellant and the other hydrophobic – that self-assemble into a sphere called a micelle, which can deliver drugs to specific structures in the cell Low-density lipoproteins20–25 nmDrugs solubilized in the lipid core or attached to the surface NanocochleatesNanocochleates facilitate delivery of biologicals such as DNA and genes Nanocrystals<1,000 nmNanoCrystal technology (Elan) has the potential to rescue a significant number of poorly soluble chemical compounds by increasing solubility Nanoemulsions20–25 nmDrugs in oil and/or liquid phases to improve absorption
Nanolipispheres25–50 nmCarrier incorporation of lipophilic and hydrophilic drugs Nanoparticle composites~ 40 nmAttached to guiding molecules such as MAbs for targeted drug delivery Nanoparticles25–200 nmContinuous matrices containing dispersed or dissolved drug Nanospheres50–500 nmHollow ceramic nanospheres created by ultrasound Nanostructured organogels50 nmMade by mixing olive oil, liquid solvents, and a simple enzyme to chemically activate a sugar and used to encapsulate drugs Nanotubes20–60 nmOffer some advantages over spherical nanoparticles Nanovalve500 nmExternally controlled release of drug into a cell Nanovesicles25–3,000 nmMultilamellar bilayer spheres containing the drugs in lipids Polymer nanocapsules50–200 nmEnclosing drugs PEG-coated PLA nanoparticlesPEG coating improves the stability of PLA nanoparticles in the gastrointestinal fluids and helps the transport of encapsulated protein across the intestinal and nasal mucus membranes Superparamagnetic iron oxide nanoparticles10–100 nmAs drug carriers for intravenous injection to evade RES of the body as well as penetrate the very small capillaries within the body tissues and therefore offer the most effective distribution PDT photodynamic therapy, MAbs monoclonal antibodies, PEG poly(ethylene glycol), PLA poly(lactic acid), HTCC N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride, RES reticuloendothelial system
deliver proteins in an active form, and transport them across the nasal and intestinal mucosa. Additionally, PEG-coating improves the stability of PLA nanoparticles in the gastrointestinal fluids and helps the transport of the encapsulated protein, teta- nus toxoid, across the intestinal and nasal mucous membranes [14]. Furthermore, intranasal administration of these nanoparticles provided high and long-lasting immune responses.
N-(2-Hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) is a water-soluble derivative of chitosan (CS), synthesized by the reaction between glycidyl-trimethyl-ammonium chloride and CS. HTCC nanoparticles have been formed based on ionic gelation process of HTCC and sodium tripolyphos- phate (TPP). Bovine serum albumin (BSA), as a model protein drug, was incorpo- rated into the HTCC nanoparticles. HTCC nanoparticles were 110–180 nm in size, and their encapsulation efficiency was up to 90%. In vitro release stud- ies showed a burst effect, followed by a slow and continuous release.
Encapsulation efficiency was obviously increased with increase in initial BSA concentration [15].
Coating of PLGA nanoparticles with the mucoadhesive CS improves the stabil- ity of the particles in the presence of lysozyme and enhanced the nasal transport of the encapsulated tetanus toxoid. Nanoparticles made solely of CS are stable upon incubation with lysozyme. Moreover, these particles are very efficient in improving the nasal absorption of insulin as well as the local and systemic immune responses to tetanus toxoid, following intranasal administration.
Polymeric Micelles
Micelles are biocompatible nanoparticles varying in size from 50 to 200 nm in which poorly soluble drugs can be encapsulated. They represent a possible solu- tion to the delivery problems associated with such compounds and could be exploited to target the drugs to particular sites in the body, potentially alleviating toxicity problems. pH-sensitive drug delivery systems can be engineered to release their contents or change their physicochemical properties in response to variations in the acidity of the surroundings. One example of this is the prepara- tion and characterization of novel polymeric micelles (PM) composed of amphiphilic pH-responsive poly(N-isopropylacrylamide) (PNIPAM) or poly(alky l(meth)acrylate) derivatives [16]. On one hand, acidification of the PNIPAM copolymers induces a coil-to-globule transition that can be exploited to destabi- lize the intracellular vesicle membranes. PNIPAM-based PMs, loaded with either doxorubicin or aluminum chloride phthalocyanine, are cytotoxic in murine tumor models. On the other hand, poly(alkyl(meth)acrylate) copolymers can be designed to interact with either hydrophobic drugs or polyions and release their cargo upon an increase in pH. Micelle-forming polymeric drugs such as NK911 (doxoru- bicin-incorporating micelle) and NK105 (taxol-incorporating micelle) are in clinical trials sponsored by Nippon Kayaku Co. and conducted at the National Cancer Center Hospital, Tokyo, Japan [17].