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Drug delivery today is at the leading edge of pharmaceutical science and product development. Historically, the field of drug delivery focused on creating new forms of established drugs. Currently, drug delivery is being used as a method of product life-cycle management to extend product
franchises by offering improved researches.
The current state of drug delivery activities are to reduce toxicity, increase the absorption of an insoluble or improve the drug release profile. Drug delivery is being considered earlier in the drug development timeline with the engineering of drug delivery systems to meet the current
therapeutic needs. By applying drug delivery earlier in the
development process, there is a potential to improve productivity as well as product outcomes and create truly best effective products.
The development of more sophisticated drug delivery systems to meet product and patient needs demands sophistication of the analytical services requires since ages. Method development of potency and purity methods has been complicated by polymers, nanotechnology, and drug infused
medical devices used in implantable time-release drug delivery systems. The drug evolution profile of these systems requires experience and expertise, as well as newer drug release instrumentation such as flow-through dissolution.
It is also observed that a significant increase in analytical development involving extractable and conclude profiles of polymeric materials used in medicated implants, as well as in device parts for dry powder inhalers and the complex coatings of transdermal devices. These complex drug delivery
matrices, require both state-of-the-art instrumentation and in-house technical expertise accustomed to working in complex products.
Increased sophistication in drug delivery systems translates into a greater portion of the drug development process being devoted to drug product formulation.
The current methods of drug delivery exhibit specific problems that scientists are attempting to address. For example, many drugs' potencies and therapeutic effects are limited or otherwise reduced because of the partial degradation that occurs before they reach a desired target in the body. Once ingested, time-release medications deliver treatment continuously, rather than providing relief of symptoms and protection from adverse events solely when necessary. Further, injectable medications
could be made less expensively and administered more easily if they could simply be dosed orally. However, this improvement cannot happen until methods are developed to safely shepherd drugs through specific areas of the body, such as the stomach, where low pH can destroy a medication, or through an area where healthy bone and tissue might be adversely affected.
On the other side the use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Interestingly pharmaceutical sciences are using nanoparticles to reduce toxicity and side effects of drugs and up to recently did not realize that carrier systems themselves may impose risks to the patient. The kind of hazards that are introduced by using nanoparticles for drug delivery are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. For nanoparticles the knowledge on particle toxicity as obtained in inhalation toxicity shows the way how to investigate the potential hazards of nanoparticles. The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs. This may vary from a rather high local exposure in the lungs and a low or neglectable exposure for other organ systems after inhalation. However, absorbed species may also influence the potential toxicity of the inhaled particles. For nanoparticles the situation is different as their size opens the potential for crossing the various biological barriers within the body.
What is drug delivery?
Drug delivery is the way in which medications are given to the patients. Due to the advances in medicine, drugs may be delivered in many different ways using many different delivery systems including: by mouth (pills or suspensions), through the vein (intravenously), through the artery (arterially), topically through the skin (transdermally), through the rectum (suppository), through the eye (ocular), through the lungs (inhaled), by injection into the skin (subcutaneously), by injection into the muscle (intramuscularly), and under the tongue (sublingually).
Inorganic nanomaterials (INMs) and nanoparticles (NPs) are important in our lives because of their use as drugs, imaging agents, and antiseptics. Among the most promising INMs being developed are metal, silica, dendrimers, organic-inorganic hybrids, and bioinorganic hybrids. Gold NPs are important in imaging, as drug carriers, and for thermotherapy of biological targets. Gold NPs, nanoshells, nanorods, and nanowires have the extensive potential to be an integral part of our imaging toolbox and useful in the fight against cancer. Metal NP contrast agents enhance magnetic resonance imaging and ultrasound results in biomedical applications of in vivo imaging. Hollow and porous INMs have been exploited for drug and gene delivery, diagnostic imaging, and photothermal therapy. Silver NPs show improved antimicrobial activity. Silica NPs have been used in drug delivery and gene therapy. Biomolecular inorganic nanohybrids and nanostructured biomaterials have been exploited for targeted imaging and therapy, drug and gene delivery, and regenerative medicine. Dendrimers find use as drug or gene carriers, contrast agents, and sensors for different metal ions.
Drug delivery and nanomedicine
1. Current (macro & microscale) methods of drug delivery â€¢ transdermalsystems â€¢ microneedles â€¢ implantable systems â€¢ tissue reaction to implantable systems
Typical drug dosages â€¢currently, typical dose of drug is tens to hundreds of micrograms -300 Î¼gepinephrine to treat anaphylactic shock (severe allergic reaction, rapid constriction of airways) -keeps airway open. -antibiotics such as penicillin ~ 1 g/day for adults -current drug formulations often contain carriers, binders, coatings, flavouringagents.
Why drug delivery? â€¢Improve therapy -Improve efficacy, prolong duration, improve bioavailability, improve targeting, mimic biopattern â€¢Increase patient compliance -Decrease dose frequency, allow selfâ€ administration â€¢Add competitive advantage (e.g. post drug patent)
Methods â€¢ Oral â€¢ Parenteral(IV, etc) â€¢ Inhalation â€¢ Ocular â€¢ Transdermal â€¢ Needleless â€¢ Implants â€¢ Liposomes
David Beebe, U. Wisconsin
Parenteral Parenteralâ€other than GI tract (i.e. intravenous, subcutaneous, intramuscular, transdermal, etc.) â€¢ Intravenous -Immediate action -Size/location (>7 Î¼m trapped in lung, <0.1 Î¼m accumulate in bone marrow, 0.1â€7 Î¼m taken up by liver/spleen) â€¢ Intramuscular / Subcutaneous -Sustained action -Injected into skeletal muscle / subcutaneous tissue
TransdermalDelivery â€¢ Skin receives 1/3 of blood â€¢ Accessible â€¢ Barriers -Permeation -Irritation â€¢ Advantages -Avoids "first pass"metabolism and GI degradation â€¢"First pass"effect â€metabolic breakdown in the liver -Ideal for continuous delivery -Improved patient compliance
Microfabricated drug delivery systems â€¢ Many approaches have been proposed for effectively delivering drugs into the human body. These new drug delivery methods can be categorized into three major groups: (a) Microneedlesfor transdermaldelivery; - avoids gastrointestinal drug degradation (oral delivery) - reduces pain from intravenous and intramuscular injection (b) implantablemicrosystems. (b) biocapsulesand microparticlesfor controlled and/or siteâ€ specific drug release; - capsules for oral delivery of peptide and prote
Biocapsulesand microparticles â€¢ By encapsulating drugs in a biodegradable microsphere or micro(nano)particle, a sustained or controlled drug release profile can be achieved.
â€¢ Siteâ€specific delivery can be achieved by binding
Diabetes -Islet transplantation â€¢ Diabetes mellitus -decreased circulating concentrations of insulin and decreased response of peripheral tissue to insulin (insulin resistance) - insulin: hormone that regulates carbohydrate metabolism. - Beta cells in the pancreatic islets produce insulin. â€¢ Insulin is usually administered subcutaneously -but kinetics do no mimic normal rapid rise and decline of insulin secretion in response to ingested nutrients â€¢ Allotransplantationof islets or whole pancreas from human donor to diabetic patient: - Recipients required to take immune suppressing drugs for the rest of their lives - Normally carried out only in conjunction with kidney transplant.
Shape-specific polymeric nanomedicine
Size and shape are fundamental properties of micro/nanoparticles that are critically important for nanomedicine applications.
Extensive studies have revealed the effect of particle size on spherical particles with respect to circulation, extravasation and
distribution in vivo. In contrast, the importance of particle shape has only recently begun to emerge. For example,
cylindrically-shaped filomicelles (diameter 22-60 nm, length 8-18 mm) have shown persistent blood circulation for up to
one week after intravenous injection, much longer than their spherical counterparts. Disc-shaped nanoparticles have
demonstrated higher in vivo targeting specificity to endothelial cells expressing intercellular adhesion molecule receptors in
mice than spherical particles of similar size. Computational models are presented to provide mechanistic understanding of the shape effects on cell targeting under flow conditions. Shapespecific
nanoparticles have the potential to significantly improve the performance of nanomedicine in diagnostic imaging
and targeted drug delivery applications.
Nanomedicine is a rapidly evolving discipline that applies the advances in nanotechnology for diagnosis and treatment of diseases. Examples include the development of targeted nanoparticles capable of delivering therapeutic
and diagnostic agents to specific biological targets. In a nanoparticle-based platform, therapeutic drugs or imaging agents are encapsulated in polymeric carriers, providing multiple advantages over conventional small molecular
formulations, such as cell targeting, reduction of clearance and systemic toxicity, the ability to deliver large
payloads of hydrophobic drugs and the potential for incorporating
multiple payloads in a single carrier for multifunctional
Over the past few decades, various nanoplatforms, including liposomes, polymeric micelles, quantum dots, Au/Si/polymer shells and dendrimers have been established with distinctive chemical compositions and
biological properties. Most current nanoparticulate systems
are spherical in shape, and extensive work has been dedicated
to studying their biological behaviors in vitro and in vivo.
Similar to size, shape is a fundamental property of micro/
nanoparticles that is critically important for their intended
biological functions. Unlike size, the biological effects of particle
shape are less well understood. Recent data have shown
that particle shape may have a profound effect on their biological
properties. For example, cylindrically shaped filomicelles
can effectively evade non-specific uptake by the
reticuloendothelial system, allowing persistent circulation for
up to one week after intravenous injection. Theoretical modeling
work has shown that non-spherical particles can signifi-
cantly increase particle adhesion to cellular receptors under
flow conditions compared with spherical particles.
Experimentally, Muzykantov and co-workers25 showed that
disk-shaped nanoparticles (0.1 _ 1 _ 3 mm) increased (.20
times increase in immunospecificity index) particle targeting to intercellular adhesion molecule 1-expressed pulmonary endothelium over spherical particles of similar size. Other non-spherical nanoparticles (e.g. carbon nanotubes, wormshaped iron oxide nanoparticles ) have also demonstrated
considerably increased accumulation and retention in tumor tissues in vivo. These data, as well as a wide array of naturally occurring shape-specific nanoparticulates are beginning to highlight the importance of controlling particle shape for nanomedicine applications.
Despite these early studies, there still is a lack of systematic and fundamental understanding of how shape affects the in vivo behavior of nanoscale constructs. One contributing factor is that conventional fabrication methods are limited in their ability to control the shape and size of nanoparticles simultaneously. This limitation hinders direct investigation
of the effects of shape independent of size or other factors. There is also a lack of integration between computational modeling and experimental
validation, an important requirement for understanding the effects of shape at nanoscale in the biological systems.
Fabrication of shape-specific nanoparticles
Both bottom-up chemistry and top-down engineering methods have the capability to produce polymeric nanostructures. Most polymeric nanoparticles currently used for biomedical applications are produced using bottom-up methods. These methods can produce nanoparticles with a spherical shape and a wide variety of sizes driven by favorable thermodynamics leading to the self-assembly of the nanoparticles.
Although non-spherical shapes are possible using diblock co-polymers, size and shape are difficult to control independently using bottom-up methods.
Several bottom-up techniques have been developed to fabricate non-spherical particles. As shown in Table 1,
Geng et al. employed a self-assembly method to produce polyethylene- glycol (PEG)-based filomicelles loaded with the antineoplastic agent paclitaxel. Park et al synthesized magnetic iron oxide worm-shaped clusters in the presence of higher molecular weight dextran. Yang et al reported the formation of high aspect-ratio ellipsoidal polymeric nanoparticles using a miniemulsion technique. Although all show exciting results with interesting science, most of these methods still lack precise and uniform control over
shape and size independently. Currently, the bottom-up methods will be limited in the production of non-spherical nanoparticles, with systematic change of one dimension at a time to test shape-specific hypotheses in biology.
In contrast, polymers can be precisely patterned and used as resistors for microelectronic applications, with good control over their final shape using electron, ion or photon beam lithographic techniques. The costliness of these techniques has led to the development of low-cost top-down techniques, such as nanoimprint lithography, soft lithography and others.
Table 1 summarizes some of the processes used to produce non-spherical polymeric particles, including particle replication in non-wetting templates elastic stretching of spherical particles, step-flash imprint lithography (S-FIL) and template-induced printing (TIP). These techniques have obtained promising results in manufacturing nonspherical platforms for nanomedicine applications.
Size and shape comparison of various naturally occurring nanoparticulate objects
Recent discoveries of the unique shape effects on biological
functions at nanoscale have spawned multiple shape-specific
particulate platforms for nanomedicine applications. Various
techniques for the fabrication of non-spherical particles have
been established. Many of these techniques, such as PRINTw,
stretching spherical particles, S-FIL and TIP, hold great
promise because of their ability to simultaneously and independently
control shape, size and chemical compositions of
fabricated polymeric nanoparticles. Computational models
of the effects of particle shape on intravascular dynamics
and cellular uptake have been developed. Both modeling
data and experimental results indicate that for particulate
platforms, shape can have a profound impact on pharmacokinetics
Future advances in the implementation of shape-specific
nanomedicine would include the capability to scale-up
without sacrificing the precise control over size and shape.
The development of efficient methods for harvesting
imprinted nanoparticles is also important for templatebased
techniques. Also necessary is a well-controlled, systematic
study of the effects of shape on particle behavior
under biologically relevant conditions. Computational
models also need to be integrated to elucidate the effects
of shape on the degradation profile, intra- and extracellular
trafficking of particles. Only with the mechanistic understanding
on how shape would affect fundamental processes
during in vivo targeting applications, can a rational design
incorporating shape into a given nanoparticulate platform be possible.