Nanobiotechnol (2009) 5:17–33 DOI 10.1007/s12030-009-9028-2
Nanotechnology-Based Drug Delivery Systems R. Ravichandran
Published online: 1 October 2009 # Humana Press Inc. 2009
Abstract In recent years, there has been a considerable interest in the development of novel drug delivery systems using nanotechnology. Nanoparticles represent a promising drug delivery system of controlled and targeted release. In this context, nanosuspensions will be effective in increasing the solubility and bioavailability of poorly soluble drugs. This review focuses on advantages, method of preparation, physical characteristics, and evaluation of drug nanosuspensions.
toxicity and side effect profiles, all of which must be dealt with simultaneously in order for the candidate to become a successful therapeutic [4]. Formulation scientists have always struggled to overcome these problems but with the advent of nanotechnology the conventional challenges can now be looked upon as new opportunities [5].
Keywords nanotechnology . nanoparticles . nanosuspensions . drug delivery
Nanotechnology, a multidisciplinary scientific undertaking, involves creation and utilization of materials, devices, or systems on the nanometer scale. The field of nanotechnology is currently undergoing explosive development on many fronts [6]. Nanotechnology deals with phenomena whose physics or chemistry differs from that of bulk materials of the same composition. Extending this interpretation, nanoparticles are particles in which the small size influences the intrinsic properties or behavior of the particle. Properties of interest may be surface properties, quantum mechanical properties, chemical or biological reactivity, etc. [7]. The term “nanoparticles” varies greatly based on the specific definition that is used. Nanotechnologists define nanoparticles as particles having dimensions of 1–100 nm. Interestingly, much of what we know about the bulk properties of materials breaks down at these scales. For example, nanomaterials such as carbon nanotubes and gold nanoparticles have physical properties that are different from their bulk counterparts [8]. Therefore, such technologies generate new opportunities and applications. Advances in nanotechnology and nanomedicine have heralded the advent of several innovative nanomaterials, which are set to revolutionize the field of drug delivery [9]. Excellent progress has been made in harnessing the potential of carbon nanotubes for several drug delivery and other applications [8]. In case of drug
Introduction Rapid advances in proteomics and genomics coupled with rational drug design and rapid screening techniques have led to revolution in the drug discovery process resulting in introduction of large number of novel therapeutics at proliferate rate [1]. However, the use of these novel therapeutics in medicine is frequently opposed by the lack of efficiency in delivery of these therapeutic agents to the target organs [2]. Consequently, in the last decade, there has been a great focus on the development of drug delivery systems for the treatment of diseases [3]. In very simple terms, drug delivery can be defined as the process of releasing a carried bioactive agent at a specific site, at a specific rate. The drug candidates often present a multiplicity of delivery challenges, including issues of solubility, in vivo stability, poor pharmacokinetics, and undesirable R. Ravichandran (*) Regional Institute of Education (NCERT), Bhopal 462 013, India e-mail:
[email protected]
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delivery, the properties that hold premier interest are surface properties (i.e., particle size, surface area, surface free energy, and surface-to-volume ratio) and biological reactivity (circumventing opsonization). These properties can be modulated at submicron size ranges, and there is no stringent requirement to hold on to the sizes of below 100 nm. Formulators, however, have their own way of defining nanoparticles, where the boundaries of size ranges dissolves away and anything submicron is considered to be a part of nanotechnology. To overcome the problems of gene and drug delivery, nanotechnology has gained interest in recent years. Nanosystems with different compositions and biological properties have been extensively investigated for drug and gene delivery applications [7]. Several anticancer drugs, including paclitaxel, doxorubicin, 5-fluorouracil, and dexamethasone, have been successfully formulated using nanomaterials [10]. Quantum dots, chitosan, polylactic/ glycolic acid (PLGA), and PLGA-based nanoparticles have also been used for in vitro RNAi delivery. Brain cancer is one of the most difficult malignancies to detect and treat mainly because of the difficulty in getting imaging and therapeutic agents past the blood–brain barrier and into the brain. Anticancer drugs such as loperamide and doxorubicin bound to nanomaterials have been shown to cross the intact blood–brain barrier and released at therapeutic concentrations in the brain. The use of nanomaterials, including peptide-based nanotubes to target the vascular endothelial growth factor receptor and cell adhesion molecules like integrins, cadherins, and selectins, is a new approach to control disease progression. Nanotechnology Properties in Drug Design In the following section, some of the fundamentals on which nanotechnology-based drug delivery systems are designed is given. Particle Size, Surface-to-Volume Ratio, Surface Area, and Surface Free Energy Around 40% of drugs developed today are poor candidates for drug delivery formulations owing to their limited water solubility. Nanosizing drug or formulating drug as a nanoparticulate system results in better dissolution and solubilization of drug. The “topdown” technique used for fabricating nanostructured materials results in increasing the effective surface area (surface area available for medium interaction) and imparting high free surface energy to the particles which in turn helps in entropically driven effective solubilization. Nanoparticles act as a carrier for drug delivery with number of drug molecules encapsulated in a single nanoparticle. Moreover, the enhanced surface-to-volume ratio further allows effective attachment of targeting moieties onto the surface of nanoparticles. Thus, the
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drug molecules are safely carried to the target site without undergoing any chemical modifications. The research on the surface parameters of nanosuspensions is very important, especially for the nanosuspensions to be administrated intravenously. Particle Size and Biological System Living organisms are built of cells that are typically 10 μm across. However, the cell parts are much smaller and are in the submicron size domain. Even smaller are the proteins with a typical size of just 5 nm, which is comparable with the dimensions of smallest manmade nanoparticles. This simple size comparison gives an idea of using nanoparticles as an effective tool in delivering drug to the target sites [11]. In fact, nanoparticles are the only colloids that can be given intravenous (i.v. route) because they do not settle or aggregate in the blood and thus cause no embolism. The smaller size also ensures easy and effective penetration not only through the biological membrane but also through the cellular pores achieving greater transfection and enabling manipulation at molecular level. Biological Reactivity The trek of a “therapeutic” from the point of administration to the intended target is full of perils, biological barriers might arise in form of tight junctions between epithelial cells, immunological hurdles are created by opsonization mediated by macrophages of reticulo endothelial system (RES), and biophysical obstacles include the charge-related agglomeration and biodistribution. Nanotechnology-based systems present themselves as well-equipped delivery agents by overcoming various barriers and other related hurdles by the virtue of their modified properties [12]. The small particle size and uniform particle distribution helps nanoparticles to overcome the biological barriers by effective and efficient transfer across biological membranes and tight junctions. Nanoparticles can be sized down below the cut-off range for easy penetration across the barriers, and because of the hydrophobicity of the particles, their journey across the membranes is not that difficult as the membranes themselves are made up of lipophilic moieties. Opsonization Opsonization, which is thought to be the greatest threat to any injectable xenobiotics, leads to engulfment of foreign particles injected into the blood stream by specific macrophages cells of RES, resulting in removal of therapeutics from the circulation and ultimately decreasing efficacy and potency of the therapy. The entire process of opsonization depends on the interaction of opsonin (endogenous proteins) with the foreign object; this interaction in turn depends on the surface physiochemical properties, i.e., size, shape, charge, density, and surface hydrophobicity. All of these can be modulated based on the techniques used for fabrication and postfabrication modifi-
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cation of nanostructured particles for, e.g., PEGylation, which includes hydrophilic coating of poly ethylene glycol on nanoparticle surface. Other non-covalent approaches include layer by layer deposition of ionic polymers, such as quantum dots. Layer by layer methods alter the surface charge of nanoparticles resulting in prevention of particle agglomeration and regulated nanoparticle biodistribution. The Pharma Industries The most promising aspect of pharmaceuticals and medicine as it relates to nanotechnology is currently drug delivery [13]. In the words of LaVan and Langer: “It is likely that the pharmaceutical industry will transition from a paradigm of drug discovery by screening compounds to the purposeful engineering of targeted molecules.” At present, there are 30 main drug delivery products on the market. The total annual income for all of these is approximately US$33 billion with an annual growth of 15% (based on global product revenue). Two major drivers are primarily responsible for this increase in the market [13]. First, present advances in diagnostic technology appear to be outpacing advances in new therapeutic agents. Highly detailed information from a patient is becoming available, thus promoting much more specific use of pharmaceuticals. Second, the acceptance of new drug formulations is expensive and slow, taking up to 15 years to obtain accreditation of new drug formulas with no guarantee of success. In response, some companies are trying to hurry the long clinical phase required in Western medicine. However, powerful incentives remain to investigate new techniques that can more effectively deliver or target existing drugs [14]. In addition, many of these new tools will have foundation in current techniques: A targeted molecule may simply add spatial or temporal resolution to an existing assay. Thus, although many potential applications are envisaged, the actual near future products are not much more than better research tools or aids to diagnosis [15, 16]. These are summarized in the following three tables (Tables 1, 2, and 3) [5].
The Problems in Drug Delivery During the last two decades, many modern technologies have been established in the pharmaceutical research and development area. The automation of the drug discovery process by technologies such as high-throughput screening, combinatorial chemistry, and computer-aided drug design is leading to a vast number of drug candidates possessing a very good efficacy [17]. Unfortunately, many of these drug candidates are exhibiting poor aqueous and non-aqueous solubility (thus insufficient bioavailability) and or erratic absorption and hence require innovative formulations and
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drug delivery systems to reach a sufficiently high bioavailability after oral administration or at least to make available intravenously injectable forms [18]. The problem is more complex for drugs such as itraconazole and carbamazepine (belonging to BCS class II; http://en.wikipedia.org/wiki/ Biopharmaceutics_Classification_System) as they are poorly soluble in both aqueous and organic media and for those drugs having a log P value of 2. (Partition coefficient P is the ratio of concentrations of a drug at equilibrium in the two immiscible phases in the body. Log P is the logarithm of the ratio of the concentrations of the un-ionized drug in the body). The performance of these drugs is dissolution ratelimited (for class II and IV drugs) and is affected by the fed/fasted state of the patient. Dissolution rates of sparingly soluble drugs are related to the shape as well as the particle size. Therefore decrease in particle size results in an increase in dissolution rate. The Biopharmaceutics Classification System BCS is a guide for predicting the intestinal drug absorption provided by the US Food and Drug Administration: class I—high permeability, high solubility; class II— high permeability, low solubility; class III—low permeability, high solubility; and class IV—low permeability, low solubility. There are number of formulation approaches like micronization, solubilization using cosolvents, use of permeation enhancers, oily solutions, surfactant dispersions, salt formation, precipitation techniques, etc. to resolve the problems of low solubility and low bioavailability [2]. These techniques have their own limitations and hence have limited utility. Micronization by colloid mills or jet mills increases the dissolution rate of drug due to increase in surface area but does not increase the saturation solubility. Other techniques like liposomes, emulsions, microemulsions, solid dispersions, and inclusion complexes using cyclodextrins show reasonable success but they lack in universal applicability to all drugs [19]. These are not applicable for drugs which are insoluble in both aqueous and organic media [3]. Also they cause toxicity problem due to the high dosage required and are crucial in injection and ophthalmic preparations. This is also evident as has been clearly demonstrated by the relatively low number of products on the market based on such technologies. In addition, poorly water-soluble drugs are specially challenging, as they cannot achieve dissolution, and therefore, they have a very difficult pass through the dissolving fluid to contact the absorbing mucosa and to be absorbed [1]. If the dissolution process of the drug molecule is slow, due to the physicochemical properties of the drug molecules or formulation factors, then dissolution may be the rate-limiting step in absorption and will influence drug bioavailability. This is the case of class II drugs, e.g., ibuprofen, rutin, hesperidin, and coenzyme Q10. For this specific kind of drugs, micronization [20–23], nanonization [24–26], complexation (e.g., cyclodextrins)
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Table 1 Application areas for nanoscale pharmaceuticals and medicine in diagnostics [5]. Material/technique Diagnostics Nanosized markers, i.e., the attachment of nanoparticles to molecules of interest “Lab-on-a-chip” technologies
Quantum dots
Property
Applications
Timescale (to market launch)
Minute quantities of a substance can be detected down to individual molecules Miniaturization and speeding up of the analytical process
For example, detection of cancer cells to allow early treatment
?
The creation of miniature, portable diagnostic laboratories for uses in the food, pharmaceutical, and chemical industries; in disease prevention and control; and in environmental monitoring Diagnosis
Although chips currently cost over £125 (US$2085) each to make, within 3 years, the costs should fall dramatically, making these tools widely available
Quantum dots can be tracked very precisely when molecules are “bar-coded” by their unique light spectrum
[19, 27–32], preparation of liposomes [33–35] and amorphous solid dispersions [36–40] have been proposed to increase the rate of dissolution and especially the drug bioavailability after oral administration for systemic drug absorption. In many cases these did not lead to a sufficiently high bioavailability. Hence there is need of some different and simple approach to tackle the formulation
In early stage of development, but there is enough interest here for some commercialization
problems to improve their efficacy and to optimize the therapy with respect to pharmacoeconomics. The Alternative Approach: Nano Nanotechnology can be used to resolve the problems associated with these conventional approaches for solubility
Table 2 Application areas for nanoscale pharmaceuticals and medicine in drug delivery [5]. Material/ technique Drug delivery Nanoparticles in the range of 50–100 nm Nanosizing in the range of 100–200 nm Polymers Ligands on a nanoparticle surface Nanocapsules
Property
Applications
Timescale (to market launch)
Larger particles cannot enter tumor pores, while nanoparticles can easily move into a tumor Low solubility
Cancer treatment
?
More effective treatment with existing drugs
?
Nanobiological drug-carrying devices
?
These molecules can be engineered to a high degree of accuracy These molecules can be engineered to a high degree of accuracy
The ligand target receptors can recognize ? damaged tissue, attach to it, and release a therapeutic drug Evading the body’s immune system while A Bucky ball-based AIDS treatment is Early clinical directing a therapeutic agent to the desired site just about to enter clinical trials Increased particle Degree of localized drug retention increased Slow drug release ? adhesion Nanoporous Evading the body’s immune system while When coupled to sensors, drug-delivering Pre-clinical: an materials directing a therapeutic agent to the desired site implants could be developed insulin-delivery system is being tested in mice “Pharmacy-onMonitor conditions and act as an artificial For example, diabetes treatment More distant than a-chip” means of regulating and maintaining the “lab-on-a-chip” body’s own hormonal balance technologies Sorting Nanopores and membranes are capable of Gene analysis and sequencing Current–? biomolecules sorting, for example, left- and right-handed versions of molecules
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Table 3 Application areas for nanoscale pharmaceuticals and medicine in tissue regeneration, growth, and repair [5]. Material/technique
Property
Tissue regeneration, growth, and repair Nanoengineered Increased miniaturization, prosthetics increased prosthetic strength and weight reduction, and improved biocompatibility Cellular Manipulation and coercion manipulation of cellular systems
Applications
Timescale (to market launch)
Retinal, auditory, spinal, and cranial implants
Most immediate will be external tissue grafts, dental and bone replacements, and internal tissue implants
Persuasion of lost nerve tissue to grow; growth of body parts
More distant, 5–7 years
and bioavailability enhancement. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10−9 m. The drug microparticles/micronized drug powder is transformed to drug nanoparticles by techniques like bottom-up technology (the drug is dissolved in a solvent, which is then added to non-solvent to precipitate the crystals) and top-down technology (the drug is disintegrated to nanosize). Nano is a Greek word, which means “dwarf.” Nano means it is the factor of 10−9 or one billionth. Some comparisons of nanoscale are given below, 0.1 nm=diameter of one hydrogen atom 2.5 nm=width of a DNA molecule17 1 μm=1,000 nm 1 nm=10−9 m=10−7 cm=10−6 mm Micron=10−6 m=10−4 cm=10−3 mm Nanoparticles This alternative and promising approach is a transformation of the micronized drug to drug nanoparticles and nanosuspensions. Nanoparticulate drug delivery system [41] may offer plenty of advantages over conventional dosage forms, which include improved efficacy, reduced toxicity, enhanced biodistribution, and improved patient compliance. Nanoparticles are colloidal particles, which are less than 1 μm in diameter. They have the unique property to accumulate at the site of inflammation and, therefore, are very suitable for targeted drug delivery. Different kinds of drugs like pilocarpine, hydrocortisone, ibuprofen, flubiprofen, Rose Bengal, and ganciclovir have been delivered by entrapping in nanoparticles [42, 43]. Nanosuspensions Nanosuspension technology [44] offers novel solution for poorly soluble drugs. Nanosuspensions are submicron colloidal dispersion of pure particles of drug stabilized by surfactants. The average particle size ranges between 200 and 600 nm. The drugs, which have high crystal energy,
i.e., high melting point, reduces the solubility of drug substances. Nanosuspension technology is used for these drugs without the necessary to solubilize them. Nanosuspension provides chemically and physically stable product. Nanosuspensions are formed by building particles as in precipitation or breaking as in milling. In both cases, new surface area is formed. Therefore, it has more free energy, and the system tends to agglomerate which is prevented by addition of surfactants. Surfactants causes high-energy barrier and prevents particles coming together. Nanosuspensions differ from nanoparticles, which are polymeric colloidal carriers of drugs (nanospheres and nanocapsules), and from solid-lipid nanoparticles, which are lipidic carriers of drug. A nanosuspension not only solves the problems of poor solubility and bioavailability but also alters the pharmacokinetics of drug and thus improves drug safety and efficacy. Potential benefits of nanosuspension technology over other conventional formulations technologies for poorly soluble drugs are given below (Tables 4 and 5) [45]. In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability. An increase in the dissolution rate of micronized particles (particle size
