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What Conditions must Drugs satisfy for them to be Deliverable via the Transdermal route?

What Conditions must Drugs satisfy for them to be Deliverable via the Transdermal route?


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What Conditions must Drugs satisfy for them to be Deliverable via the Transdermal route? I assume a high $log{P}$ (lipophilicity) would be one, are there any others?


Whether a drug can be delivered transdermally? I think that carriers can be formulated to carry a small molecule through the skin into circulation, so I don't even know about lipophilicity. I believe if you spend enough money, you can overcome many of these problems. I think that pharmacology might be just as important.

I think the first condition of a transdermal administration is that the drug cannot be effectively administered orally. This is the most cost effective route go get a pharma compound into the body. It requires no devices, no fancy coatings or vaporizors.

Reasons that a pill (or its less popular cousins the suppository and sublingual tablet) cannot be used as the delivery system for a drug include effect of pH and other degradation of the compound in the GI tract, absorption rate from the GI tract and other factors such as effect of food in the system, other drugs which might interact in the system.

Another advantage of absorption through the GI tract is that this is the physiological system which is meant to be ingested and introduced into the body - its relatively fault tolerant, even if less of the drug actually reaches the blood stream. There's more, but that's not a bad outline.

After pills and the like, the second choice is intravenous administration, which puts 100% of the drug into the circulatory system. This has its own disadvantages, requires a clinical setting and the needle and breaking of the skin are not ideal in many cases.

If the drug needs continuous and non clinical administration there are many other means of drug delivery, including transdermal administration. Differentiating these methods often includes making sure the drug is available specifically to the part of the body that needs it. E.g. topical administration; putting on a medicated cream for a skin condition or use of an inhaler which delivers the drug directly to the lung for an asthmatic condition.

Transdermal administration has its own specific advantages; continuous distribution of the compound over long periods of time. Disadvantages include: poor ADME properties for biologicals like antibodies and other proteins, low delivery concentrations where you need a large amount added (epinephrine, and maybe antibiotics come to mind).

Examples of successful transdermal delivery are testosterone gels and the nicotine patch. Both of which apply continuous controlled low dosage that is important there.

There are three typical routes of drug absorption in transdermal delivery. The drugs can diffuse through the membranes of dead cells of the stratum corneum, which works if the drugs are lipophilic enough. They can diffuse around these cells, through the intercellular spaces, which can work for more polar drugs although this path is not usually as efficient. The most extreme means are patches which contain tiny needles that can deliver straight through the protective layer of the skin. With enough economic investment probably any sort of compound could be introduced through a patch.

Most of this is just cribbing off the notes from this lecture on coursera: Fundamentals of Pharmacology. Its probably outlined on any pharmacology text.


What Is Chelation Therapy?

When metals like lead, mercury, iron, and arsenic build up in your body, they can be toxic. Chelation therapy is a treatment that uses medicine to remove these metals so they don't make you sick.

Some alternative health care providers also use it to treat heart disease, autism, and Alzheimer's disease. But there's very little evidence it works for those conditions. In fact, chelation therapy can cause serious side effects -- including death -- especially if it's used in the wrong way.


Abstract

The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies — such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs — and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.


NOVEL DRUG DELIVERY SYSTEM

1. INTRODUCTION
1.1 NOVEL DRUG DELIVERY SYSTEM:
The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of therapeutics to targets in tissues. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and efficacy of drugs were generated. These new strategies, often called drug delivery systems (DDS), are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry, and molecular biology.

REFERENCE ID: PHARMATUTOR-ART-1652

To minimize drug degradation and loss, to prevent harmful side-effects and to increase drug bioavailability and the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are currently under development. Among drug carriers one can name soluble polymers, microparticles made of insoluble or biodegradable natural and synthetic polymers, microcapsules, cells, cell ghosts, lipoproteins, liposomes, and micelles. The carriers can be made slowly degradable, stimuli-reactive (e.g., pH- or temperature-sensitive), and even targeted (e.g., by conjugating them with specific antibodies against certain characteristic components of the area of interest). Targeting is the ability to direct the drug-loaded system to the site of interest. Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting. An example of passive targeting is the preferential accumulation of chemotherapeutic agents in solid tumors as a result of the enhanced vascular permeability of tumor tissues compared with healthy tissue. A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest. Since ligand–receptor interactions can be highly selective, this could allow a more precise targeting of the site of interest.

Controlled drug release and subsequent biodegradation are important for developing successful formulations. Potential release mechanisms involve: (i) desorption of surface-bound /adsorbed drugs (ii) diffusion through the carrier matrix (iii) diffusion (in the case of nanocapsules) through the carrier wall (iv) carrier matrix erosion and (v) a combined erosion /diffusion process. The mode of delivery can be the difference between a drug’s success and failure, as the choice of a drug is often influenced by the way the medicine is administered. Sustained (or continuous) release of a drug involves polymers that release the drug at a controlled rate due to diffusion out of the polymer or by degradation of the polymer over time. Pulsatile release is often the preferred method of drug delivery, as it closely mimics the way by which the body naturally produces hormones such as insulin. It is achieved by using drug-carrying polymers that respond to specific stimuli (e.g., exposure to light, changes in pH or temperature).

For over 20 years, researchers have appreciated the potential benefits of nanotechnology in providing vast improvements in drug delivery and drug targeting. Improving delivery techniques that minimize toxicity and improve efficacy offers great potential benefits to patients, and opens up new markets for pharmaceutical and drug delivery companies. Other approaches to drug delivery are focused on crossing particular physical barriers, such as the blood brain barrier, in order to better target the drug and improve its effectiveness or on finding alternative and acceptable routes for the delivery of protein drugs other than via the gastro-intestinal tract, where degradation can occur.

1.1.1 Drug Delivery Carriers
Colloidal drug carrier systems such as micellar solutions, vesicle and liquid crystal dispersions, as well as nanoparticle dispersions consisting of small particles of 10–400 nm diameter show great promise as drug delivery systems. When developing these formulations, the goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties.

Figure: 1 Pharmaceutical carriers

a) MICELLES:
Micelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. In addition, the corona may prevent recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. A final feature that makes amphiphilic block copolymers attractive for drug delivery applications is the fact that their chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles. Functionalization of block copolymers with crosslinkable groups can increase the stability of the corresponding micelles and improve their temporal control. Substitution of block copolymer micelles with specific ligands is a very promising strategy to a broader range of sites of activity with a much higher selectivity.

Figure: 2 Block copolymer micelles.

b) LIPOSOMES:
Liposomes are a form of vesicles that consist either of many, few or just one phospholipid bilayers. The polar character of the liposomal core enables polar drug molecules to be encapsulated. Amphiphilic and lipophilic molecules are solubilized within the phospholipid bilayer according to their affinity towards the phospholipids. Participation of nonionic surfactants instead of phospholipids in the bilayer formation results in niosomes. Channel proteins can be incorporated without loss of their activity within the hydrophobic domain of vesicle membranes, acting as a size-selective filter, only allowing passive diffusion of small solutes such as ions, nutrients and antibiotics. Thus, drugs that are encapsulated in a nanocage-functionalized with channel proteins are effectively protected from premature degradation by proteolytic enzymes. The drug molecule, however, is able to diffuse through the channel, driven by the concentration difference between the interior and the exterior of the nanocage.

Figure: 3 Drug encapsulation in liposomes

c) DENDRIMERS:
Dendrimers are nanometer-sized, highly branched and monodisperse macromolecules with symmetrical architecture. They consist of a central core, branching units and terminal functional groups. The core together with the internal units, determine the environment of the nanocavities and consequently their solubilizing properties, whereas the external groups the solubility and chemical behaviour of these polymers. Targeting effectiveness is affected by attaching targeting ligands at the external surface of dendrimers, while their stability and protection from the Mononuclear Phagocyte System (MPS) is being achieved by functionalization of the dendrimers with polyethylene glycol chains (PEG).

d) LIQUID CRYSTALS:
Liquid Crystals combine the properties of both liquid and solid states. They can be made to form different geometries, with alternative polar and non-polar layers (i.e., a lamellar phase) where aqueous drug solutions can be included.

d) LIQUID CRYSTALS:
Liquid Crystals combine the properties of both liquid and solid states. They can be made to form different geometries, with alternative polar and non-polar layers (i.e., a lamellar phase) where aqueous drug solutions can be included.

e) NANOPARTICLES:
Nanoparticles (including nanospheres and nanocapsules of size 10-200 nm) are in the solid state and are either amorphous or crystalline. They are able to adsorb and/or encapsulate a drug, thus protecting it against chemical and enzymatic degradation. Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed. Nanoparticles as drug carriers can be formed from both biodegradable polymers and non-biodegradable polymers. In recent years, biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in the controlled release of drugs, in targeting particular organs / tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes through the peroral route.

f) HYDROGELS:
Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids. The networks are composed of homopolymers or copolymers, and are insoluble due to the presence of chemical crosslinks (tie-points, junctions), or physical crosslinks, such as entanglements or crystallites. Hydrogels exhibit a thermodynamic compatibility with water, which allows them to swell in aqueous media. They are used to regulate drug release in reservoir-based, controlled release systems or as carriers in swellable and swelling-controlled release devices. On the forefront of controlled drug delivery, hydrogels as enviro-intelligent and stimuli-sensitive gel systems modulate release in response to pH, temperature, ionic strength, electric field, or specific analyte concentration differences. In these systems, release can be designed to occur within specific areas of the body (e.g., within a certain pH of the digestive tract) or also via specific sites (adhesive or cell-receptor specific gels via tethered chains from the hydrogel surface). Hydrogels as drug delivery systems can be very promising materials if combined with the technique of molecular imprinting.

Figure: 4 Pegylated and pH sensitive micro- or nanogels

1.1.2 Administration Routes
The choice of a delivery route is driven by patient acceptability, the properties of the drug (such as its solubility), access to a disease location, or effectiveness in dealing with the specific disease.

a) PERORAL ROUTE:
The most important drug delivery route is the peroral route. An increasing number of drugs are protein- and peptide-based. They offer the greatest potential for more effective therapeutics, but they do not easily cross mucosal surfaces and biological membranes they are easily denatured or degraded, prone to rapid clearance in the liver and other body tissues and require precise dosing. At present, protein drugs are usually administered by injection, but this route is less pleasant and also poses problems of oscillating blood drug concentrations. So, despite the barriers to successful drug delivery that exist in the gastrointestinal tract (i.e., acid-induced hydrolysis in the stomach, enzymatic degradation throughout the gastrointestinal tract by several proteolytic enzymes, bacterial fermentation in the colon), the peroral route is still the most intensively investigated as it offers advantages of convenience and cheapness of administration, and potential manufacturing cost savings.

b) PULMONARY ROUTE:
Pulmonary delivery is also important and is effected in a variety of ways - via aerosols, metered dose inhaler systems (MDIs), powders (dry powder inhalers, DPIs) and solutions (nebulizers), all of which may contain nanostructures such as liposomes, micelles, nanoparticles and dendrimers. Aerosol products for pulmonary delivery comprise more than 30% of the global drug delivery market. Research into lung delivery is driven by the potential for successful protein and peptide drug delivery, and by the promise of an effective delivery mechanism for gene therapy (for example, in the treatment of cystic fibrosis), as well as the need to replace chlorofluorocarbon propellants in MDIs. Pulmonary drug delivery offers both local targeting for the treatment of respiratory diseases and increasingly appears to be a viable option for the delivery of drugs systemically. However, the pulmonary delivery of proteins suffers by proteases in the lung, which reduce the overall bioavailability, and by the barrier between capillary blood and alveolar air (air-blood barrier).

c) TRANSDERMAL ROUTE:
Transdermal drug delivery avoids problems such as gastrointestinal irritation, metabolism, variations in delivery rates and interference due to the presence of food. It is also suitable for unconscious patients. The technique is generally non-invasive and aesthetically acceptable, and can be used to provide local delivery over several days. Limitations include slow penetration rates, lack of dosage flexibility and / or precision, and a restriction to relatively low dosage drugs.

d) PARENTERAL ROUTE: Parenteral routes (intravenous, intramuscular, subcutaneous) are very important. The only nanosystems presently in the market (liposomes) are administered intravenously. Nanoscale drug carriers have a great potential for improving the delivery of drugs through nasal and sublingual routes, both of which avoid first-pass metabolism and for difficult-access ocular, brain and intra-articular cavities. For example, it has been possible to deliver peptides and vaccines systemically, using the nasal route, thanks to the association of the active drug macromolecules with nanoparticles. In addition, there is the possibility of improving the occular bioavailability of drugs if administered in a colloidal drug carrier.

e) TRANS TISSUE AND LOCAL ROUTE:
Trans-tissue and local delivery systems require to be tightly fixed to resected tissues during surgery. The aim is to produce an elevated pharmacological effect, while minimizing systemic, administration-associated toxicity. Trans-tissue systems include: drug-loaded gelatinous gels, which are formed in-situ and adhere to resected tissues, releasing drugs, proteins or gene-encoding adenoviruses antibody-fixed gelatinous gels (cytokine barrier) that form a barrier, which, on a target tissue could prevent the permeation of cytokines into that tissue cell-based delivery, which involves a gene-transduced oral mucosal epithelial cell (OMEC)-implanted sheet device-directed delivery - a rechargeable drug infusion device that can be attached to the resected site.

f) GENE DELIVERY:
Gene delivery is a challenging task in the treatment of genetic disorders. In the case of gene delivery, the plasmid DNA has to be introduced into the target cells, which should get transcribed and the genetic information should ultimately be translated into the corresponding protein. To achieve this goal, a number of hurdles are to be overcome by the gene delivery system. Transfection is affected by: (a) targeting the delivery system to the target cell, (b) transport through the cell membrane, (c) uptake and degradation in the endolysosomes and (d) intracellular trafficking of plasmid DNA to the nucleus.

2. NANOPARTICLES
The prefix nano means a billionth (10 -9 ). Thus, a nanometre (nm) is a billionth of a metre. Nanotechnology is concerned with the creation or manipulation of particles and materials whose minimum dimensions are nanometric, though normally less than 100 nm. These materials may be produced from the structured organization of groups of atoms and molecules or by reducing macroscopic materials to a nanometric scale.

The current definition defines nanoparticles as “particles with at least one dimension smaller than 100 nm or 0.1 μm, and with different properties than particles of larger diameters made of the same material”.

While the development of nanotechnologies is a very modern, multidisciplinary science, the manufacture of nanomaterials, both by nature and by humans, dates from time immemorial.Indeed, several natural structures, including proteins and the DNA diameter fit the above definition of nanomaterials.

while viruses represent the smallest naturally occurring functional nano-objects. To illustrate the orders of magnitude involved, the diameter of a DNA molecule is of the order of 2 to 12 nanometres (nm), a red blood cell has a diameter of 5,000 nm and a human hair a diameter 10,000 to 50,000 nm.

Romans in the pre-Christian era were already introducing metals with nanometric dimensions in glass-making a cup describing the death of King Lycurgus (circa 800 BC) contains nanoparticles of silver and gold when a light source is placed inside the cup, its colour changes from green to red.

The colours of certain Mayan paintings stem from the presence of metallic nanoparticles, as does the lustre of Italian Renaissance pottery. The stained-glass windows of the great medieval cathedrals also contain metallic nanoparticles.Photography, which was developed in the 18 th and 19 th centuries, provides a more recent example of the use of nanoparticles, which in this example is made up of particles of silver sensitive to light.

Due to their low granulometry, many condensation products deriving from the combustion process contain nanoparticles these include diesel gases, industrial furnace emissions and welding fumes. In 1993 alone, synthesis through flame pyrolysis of six million tonnes of carbon black with a high specific surface area produced carbon powder of nanometric dimensions. Combustion or flame pyrolysis is also used in the mass production of silica fume, ultrafine titanium dioxide particles and ultrafine metal particles, all of nanometric dimensions.

In addition, the definition of nanoparticles based on size, allows us to include colloids and soils that have been used for over a hundred years. In 1857, Faraday, had already described the use of colloidal gold in his experiments . Since then, colloidal science has evolved a lot. The new colloids are used in the production of metals, oxides and organic and pharmaceutical products. Given this broad definition, it is important to home in on the subject-matter of our inquiry.

In 1960, Richard Feynman, the 1965 Nobel prizewinner in Physics, began speculating on the possibilities and potential of nanometric materials, and on the fact that the manipulation of individual atoms could allow us to create very small structures whose properties would be very different from larger structures with the same composition. With the major technological developments of recent decades, it has now become possible to manipulate atoms one by one. It has been demonstrated that these structures do, in effect, have unique properties, which accounts for the interest in research in this field, especially over the last decade.

Articles describing nanomaterials may be divided into two major categories:
a)those that are produced by collecting individual atoms this is the bottom-up approach, and

b)those that are produced by subdividing bulk materials into nanometric sizes this is the top-down approach.

In both cases, their dimensions are smaller than the critical length characterizing most physical phenomena, and this is what gives them their unique properties.

Nanomaterials often demonstrate characteristics such as extraordinary strength or unsuspected electrical, physical or chemical properties that are completely different from those demonstrated by the same products with larger dimensions.

The fields with current commercial uses and producing the greatest revenue are mechanico-chemical polishing, magnetic recording tapes, sunscreens, automotive catalyst supports, bio-labeling, electroconductive coatings and optical fibers. The biomedical and pharmaceutical fields, electronics, metallurgy, agriculture, textiles,coatings, cosmetics, energy and catalysts are other sectors with growing applications. Roco (2004) maintains that we are already in the second generation of the nanotechnology age.

The first generation dealt with passive nanostructures such as coatings, nanoparticles, nanostructured metals, polymers and ceramics.

The current generation deals with active nanostructures such as transistors, amplifiers, targeteddrugs and adaptive structures.

Many observers think that nanoparticles and nanotechnologies will constitute the focus of the next industrial revolution. Research in the field is growing very rapidly and all industrialized countries see potential for expansion and applications in numerous fields as well as colossal potential economic spin-offs. Governments and large companies are developing strategies and investing massively in research. For example, Europe has made nanotechnology one of its seven priority project-oriented research areas and is investing 1.3 billion Euros in it for the 2002-2006 period. In the United States, the National Nanotechnology Initiative (NNI) budget for 2005 alone amounted to a billion dollars.

The Government of Canada is currently building a research centre in Alberta that will be dedicated exclusively to nanotechnologies. The federal government is also preparing a national nanotechnology plan. Quebec has set up NanoQuebec to support the transfer and marketing of applications developed in universities, and to increase the use of nanotechnologies in research on problems encountered by Quebec companies in all industrial sectors.

Unfortunately, only a very small proportion of research on nanoparticles is concerned with its occupational health and safety risks, or with its threat to the environment and the health of populations. The field of nanomaterials and nanotechnologies cannot be covered exhaustively because it is too vast, too multidisciplinary and is changing too rapidly. Nevertheless, the present report, which is based on a literature review extending to June 2005, is designed to provide an overall portrait of nanomaterials and nanotechnologies as well as their main potential applications.

It places special emphasis on the situation in Quebec, the known risks to the health and safety of workers and prevention. Rapid technological changes have already facilitated the start-up of about forty nanotechnology companies in Quebec. Further efforts must be made in the area of health and safety know-how transfer to effectively support Quebec companies and research teams investigating ways to protect the health and safety of workers producing or using these substances.

ADVANTAGES:
* Increased efficacy and therapeutic index.
* Increased stability via encapsulation.
* Improved pharmacokinetic effect.
* Producible with various sizes,compound surface propt’s.
* Entrap both hydrophilic & lipophillic drug Protect entrapped drug from enzymatic degradation.
* Large variety of drugs(antineoplastic, antibiotic) peptides or protein(including antibodies) &viruses &bacteria can be incorporated into nanoparticles.
* Water soluble drugs are trapped in aqueous compartment & lipophillic drugs without the need for chemical modification.
* Nanoparticles encapsulated drugs are delivered intact to various tissue and cells and can be released when nanoparticles are destroyed ,enabling site specific and targeted drug delivery.
* Other tissues and cells of the body are protected from drug until it is released by nanoparticles thus decreasing drug toxicity.
* Size change and other characteristics can be altered depending on the rug and intended use of the product.

DISADVANTAGES:
* Include their tendency to be taken up by cells of reticoendothelial system and the slow release of the drug when the liposomes are taken up by phagocytes through endocytosis,fusion,surface adsorption or lipid exchange.
* Stabilizing the formulated liposomes is also difficult, but many approaches are now used for their stabilization.

2.1 Classification:
Briefly, nanomaterials can be classified in terms of dimensioning of the nanostructures involved
A) one nanometric dimension: surface coatings, thin films and interfaces.

B) Two nanometric dimensions: nanometric domain. Nanotubes, dendrimers, nanowires, fibers and fibrils.

C) Three nanometric dimentions: quantum dots or nanocrystals, fullerenes, particles, precipitates, colloids and catalysts.

One-dimensional systems, such as thin films or manufactured surfaces, have been used for decades in electronics, chemistry and engineering. Production of thin films or monolayers is now commonplace in the electronic field, just as the use of customized surfaces is common in the field of solar cells or catalysis. These fields are well known and the risks are properly controlled.

The properties of two-dimensional systems (carbon nanotubes, inorganic nanotubes, nanowires and biopolymers) are less understood and the manufacturing capabilities are less advanced.

Finally, some 3-D systems, such as natural nanomaterials and combustion products, metallic oxides, carbon black, titanium oxide (TiO2) and zinc oxide (ZnO) are well known, while others such as fullerenes, dendrimers and quantum dots represent the greatest challenges in terms of production and understanding of properties (Royal Society and Royal Academy of Engineering, 2004).

2.2 Characteristics and Properties of Nanoparticles:
Nanoparticles display properties that differ from those of the bulk materials from which they derive. In general, the integration of nanoparticles will seek modification of electrical, mechanical, magnetic, optical or chemical properties. Here are the main examples:

A) Fullerenes
Fullerenes are spherical cages containing from 28 to more than 100 carbon atoms . The most widely studied form, synthesized for the first time in 1985, contains 60 carbon atoms,(C60). This is a hollow ball composed of interconnected carbon pentagons and hexagons, resembling a soccer ball. Fullerenes are a class of materials displaying unique physical properties. They can be subjected to extreme pressures and regain their original shape when the pressure is released.

These molecules do not combine with each other, thus giving them major potential for application as lubricants. When fullerenes are manufactured, certain carbon atoms can be replaced with nitrogen atoms and form bondable molecules, thus producing a hard but elastic material. Fullerenes, whether modified or not, have also shown major potential as catalysts. They have interesting electrical properties and it has been suggested to use them in the electronics field, ranging from data storage to production of solar cells.

Figure: 5 Schematic representation of a fullerene

Incorporating them into carbon nanotubes modifies the electrical behaviour of fullerenes, creating regions with varying semiconductive properties, thus offering potential applications in nanoelectronics. Their properties vary according to wavelength, thus finding applications in telecommunications. Since fullerenes are empty structures with dimensions similar to several biologically active molecules, they can be filled with different substances and find medical applications.

Figure: 6 Schematic representation of a modified fullerene

B) Carbon nanotubes:
Discovered barely a decade ago, carbon nanotubes are a new form of carbon molecule. Wound in a hexagonal network of carbon atoms, these hollow cylinders can have diameters as small as 0.7 nm and reach several millimeters in length. Each end can be opened or closed by a fullerene half-molecule. These nanotubes can have a single layer (like a straw) or several layers (like a poster rolled in a tube) of coaxial cylinders of increasing diameters in a common axis. Multilayer carbon nanotubes can reach diameters of 20 nm.

The small dimensions of carbon nanotubes, combined with their remarkable physical, mechanical and electrical properties, make them a unique material. They display metallic or semiconductive properties, depending onhow the carbon leaf is wound on itself. The current density that a nanotube can carry is extremely high and can reach one billion amperes per square metre, making it a superconductor. Light and flexible, the mechanical strength of carbon nanotubes is more than sixty times greater than that of the best steels, even though they weigh six times less. They also present a very large specific surface area, are excellent heat conductors , and display unique electronic properties, offering a threedimensional configuration. They have a great capacity for molecular absorption. Moreover, they are chemically and thermally very stable.

Figure: 7 Schematic representation ofmonolayer or multilayer carbon nanotubes or nanotubes containing other elements

C) Nanowires
Nanowires are conductive or semiconductive particles with a crystalline structure of a few dozen nm and a high length/diameter ratio. Silicon, cobalt, gold or copper-based nanowires have already been produced. They are used to transport electrons in nanoelectronics. They could be composed of different metals, oxides, sulphides and nitrides.

D) Carbon nanofoams
Carbon nanofoams are the fifth known allotrope of carbon, after graphite, diamond, carbon nanofibers and fullerenes. In carbon nanofoam, islands of carbon atoms, typically from 6 to 9 nm, are randomly interconnected to form a very light, solid and spongy three-dimensional structure, which can act as a semiconductor. Carbon nanofoams display temporary magnetic properties.

E) Quantum dots
An important field of research for about the past five years, quantum dots (also called nanocrystals or artificial atoms) represent a special form of spherical nanocrystals from 1 to 10 nm in diameter. They have been developed in the form of semiconductors, insulators, metals, magnetic materials or metallic oxides. The number of atoms in quantum dots, which can range from 1,000 to 100,000, makes them neither an extended solid structure nor a molecular entity. The principal research studies have focused on semiconductor quantum dots, which display distinctive quantal effects depending on the dimensions. The light emitted can be adjusted to the desired wavelength by changing the overall dimension.

Figure: 8 Different forms of quantum dots showthe organization of the individual atoms

F) Dendrimers
Dendrimers represent a new class of controlled-structure polymers with nanometric dimensions. They are considered to be basic elements for large-scale synthesis of organic and inorganic nanostructures with dimensions of 1 to 100 nm, displaying unique properties. Dendrimers allow precise, atom-by-atom control of the synthesis of nanostructures according to the desired dimensions, shape and surface chemistry. Given that dendrimers can be developed to display hydrophilic or hydrophobic characteristics, their uses can be highly diversified. With different reactive surface groupings, their abundant use is particularly envisioned in the medical and biomedical field. Compatible with organic structures such as DNA, they can also be fabricated to interact with metallic nanocrystals and nanotubes or to possess an encapsulation capacity or display a unimolecular functionality.

G) Other nanoparticles
Some nanoparticles tend to agglomerate and form structures in chains or with multiple branches. This category normally includes welding fumes, silica fumes, carbon black and other nanoparticles, which are often synthesized by flame pyrolysis. These nanoparticles may include metals, metallic oxides, semiconductors, ceramics and organic material. They may also include composites with a metallic core and an oxide or alloy coating, for example. Colloids, which have been known for a long time, are nanometric dimensions. These nanoparticles will not be considered in this study.

2.3 Nanoparticle characterization tools
The characterization of nanomaterials and the understanding of their behaviour is fundamental to the development of new applications and the reproducible and reliable production of nanomaterials. Process nanometrology uses precision instruments with very high sensitivity, capable of measuring at dimensions that are often less than a nanometer. These instruments allow manipulation of individual atoms and measurement of lengths, shapes, forces, masses, electrical properties and other physical properties. They also use electron beam techniques, including high-resolution transmission electron microscopy. Scanning probe techniques include scanning tunneling microscopy and atomic force microscopy. Optical manipulators allow manipulation and measurement of individual atoms.

3. DEVELOPMENT AND PRODUCTION OF NANOPARTICLES
Development of nanoparticles and nanotechnologies is currently one of the most active research fields worldwide. Several industrialized countries are making it a strategic priority for sustainable technological, economic and societal development. Indeed, in 2001 it was estimated that the potential world market would reach one thousand billion1 US dollars by 2015. In 2003, the British Department of Trade and Industry estimated that there would be a world market of USD100 billion by 2005 (Arnall, 2003). The creation of the US Nanobusiness Alliance, the Europe Nanobusiness Association and the Asia-Pacific Nanotechnology Forum, whose shared objective is to commercialize nanoproducts, clearly illustrates the expected magnitude of these markets and the international competition in the field. Quebec is doing likewise via NanoQuebec.

3.1 Worldwide research efforts
A study published in 2002 concluded that, from 1989 to 1998, the rate of increase of scientific publications on nanomaterials increased annually by 27%. This data indicated that over 30 countries were involved in research in this field, the most active being the United States, Japan, China, France, Great Britain and Russia, which accounted for 70% of publications. Also in 2002, Holister concluded that 455 private companies and 271 academic institutions and government entities were already involved in researching short-term applications in nanotechnology around the world. Since then, this field has continued to grow.

Over the past five years, many countries have developed strategic plans and decided to invest massively in nanotechnology research. This will result in an ongoing increase in scientific articles on the subject and a wider variety of research topics. Roco (2001, 2003) reported that government investments had risen from USD 432 million in 1997 to over USD 2.98 billion in 2003.

Worldwide research efforts are currently estimated at over USD 8 billion for the year 2005 alone, about 40% of which would come from the private sector. A detailed review of international investments was carried out by Waters (2003) and by the European Commission (2004a). Despite these colossal investments aimed at development of new commercial applications, research in the occupational health and safety field is still in its infancy.

Five leading Asian countries are heavily involved in research into the development of new products: Japan, China, South Korea, Taiwan and Singapore. Japan is the most important Asian stakeholder in the field and has a completely integrated development policy, which the government sees as the key to the country’s economic recovery. In 2003, the Japanese government invested the equivalent of USD 800 million in the nanotechnology field, while the private sector invested an additional USD 830 million. The British Department of Trade and Industry reported, in 2002, that the first 1 One thousand billion or one million million carbon nanotube and fullerene production plants were under construction in Japan.

The European Union’s 6th Framework Program, known as Nanoforum, allocated USD1.44 billion for the 2002-2006 period and is seeking to develop a European research and communications network integrating all aspects of nanotechnology, ranging from business to science and information intended for the general public. In May 2004, the Commission adopted a plan in which it proposed a safe, integrated and responsible European strategy. Following broad consultations of its members, the 7th Framework Program , proposes to increase the European Union’s R&D investments to strengthen Europe’s global position in this field.

One of the specific objectives of this European initiative is long-term interdisciplinary research to understand the phenomena involved, master the processes and develop research tools. There is particular interest in nanobiotechnologies, nanoengineering techniques, implications for the fields of health and medical systems, chemistry, energy, optics, food and the environment. This European program also covers production and processing of multifunctional materials, the involvement of engineering for the development of materials, and the development of new processes and flexible and intelligent manufacturing systems. The specific initiatives of several countries must be added to these European efforts. Waters (2003) estimates that the aggregate European investments will range between dollar 3.8 billion and dollar 7.8 billion in 2002-2006. However, private enterprise seems to be much less active than in the United States or Japan. Among the most active European countries are Germany, Great Britain, France, Switzerland, Belgium and the Netherlands. Other European countries are also active in nanotechnology R&D, but their investments are more limited: Ireland, Luxembourg, Italy, Austria, Denmark, Finland, Sweden and Norway.

3.2 The most actively studied nanoparticles
The most active research in the nanoparticle field concerns carbon nanotubes, which are expected to have a wide variety of applications in numerous fields. In particular, the use of nanotubes is being considered in electronics, in electrochemistry, as mechanical reinforcements for high-performance composites, as cathode ray transmitters, as a means of energy production or hydrogen storage, or as templates for the creation of other nanostructures, such as production of metallic nanowires by filling carbon tubes. The exceptional strength of the bonds uniting the carbon atoms in a nanotube structure makes them an ideal candidate as reinforcing agents in composites. Among the other uses envisioned, carbon nanotubes could be employed as sensors for high-resolution imaging, in nanolithography, in production of nanoelectrodes or as vectors to transport drugs to specific locations in the human body.

3.3 Polymers used in nanoparticles

Polymeric Nanoparticles:
As name only suggest polymeric nanoparticles are nanoparticles which are
prepared from polymers. The drug is dissolved, entrapped, encapsulated or
attached to a nanoparticles and depending upon the method of preparation,
nanoparticles, nanospheres or nanocapsules can be obtained. Nanocapsules
are vesicular systems in which the drug is confined to a cavity surrounded by
a polymer membrane, while nanospheres are matrix systems in which the
drug is physically and uniformly dispersed.

In recent years, biodegradable polymeric nanoparticles have attracted
considerable attention as potential drug delivery devices in view of their
applications in drug targeting to particular organs/tissues, as carriers of DNA
in gene therapy, and in their ability to deliver proteins, peptides and genes
through a per oral route of administration.


PASSIVE DIFFUSION OF DRUG

The drug undergoes passive diffusion across the skin layers along the concentration gradient, which is thermodynamically a spontaneous process. A simple approach to mathematically explain the passive diffusion of drugs across the skin layers is through Fick&rsquos first law:

Where J is the flux (rate of drug transfer per unit surface expressed mass/unit time/unit area), Cd is the concentration of drug in the formulation, and Cr is the concentration of drug in the receiver, which is generally considered as skin interstitial fluid or systemic circulation. Cd&ndashCr represents the concentration gradient across the barrier where h is thickness of the membrane. D is the diffusion coefficient of the drug in the stratum corneum (cm 2 /sec). K is the partition coefficient of drug between formulation and stratum corneum. (Generally, the partition coefficient of drug in octanol and water system is considered in this case.)


Results

NTX Pharmacokinetics in Humans After TD Administration.

The principal question we wanted to address was whether pretreatment of skin with MNs, and subsequent placement of a TD patch, would permit rapid attainment of pharmacologic, clinically relevant and sustained plasma levels of a hydrophilic molecule not normally absorbed across intact skin. To address this question, our data show that MN pretreatment of the skin permitted rapid systemic exposure to NTX. Measurable plasma levels were demonstrable within 15 min after patch placement in three MN-treated subjects and within 30 min for the remaining three subjects. The concentration–time curve (Fig. 1) shows a rapid rise or burst of absorption within the first several hours of application. Maximum concentrations occurred within a range of 1.5 to 18 h.

Mean (SD) NTX plasma concentrations for 72 h of patch application. (Inset) Early sampling points.

Additional questions regarding our technique relate to the length of time the micropores remain open. Would the pore function for several days, permitting relatively constant rates of drug delivery for systemic absorption, or rapidly undergo healing changes that would retard drug absorption? We demonstrate steady-state or a relatively constant plasma concentration of NTX was achieved within hours, to at most 1 day after patch placement, which indicates rapid transit, localized diffusion, equilibrium of NTX through dermal layers, and absorption into capillary beds (Table 1). Approximately zero-order delivery appeared to be achieved for 48 h with a steady-state plasma concentration of ≈2.5 ng/ml, consistent with levels associated with pharmacologic activity. The maximum concentration obtained was somewhat variable and ranged from 1.6 to 8.1 ng/ml. Subjects with the lower concentration profiles tended to have lower peak-to-trough differences over the 72-h administration period. Similarly, the time to maximum concentration had a wide range, from as little as 1–2 h in two subjects, to as long as 18 h in two other subjects.

NTX and NTXOL exposure after MN-enhanced TD delivery

Skin micropores appeared to have remained open for at least 48 h as plasma levels appeared to be relatively constant for the first 48 h of administration. Two subjects had a profile suggesting drug permeation up to 72 h. Average plasma levels appeared to be consistent for at least 48 h, with a modest average decline of NTX concentration by ≈50% at 72 h. The 72-h time-point average concentration of 1.8 ng/ml was ≈25% of the maximum concentration and 50% of the steady-state concentration. Pharmacologically active plasma concentrations were still evident at the last time point, 72 h after patch placement. The apparent plasma clearance of NTX indicates an approximate half-life of 4.4 h, suggesting that 95% of NTX would be eliminated within 24 h of patch removal. In contrast to the MN-treated subjects, the control subjects had undetectable (<1 ng/ml) NTX plasma levels, indicating minimal transfer of drug across the skin. Average peak levels in MN-treated subjects were 4.5 times larger than the assay detection limit.

Drug delivery systems that avoid presystemic drug clearance have been demonstrated to remarkably change the metabolite profile of certain medications. Similarly, we wanted to understand whether the TD system would significantly alter, and perhaps even reverse the ratio of the parent drug NTX to the metabolite. Naltrexol (NTXOL primary metabolite of NTX) plasma concentrations were significantly less than the parent drug NTX (Fig. 2). This finding is consistent with avoiding presystemic first-pass metabolism of NTX. In contrast, NTXOL plasma concentrations are significantly higher than the parent drug NTX after oral administration (24). The reversal of parent-to-metabolite ratio is a desirable outcome, because the NTXOL metabolite is associated with adverse effects.

Mean (SD) NTXOL plasma concentrations for 72 h of patch application. (Inset) Early sampling points.

A steady-state concentration of 0.6 ng/ml NTXOL was obtained throughout the 72-h patch placement. The time to reach steady state was comparable to NTX, indicating a slight delay in presentation to the hepatic system for metabolism. Maximum NTXOL concentrations were also modest and were not obtained until an average of 45 h after patch placement. Thus, the MN-facilitated TD delivery of NTX resulted in generation of a much lower quantity of the metabolite (NTXOL) and at a much later time, i.e., 45 h after TD administration using MN versus 1 h after administration of a tablet (19). The study by King et al. (21) suggests our result could lower the side-effect profile of NTX, and improve compliance and retention in treatment, because withdrawal from oral drug treatment is associated with subjects who generate high levels of NTXOL.

Effect of MNs and NTX Patch on Human Skin.

Limited previous studies have been reported on local tolerance of MNs themselves in humans. In our study we wanted to determine the tolerability of the MN arrays combined with a drug formulation and delivery system in humans. Our article demonstrates the tolerability of the combined technologies in humans. MN arrays and patches were easy to administer. Administration of MNs simply required removing their protective liner and pressing the MN against the skin by hand. Application time for MNs and TD patches took 1–2 min, which is quite short, given the nature of the prototype MN and patch systems. MN arrays were examined for physical damage after their application to each subject. No MN array had bent or broken needles, and no needles were broken off into the subjects' skin.

The MN-treated subjects tolerated the MN and patch application system well. Subjects reported no pain when MNs were applied to their skin. The sensation of placement was described as simply of pressure applied at the site. Two subjects reported mild systemic side effects associated with NTX, such as nausea and lethargy, which are believed to be drug-specific and not directly associated with the MN delivery route. There was no clinically significant change in vital signs or liver function tests as a result of TD NTX administration. Control subjects also tolerated the patch system and reported no systemic-related side effects.

Four of the six MN-treated subjects did have skin changes observed when the patch and occlusive dressing were removed after 72 h of application, such as localized irritation and erythema outside of the patch placement site but within the dressing area for two of the subjects. Upon removal of the patch, two of the four subjects demonstrated contact dermatitis that exactly outlined the dimensions of the MN arrays insertion grid. Inside the raised areas were very small crusts that may represent the insertion points of the MNs and the subsequent micropores. The affected subjects were prescribed diphenhydramine capsules (antihistamine) and topical hydrocortisone cream as treatment. Subjects were seen in the clinic 4–6 days later and had responded to treatment. Re-examination of the skin demonstrated the contact dermatitis was greatly diminished and within 1–2 weeks had disappeared. However, the crusts continued healing throughout the 2-week observation period, with a faint outline of the MN array insertion points still evident. Only one control subject demonstrated any finding on skin examination. The subject complained of itchiness and irritation, which was under the occlusive dressing and the patch. The findings disappeared upon removal of the patch.

To better understand the possible causes of skin irritation seen in this study, we carried out an additional study in 10 subjects to assess the effect of just MN insertion followed by occlusion of the skin. No NTX or patch formulation was used. Immediately after insertion, erythema was typically seen at the punctate sites where each MN penetrated into the skin (data not shown). The degree of erythema varied from barely visible to moderate, highly localized, submillimeter spots of redness. Within a few hours, erythema disappeared in most cases, such that it was not possible to distinguish between MN-treated skin and adjacent skin. The more dramatic effects of contact dermatitis observed in the two patients administered NTX were not seen in any of the subjects treated with MNs alone. We therefore conclude that MNs themselves cause little to no skin irritation that is highly transient and that the NTX and/or formulation excipients were responsible for the skin irritation observed in some subjects in this study. Further optimization of patch formulation could reduce or eliminate this irritation.

To better understand the lifetime of TD transport pathways created in the skin by MNs, we carried out a supplemental study in which skin electrical resistance was measured as a function of time after piercing the skin with MNs in 10 human subjects. Skin electrical resistance has been shown to correlate well with skin permeability to various molecules (25). Average skin resistance dropped from 397 ± 183 kΩ before treatment to 11.7 ± 5.5 kΩ after MN insertion and removal. After covering with an occlusive dressing, skin resistance steadily increased but remained significantly less than the resistance of an adjacent control site of untreated skin for 30 h (Student's t test, P < 0.05). These measurements are consistent with the measurements of NTX pharmacokinetics, which both show that brief treatment of skin with MNs creates long-lived permeability. There are quantitative differences between the measurements, however, because the electrical resistance measurement indicated a permeability lifetime of 30 h, whereas the NTX delivery measurement indicated a lifetime up to 72 h. This difference may exist because the electrical measurement assessed the barrier properties of skin's SC, whereas the NTX measurement assessed the kinetics of drug delivery into the bloodstream, which is influenced not only by the SC barrier, but can also be influenced by diffusion, pooling, and possible binding in the skin en route to the bloodstream, which can delay the kinetics of drug clearance.


Toxicological challenges of intranasal application

Safety is a key issue when designing an effective and safe drug formulation, for IN administration. During the development process, safety consideration not only of the drug itself but also of the active ingredients and excipients within the formulation must be considered. Absorption enhancers are necessary for large molecules such as peptides and proteins. They increase the bioavailability of the drug following IN administration by improving the permeability of the nasal mucosa. Other excipients act as mucoadhesives and prolong the contact time with the nasal mucosa. Because of their own safety profile and the increased local exposure time of the drug, the excipients can significantly decrease the safety of the final drug product [192�]. Also, the toxicological considerations must be discussed regarding local, systemic, CNS and pulmonary effects of the drug formulation.

Local side effects

The local tolerability of a drug product depends on many different factors and differs between individuals. Environmental cues such as temperature and humidification, psychologic factors but also individual physiological factors such as infections, pre-existing illness or allergies influence the local interactions between drug product and nasal mucosa. For this review, only intrinsic biologic factors are considered. Those biological factors are affecting the drug absorption in the nasal mucosa and therefore influence the toxicologic profile of the final drug product. The nasal blood flow regulates important conditions in the nose such as temperature or humidification of inhaled air. There is a range of drugs that are known to influence the blood flow, such as vasomotors. Oxymetazoline, which is used as a decongestant for allergies and colds, was shown to decrease the blood flow within the nose as a vasoconstrictor [195�]. Further, IN corticosteroids are also vasoconstrictors leading to relief in patients with seasonal rhinitis. Rare side effects such as nose bleeding and the very rare occurrence of nasal septal perforation were observed [113, 115, 198, 199]. In contrast, other drugs increase the blood flow in the nose, for example histamine, albuterol, isoproterenol and fenoterol [113, 118].

Another biologic factor which should be considered regarding toxicologic and safety issues is the enzymatic activity in the nasal mucosa. As the nasal mucosa is a direct contact zone towards environmental keys, it also represents a barrier towards harmful substances and xenobiotics. Hence, there are also defensive enzymes present that metabolise substances and drugs. To date, it is known that the nasal mucosa has a wide spectrum of xenobiotic-metabolizing enzymes, comprising enzymes belonging to the P450-dependent metabolism pathway (e.g. P450 monoxygenase), Phase I enzymes (flavin monooxygenases, aldehyde dehydrogenases, epoxide hydrolases, carboxylesterases, etc.) and Phase II enzymes (glucuronyl and sulphate transferases, glutathione transferase) [118, 200, 201]. It can be assumed that these enzymes are also metabolizing intranasally administered small-molecule drugs such as opioids, histamines, corticosteroids and more [118, 202].

Not only enzymes protect the nose and upper airways from potentially harmful substances and xenobiotics, but also the nasal mucociliary system represents a major part of defence mechanisms within the nose. The mucus layer covers the nasal epithelium and transports particles through ciliary beating towards the nasopharynx. The ciliary beating frequency (CBF) is under cellular control, regulated by temperature, intracellular Ca 2+ , cAMP and extracellular ATP level. Other physiological functions of the nasal mucosa include its water-holding capacity and its responsibility for the efficient heat transfer within the airway. Further, it exhibits surface electrical activity [193]. Thus, the impairment of these systems can lead to longer contact times of formulations, physiologic impairment and damage of the mucosa and the nasal epithelium.

The human nasal mucosa has an average physiologic pH of 6.3 and is therefore slightly acidic. The maintenance of the pH in the mucus ensures the function of the ciliary clearance [203]. Therefore, the pH of nasal formulations should be within a pH range of 4.5 to 6.5 to avoid nasal irritation [118]. Not only the pH but also the osmolarity has an influence on the ciliary beat and can therefore contribute to local toxicological considerations [118, 190]. Many substances are however influencing the mucociliary clearance (MCC) through either stimulation or inhibition. Instead of stimulation effects, the inhibitory effects are the main cause of adverse side effects such as nasal dryness, irritation, sneezing, nasal itching but also rhinitis medicamentosa and congestion. It is worth to mention that MCC and CBF effects are usually evaluated in vitro. Those in vitro tests do not allow predictions about ultimate effects in vivo, as in vitro tests show effects on MCC and CBF, whereas in vivo the same compounds often do not lead to detectable side effects [204]. In general, it was shown for many compounds that the inhibitory effect on the mucosal clearance and CBF is dose and time dependent. For example, the α-adrenergic receptor agonists oxymetazoline and xylometazoline showed inhibitory effects for human nasal mucosa in vitro in a dose-dependent manner [205, 206]. Many corticosteroids and anti-histamines are also influencing the MCC and CBF in in vitro studies but at the same time show no adverse effects in vivo [194, 207�]. The mucociliary effect of drugs is however only one aspect. Excipients are used not only to improve the drug transport and bioavailability through the nasal mucosa and epithelia but also to protect the drug product from microbial contamination and degradation. Those enhancers and preservatives have to be considered and evaluated in toxicological examinations. A prominent example for the toxicologic relevance of preservatives is benzalkonium chloride (BKC), which is used for cosmetics and in several nasal formulations. BKC showed in different animal models such as chicken embryo tracheas, rat and guinea pig tracheal tissue the inhibitory effect on CBF. This effect is dose and time dependent with ciliostasis and ciliotoxicity as the ultimate response [210, 211]. In vivo histological examinations in rats showed that BKC can also provoke nasal lesions. Concentrations of 0.05 and 0.10 w/v % BKC administered into the nasal cavity of rats led to histopathological findings such as epithelial desquamation, degeneration, oedema or neutrophilic cellular infiltration in the anterior parts of the nasal mucosa [212]. Further studies support the toxic effect of BKC on the nasal mucosa in vivo [213]. For example, in one study, 10 µl of nasal steroid formulations was administered twice daily to rats for 21ꃚys, either with or without BKC (310 or 220 µg/ml). In the nasal cavities of rats receiving a formulation containing BKC, a range of alterations including reduced epithelial cell high, pleomorphism of individual epithelial cells, reduced number of cilia and goblet cells associated with a loss of mucus covering the epithelial cell layer was observed [214]. Further, in in vitro studies, the toxic and CBF inhibitory effects on human nasal mucosa were observed as well [207, 215]. Nevertheless, the safety concern about BKC remains controversial, as there are studies reporting no toxic effect of BKC in vivo. However, the use of BKC in aqueous formulation in vivo has been considered as safe [194, 213, 216]. The European Medicines Agency (EMA) summarises that the average nasal use of BKC in medicine products is between 0.02 and 0.33 mg/mL and that preclinical data show a time- and concentration0dependent toxic effect on cilia in vitro and in vivo in rats. Further, they state that it is not possible to recommend any safety limit for the general population of patients [217].

Besides preservatives, also penetration enhancers are used in nasal formulations. They are improving the bioavailability and transport of compounds across the nasal epithelium and mucosa. Wanted effects of enhancers include opening of TJs, alteration of the mucus layer and inhibition of proteolytic enzymes. In turn, those functions have a disruptive character and can thus lead to adverse side effects, which can be additive [192, 194, 204, 216]. It is essential to consider that many substances and compounds act as irritants to the nasal mucosa but are non-damaging. The local effects of a formulation are always an interplay between drug and excipients. Further, the testing procedure such as dose, time and in vitro test system as well as animal species has to be evaluated carefully before concluding about safety issues.

Systemic and CNS side effects

One of the main advantages using INDD compared with other administration routes such as oral or intravenous application is the bypassing of the metabolic first-pass effect and the reduced risk of systemic adverse effects. Intranasal 17 b-estradiol, marketed as AERODIOL, is an example for the possible superiority of IN drug delivery over oral drug delivery. Several clinical studies showed that AERODIOL leads to less systemic adverse side effects, such as mastalgia and breakthrough bleeding, compared with oral or transdermal delivery, while exhibiting at least the same efficiency [132�, 218]. The same was observed for intranasally delivered benzodiazepines such as diazepam and midazolam, which are used to treat seizures and epilepsy in emergency situations besides other indications. Major observed systemic side effects include not only sedation, drowsiness, sleepiness or amnesia, but also respiratory depression is a potential side effect [219]. However, clinical and pre-hospital studies are supporting the view that IN benzodiazepines are as safe or safer than oral, rectal or intravenous administration [220, 221]. Many systemic side effects and effects on the CNS are the result from the ability of the substance to reach the blood circulation and traverse the BBB. In conventional epilepsy treatments, drug resistance to anti-epileptic drugs can occur when drug does not pass the BBB sufficiently, as a result from improper dosing and wrong drug choice [222]. These complications, as well as drug-associated toxicities, can be overcome by suitable drug delivery systems. Nanotechnology-based systems are a rising technology for improving ntb delivery. They facilitate a more targeted and efficient brain delivery and reduce side effects at the same time [223]. The advantage of using nanotechnology-based drug delivery systems has been shown for different CNS indications, such as epilepsy, psychosis-related disorders and glioma [152, 223�].

The nasally administered sympathomimetic oxymetazoline is used not only as a topical treatment for rhinitis but also as an anaesthetic and for the treatment of epistaxis. Oxymetazoline is a potent peripheral alpha adrenergic 1 and 2 agonist, but when it reaches the systemic blood circulation, it can also stimulate central alpha 2 adrenoreceptors. Hence, adverse systemic effects include, amongst others, vasoconstriction and sympathetic effects such as fast, irregular or pounding heartbeat, headache, dizziness, drowsiness, high blood pressure, nervousness and trembling [197, 228, 229]. These effects can cause hypertension, tachycardia and peripheral vasoconstriction. However, the adverse side effect profile of intranasal oxymetazoline is not unique and aligned with the side effects of sympathomimetics in general, regardless of the administration route. Further, those side effects are in particular relevant in paediatric medicine and for patients with underlying medical conditions [228�].

Intranasally administered drugs and formulations show an overall better systemic tolerability compared with other administration routes such as intravenous or oral application. This is mainly due to bypassing of the metabolic fist-pass effect. Further, systemic adverse effects observed in the clinic, such as drug resistance to anti-epileptic drugs, depend on the properties of the drug itself, wrong handling or overdosing but not on the administration route [222].

Pulmonary effects

Drug or substance-induced respiratory and pulmonary problems are intensively described in clinical and histological observations. They range from mild effects such as coughing or breathing problems during sleep to severe effects such as pulmonary toxicity, infections, pneumonia and acidosis. Over 1300 substances and drugs are listed to affect the respiratory tract (www.pneumotox.com). In this review article, we will only focus on drugs inducing adverse respiratory effects after IN administration. As described above, benzodiazepines are applied intranasally to treat emergency seizure events in paediatric populations. One known adverse side effect is treatment-induced respiratory depression. This side effect is, however, independent of the administration route. In fact, collected data suggests that IN delivery of benzodiazepines such as midazolam and diazepam is safer with regard to respiratory depression compared with oral or intravenous administration. It is judged to be as safe as rectal administration [219, 233, 234]. Another example is the neurohormone oxytocin, which is used intravenously for labour induction, for abortions or for the control of post-partum bleeding. Even though oxytocin is described as a relatively safe medication, rare cases of treatment-induced severe adverse and life-threatening side effects such as pulmonary hypertension and pulmonary oedema were reported [235�]. Intranasally delivered oxytocin is under investigation to treat psychiatric disorders. There are a number of IN oxytocin studies in humans however, adverse events are not described according to a standardised scheme and are therefore inconsistently reported [161�, 239, 240]. Since IN delivery is not a popular administration route, studies comparing effects on safety of IN vs IV administration of oxytocin are rare. Literature reviews that report safety data of IN oxytocin administration have only mentioned mild respiratory effects such as asthma attacks [241, 242].

Pulmonary effects can be an important reason for a drug formulation to get delayed market approval or even withdrawn after approval. This was a lesson learned for the field of pulmonary drug delivery. Exubera® was the first approved formulation of inhalable insulin from Pfizer Labs (New York, NY), which reached the US market in 2006. It was used to treat type 1 and 2 diabetes in non-smokers without pulmonary diseases [243]. Apart from economic reasons for withdrawing Exbuera®, it showed pulmonary toxicity issues [244]. During clinical use, symptoms such as non-progressive dry cough were observed, and pulmonary function test became necessary, as pulmonary function parameters decreased during long-term use [243, 245]. Further, there were some cases of previous smokers treated with Exbuera® who developed lung cancer. Insulin is a growth factor, and inhalation of insulin could lead to a secondary activation of pro-proliferative insulin-like growth factor (IGF-1) pathway [246]. There were, however, too fewꃊses to determine whether these lung cancer cases were associated with the inhaled insulin formulation [243]. Since, 2014, the company Mannkind Cooperation received the US market approval for Afrezza, an inhaled insulin with improved PK/PD properties, but the pulmonary toxicity issue could not be ruled out after all [247].

It is important to consider that not only the drug itself but also other components of a drug formulation can result in adverse pulmonary and respiratory effects. In a dose- and concentration-dependent manner, benzalkonium chloride showed that its target organ is the lung. It induces lung irritation, inflammation and alveolar damage after inhalation and can lead to pulmonary oedema and pneumonia after oral or intravenous administration in rats [248]. Indeed, benzalkonium chloride used as a preservative in nasal sprays in low concentrations of 0.007𠄰.01% is considered to be safe regarding pulmonary effects [249].


API Delivery System Development

Organisms are controlled on the cellular level by a multitude of bioactive molecules. It is highly likely that throughout an organism’s lifetime one of these systems will falter due to disease or injury and a therapeutic API could be employed to aid in the recovery of normal function (7). The complex nature of an organism’s cells and physiology provide many opportunities for API intervention (for instance, specific intracellular functions) when required to affect the desired response (7). APIs have a therapeutic window (as depicted in Figure 1). Below the therapeutic window we observe the subtherapeutic region in which an API is ineffective at providing the desired effect, whereas above the therapeutic window unwanted side effects and toxicity may be observed (8).

Fig. 1.

Examples of release profiles

The formulation of APIs to deliver quantities of the API within the therapeutic regime is of key importance to their clinical translation and success. Formulations can be divided into two broad categories: non-synthetic formulations (the most common) where the API is used unmodified in combination with other ingredients in order to achieve the desired effect (see Table II for examples) or synthetic formulations, where the API is synthetically modified to impart the desired properties, for example, prodrugs (14). Formulations need to be tailored to suit their route of administration such as inhalation, injection, oral or transdermal. For humans, oral intake is by far the most popular, providing fast release, cost effectiveness and relatively high patient compliance (15). The fast release provided by traditional methods of API delivery such as inhalation, injection, oral and transdermal can be beneficial for pain relief, however they often require the patient to take a relatively high dose of an API to ensure a small amount of the API reaches the desired location to elicit the desired therapeutic response (16). This may also result in issues related to API clearance from the body (metabolised or excreted via the renal system) which can limit the duration the API is within the therapeutic window. Other factors including the biological and physicochemical properties of the APIs (such as solubility and absorption) (17, 18) and patient compliance (of growing importance with ageing populations worldwide) highlight the market need for controllable API delivery systems for medical or veterinary applications, similarly for agrochemical applications (19). Indeed, API delivery systems that reduce the number of administrations required offer potentially significant economic, health and societal impacts (20).

Table II

Examples of Clinically Translated Stimuli-Responsive Formulation Systems

Stimulus Treatment Reference
Radiation Radiotherapy (9)
Light Photodynamic therapy (10)
Electricity Electroconvulsive therapy (11)
Ultrasound Sonograms (12)
Infrared Thermography (13)

Researchers based in industry and academia have therefore invested significant effort in the development of API delivery systems to address these issues, which are often classified generationally, with first generation delivery systems developed between 1950–1980, second generation delivery systems developed between 1980–2010 and third generation delivery systems developed from 2010 onwards (21–23). The first case of controlled API release was published by Smith, Kline & French, USA, when they demonstrated the ability to release dextroamphetamine (Figure 2) over a 12 h period in 1952 (24). The success of this breakthrough prompted an investigation of new controlled API delivery systems designed to reduce intake to once or twice a day and mechanisms of API release (osmosis, ion-exchange, diffusion and dissolution) (25). By understanding these release mechanisms it was possible to begin to control the physicochemical characteristics of API delivery systems and thereby the release profiles of the APIs. While first generation API delivery systems delivered their payloads at a predetermined rate that was often short and did not account for patient needs or varying physiological conditions (8), second generation API delivery systems are characterised by attempts to control the level of API within target tissues above the minimum effective level for prolonged periods. The maintenance of the minimum effective level is important not only to ensure the benefit of the API to the patient over an extended period of time, but also to prevent the onset of side effects and immune responses. An interesting example of this is a formulation capable of sustained release of quetiapine (Figure 2, which is used in the treatment of schizophrenia) that has reduced the administration regime to a single dose per day, diminishing problems with patient compliance (26, 27).

Fig. 2.

Examples of chemical structures

Second generation API delivery systems also include examples capable of delivering high molecular weight APIs (peptides, proteins and DNA) potentially from hydrogel- or nanoparticle-based API delivery systems, that were optionally cell-targeted or stimuli-responsive (25). The third generation API delivery systems are characterised by efforts to: deliver poorly soluble APIs tightly control release kinetics (for example via application of one or more external stimuli) and overcome biological barriers (such as the blood-brain barrier) (23, 25).

An ideal API delivery system would be a source of a specific amount of API to a precise location with temporal control, thereby allowing maintenance of a minimum effective level of the API for the duration required to have its therapeutic effect (illustrated in Figure 1) (28). Different situations require different API release profiles and application- or patient-specific API delivery profiles are desirable for the medical, veterinary and agrochemical industries (29).

API delivery systems incorporating polymers have been developed for first, second and third generation of delivery systems and polymers of various architectures are key components of both non-synthetic (such as aerosols, dispersions, emulsions, foams and suspensions) and synthetic formulations (for instance, as a polymer prodrug). The pioneering research of Robert Langer and coworkers underpins the development of polymer- based drug delivery systems (DDS) in academic and industrial settings (30–32). Polymer chemistry and engineering to tailor the structures of polymers for specific applications is an area of intense ongoing research interest (33), particularly with a view to developing API delivery systems that provide control over the quantity, location and time of API delivery (34).

Polymer-based API delivery systems can enhance the duration of activity for APIs with short half-lives (28). API delivery systems that encapsulate a payload of API and break down at a predictable rate can be utilised for a variety of therapeutic agents, particularly when displaying a moiety that targets the API to specific cells or tissues (35). Poly(ethylene glycol) (PEG, Figure 2) is a polymer often conjugated to macromolecular APIs (commonly known as PEGylation) (36) to enhance their half-lives by reducing their rate of clearance via the renal system and eliciting minimal inflammatory response (37).

The utilisation of biodegradable and bioerodible polymers such as poly(caprolactone) (PCL, Figure 2), poly(D,L-lactic-co-glycolic acid) (PLGA, Figure 2) and PEG that respond to enzymes such as esterases and lipases are now very popular as a result of their biocompatibility in vivo reducing the immune response and averting systemic toxicity (38, 39). Cisplatin (Figure 2) (40) is a common anticancer API that has proved effective in the treatment of a variety of tumours however its inherent toxicity and resistance limitations have prevented the full potential of this API being reached (41). A recent study into the construction of platinum(IV)-encapsulated prostate-targeted nanoparticles of PLGA-PEG functionalised with prostate-specific membrane antigen (PSMA) targeting aptamers was found to help optimise the delivery of a lethal dose of cisplatin to prostate cancer cells (41). The use of these polymeric agents in this manner not only provides controlled breakdown of the DDS giving slow release of the API but also provides specific targeting of cancer cells.

Other physicochemical triggers (for instance, pH) are also of interest for API delivery systems. Cancer cells are associated with a lower pH (normally ca. 5/6) than normal cells thus making pH sensitive API delivery systems desirable as damage to healthy cells can be minimised (42). Likewise, the acidic milieu within dental caries-producing biofilms are another situation in which pH can be a useful trigger for oral drug delivery (43).


Stratum corneum and its lipid architecture

Skin acts as a barrier for diffusion of substances through it and the major barrier for most substances resides in the SC, outermost layer of the skin. The SC consists of flat, non-nucleated keratin enriched dead cells, corneocytes surrounded by intercellular non-polar lipid domains. Interconnecting the corneocytes are protein structures, referred to as desmosomes [ 12 , 13 ]. Corneocyte wall is a very dense, cross-linked protein structure that reduces absorption of drugs into the cells [ 14 ]. The intercellular lipid matrix forms a continuous pathway from the skin surface to the viable skin tissues creating the principle path of entry for many chemicals. Therefore, it is crucial to understand the nature of the extracellular lipid matrix of the SC to deal with the permeability of human skin (Figure 2) [ 15 ].

Published online:

Figure 2. Different penetration pathways across the skin (the upper right corner shows the channel formed by intercellular lipid matrix).

Figure 2. Different penetration pathways across the skin (the upper right corner shows the channel formed by intercellular lipid matrix).

Human SC lipids consist of free fatty acids (FFAs), ceramides (CERs) and cholesterol (CHOL) in an approximately equimolar ratio. FFAs in humans are predominantly saturated and consists of chain lengths up to 36 carbon atoms, with C12, C18, C24 and C26 being the most prominent FFAs. In addition to the saturated FFAs, minimal amount of mono-unsaturated FFAs (MUFA), poly unsaturated fatty acids (PUFAs) and hydroxyl FFAs are found. Unlike FFAs, CERs consist of two carbon chains, viz. one fatty acid (acyl) amide connected to sphingoid base. The acyl chain of CERs differs from C14 to C32 and that of sphingoid base constitutes between C14 and C28. In addition, each acyl and sphingoid base has an additional functional group. The variety of chain lengths and head group structures thus results in the existence of over 400 different CER species. Next to CHOL, CERs and FFAs, SC also contains other lipid classes, such as the glucosyl CERs, precursor of CERs, and CHOL sulphate having significant part in desquamation process [ 16 ]. The arrangement of lipid matrix in SC can be understood by lateral organization (i.e. the molecular packing of lipids in lamellar plane generally parallel to the SC surface) and lamellar organization (i.e. the symmetry and the repeated distance perpendicular to the SC surface of lipids). Lamellar organization of SC consists of stacks of lamellae of so-called broad-narrow-broad arrangement having regular repetitive units with a repeated distance of 13 nm particularly referred to as long periodicity phase (LPP). Besides a 13 nm lamellar phase, a second lamellar phase has also been detected having periodicity approximately 6 nm and is therefore called as the short periodicity phase (SPP). The LPP is found between the large, flat surfaces of adjacent corneocytes and the SPP – close to their edges. Lateral lipids in the intercellular matrix can adopt three varieties of packing arrangements which differ in their rotational and translational motilities. In the most densely packed, orthorhombic (OR) phase, the lipid chains adopt an all-trans conformation and are organized in a rectangular crystalline lattice with no rotational or translational mobility. In the hexagonal (HEX) phase, the all-trans lipid chains have some rotational mobility along their long axis, but their translational mobility is restricted whereas in the liquid-crystalline (LIQ) phase, the chains have both high rotational and high translational mobility. All these three phases co-exist in healthy human SC, with a notable prevalence of the OR phase [ 15 , 17 ].


Lesson Get in My Body: Drug Delivery

Units serve as guides to a particular content or subject area. Nested under units are lessons (in purple) and hands-on activities (in blue).

Note that not all lessons and activities will exist under a unit, and instead may exist as "standalone" curriculum.

TE Newsletter

Daily insulin can be administered by various drug delivery methods.

Summary

Engineering Connection

Pharmaceuticals are commonly used to relieve pain, fight disease and stabilize hormone levels. Each drug has its own method of action and is designed by chemical engineers to reach specific body locations. In order to reach its destination, a drug may pass through the harsh conditions of the stomach or be injected through the skin. Engineers design drug encapsulations to release drugs at the optimal time or alter drug properties to increase bioavailability through cocrystallization. These sorts of inventions and technologies designed by engineers are focused on improving our health, happiness and safety.

Learning Objectives

After this lesson, students should be able to:

  • Describe the advantages and disadvantages of drug administration methods.
  • List pharmaceutical design considerations.
  • Discuss new drug administration methods and current drug delivery research.

Educational Standards

Each TeachEngineering lesson or activity is correlated to one or more K-12 science, technology, engineering or math (STEM) educational standards.

All 100,000+ K-12 STEM standards covered in TeachEngineering are collected, maintained and packaged by the Achievement Standards Network (ASN), a project of D2L (www.achievementstandards.org).

In the ASN, standards are hierarchically structured: first by source e.g., by state within source by type e.g., science or mathematics within type by subtype, then by grade, etc.

NGSS: Next Generation Science Standards - Science

HS-ETS1-1. Analyze a major global challenge to specify qualitative and quantitative criteria and constraints for solutions that account for societal needs and wants. (Grades 9 - 12)

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Humanity faces major global challenges today, such as the need for supplies of clean water and food or for energy sources that minimize pollution, which can be addressed through engineering. These global challenges also may have manifestations in local communities.

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International Technology and Engineering Educators Association - Technology

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State Standards
Texas - Science
  • communicate valid conclusions supported by the data through methods such as lab reports, labeled drawings, graphic organizers, journals, summaries, oral reports, and technology-based reports. (Grades 9 - 11) More Details

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Worksheets and Attachments

More Curriculum Like This

Students learn about various crystals, such as kidney stones, within the human body. They also learn about how crystals grow and ways to inhibit their growth. They also learn how researchers such as chemical engineers design drugs with the intent to inhibit crystal growth for medical treatment purpo.

Students experience the engineering design process as they design, fabricate, test and redesign their own methods for encapsulation of a (hypothetical) new miracle drug. The objective is to delay the drug release by a certain time and have a long release duration—patterned after the timed release re.

Pre-Req Knowledge

A basic understanding of human anatomy, the circulatory system and pharmaceuticals, as well as a familiarity with polymers, crystals and stoichiometry.

Introduction/Motivation

(Be ready to show the class the 16-slide Get in My Body: Drug Delivery Presentation, a PowerPoint ® file. In addition, hand out copies of the Drug Delivery Worksheet for students to individually complete during the presentation.)

Pharmaceuticals help save lives by combating disease, providing vaccination against pathogens, fighting infection and adjusting hormone levels in the human body. Earlier and simpler methods of pharmaceutical administration include eating herbs that contain pharmaceutical compounds, infusing drugs into tea and using pastes such as Vicks ® VapoRub TM topical ointment. As more pharmaceuticals are discovered and/or created, administration methods have evolved. For example, the invention of injections enabled doctors to save and/or improve more lives.

(Open the PowerPoint ® presentation to show the entire class.)

(Slide 2) Challenge question: Imagine that you are a doctor, physician assistant or nurse practitioner. Your patient has a condition that requires her to keep constant levels of a medication in her body, but she is unable to swallow. She needs to take her medication at least twice a day for the rest of her life. What other method(s) can you use to administer her medication? To ensure patient compliance and safety, the drug delivery method must be as simple as possible.

(In groups of four or five students each, have students discuss the challenge question for five minutes. Then, have the groups share their ideas with the class. Some ideas include injections or shots, inhalation administration, topical cream so the blood absorbs the drug through the skin, etc.)

(Continue with the presentation, as guided by the Lesson Background section information.)

Lesson Background and Concepts for Teachers

Pharmaceuticals are an important aspect of medicine some people need them to survive. Each drug has a specific target location inside the body where it interacts. How do pharmaceuticals reach their destinations? Various methods of drug delivery have been invented choosing the type of administration is determined by the type of injury or malady, and the patient. This lesson covers five types of pharmaceutical administration: 1) oral, 2) injection, 3) topical, 4) inhalation and 5) suppository.

(slide 3) For oral administration, a pill or liquid pharmaceutical is taken by mouth and travels through the digestive tract. Common examples of oral medication include aspirin, Advil ® , Tylenol ® , cough syrup, as well as some steroids and painkillers. The benefits of oral administration include ease of application and slow drug release. Oral administration is ideal in cases in which the drug needs to be long-lasting encapsulation is often used to protect the drugs from strong digestive enzymes. Refer to the associated activity, Proof of Concept: Miracle Drug Encapsulation for students to practice with the engineering design cycle to prototype large-size shell encapsulation for oral drug delivery using household materials. Many people prefer this convenient method and it can be used in many instances, except when a person cannot swallow or is vomiting profusely. However, slow adsorption of a drug into the bloodstream is not ideal in cases when patients need something immediately, so in those cases, oral administration is not the best option. Also, pharmaceuticals administered orally have unpredictable adsorption due to degradation. Drugs are administered differently depending on the patient malady: pills and capsules are taken orally, vaccinations via syringe, lotions and soaps on the skin.

(slide 4) Injection encompasses three methods: intravenous, intramuscular and subcutaneous. They all require some type of needle inserted into the vein, muscle or skin:

(slide 5) For intravenous (IV) administration, drugs are infused directly into veins. The entire dosage reaches the bloodstream immediately and the effects are dependable and reproducible, eliminating any worry about adsorption. In fact, compared to all pharmaceutical administration methods, intravenous administration delivers the highest percentage of the drug to the circulatory system. Conversely, intravenous administration is also more labor intensive, expensive, requires a cannula (IV line), can be distressing to patients and is more prone to cause them infections.

IV lines can be placed in any vein, though they are commonly inserted into a person's hand, wrist or arm. As veins "blow out," other veins in the body are used such as those in the legs, feet, chest and neck.

Common medications that utilize intravenous administration include blood transfusions, saline (for dehydration), propofol (a sleeping drug) and anesthesia medications for surgeries.

(slide 6) For intramuscular administration, drugs are injected into the muscles of the body. Flu vaccinations are intramuscular injections. When nurses insert needles into the body, they pull the syringe back to determine that they did not hit a vein or artery to ensure proper delivery into the muscle. If the vaccine is injected into the wrong area, it could have a different effect inside the body.

For subcutaneous delivery, drugs are injected into the cutis layer of the skin. The cutis layer includes the two outer layers of the skin, the epidermis and dermis.

Subcutaneous and intramuscular methods of pharmaceutical administration provide good adsorption, especially for long-lasting drugs with low oral bioavailability and rapid effects. However the adsorption can be unpredictable and injections can be painful, leave bruises and be troublesome for needle-phobic patients.

Medications commonly administered by intramuscular and subcutaneous delivery include insulin (for diabetes), morphine, vaccines (hepatitis A, rabies, influenza), penicillin, diazepam (Valium).

Diabetes is a disease in which either the body does not produce insulin at all or it does not correctly respond to insulin. Since, insulin is a hormone that regulates the amount of sugar in the bloodstream, people with diabetes who do not produce insulin at all require insulin injections daily to stabilize their levels. Early on, insulin was only available as a shot, but now insulin pumps are commonly used. As directed by the patient, the pumps insert a small tube into the skin and release insulin over days.

(slide 7) Using topical administration, a drug is delivered directly to the desired body site. This easy, non-invasive method often has high patient satisfaction, though slow adsorption makes it difficult to control dosage. Many drugs with low lipid solubility and high molecular weight cannot be absorbed through the skin and mucous membranes. Several types of common medications that use topical administration include skin ointments and creams for poison ivy and rashes, eye drops, ear drops and some birth control patches.

(slide 8) The inhalation of medication into the bloodstream via the lungs and respiratory system provides rapid adsorption due the large surface area of the lungs and is the fastest drug delivery route to the brain. Proper inhaler technique is essential to ensure that people receive the correct dosage, and it can cause patients to experience an unpleasant taste and/or mouth irritation. Drug size determines its bioavailability as an inhalation medication large molecules cannot pass through the membranes in the lungs to the bloodstream. Common medications that are administered using inhalation include adrenocorticoid steroids (such as beclomethasone), bronchodilators (such as isoproterenol, metaproterenol and albuterol), and antiallergics (such as cromolyn).

(slide 9) Suppository administration delivers medication to the body via the rectum, vagina or urethra. Because the hemorrhoidal vein drains directly to the inferior vein cava (the largest vein in the human body), suppositories provide good adsorption, but cannot be used after rectal or anal surgery and can be uncomfortable and disliked by patients. Some common suppository medications include laxatives, diclofenac (nonsteroidal anti-inflammatory drug) and hemorrhoid medication. When a patient is vomiting and cannot take oral medications, suppository administration is likely.

(slide 10) Design considerations for the creation of pharmaceuticals include: 1) toxicity, 2) efficacy, 3) drug size, 4) solubility/bioavailability and 5) drug release duration.

  • Toxicity: While the desired drug effect may eliminate certain bacteria from a patient's body, we do not want the drug to kill the healthy cells in the body. For example, in chemotherapy, the body is exposed to cytotoxic drugs to destroy the body's mutated cells, but it also has large unwanted side effects on the body's healthy cells (such as in hair follicles). Ideally, toxic medications result in more of the desired therapeutic effect than the undesirable side effects, making them useful. Pharmaceutical efficacy must be determined if a drug is highly efficacious, 100% inhibition or eradication from the body can be achieved.
  • Drug size plays a major role in whether or not certain administration methods can be utilized. If the drug's molecules are very large, they may not be able to pass through the necessary body membranes, preventing the medicine from being absorbed and reaching its intended destination.
  • In order for a drug to be useful, it must be soluble, or bioavailable, in the environment where it is designed to function. Throughout the body, pH levels vary, so while a drug may dissolve in one area of the body, it may not dissolve in another area. For a drug to be effective, it must be soluble, so as pH varies, drug solubility varies.
  • The duration of drug release must be considered by engineers and doctors depending on the malady, short or long drug release duration may be desirable.

(slide 11) The circulatory system transports drugs throughout the body. Each body area has a specific pH. For example, the stomach pH ranges from 1.5 to 3.5, while the duodenum, the first section of the small intestine, has a pH of 6. The small intestine starts with a pH of 6 and increases to a pH of 7.4, while the large intestine has a lower pH of 5.7. The rectum has a slightly acidic pH of 6.7. The bloodstream has a neutral pH range of 7.35 to 7.45. As mentioned before, the pH determines drug molecule solubility/bioavailability.

(slide 12) High molecular weight drugs are difficult to administer. Polymers are used to encapsulate high molecular weight drugs so that they can be delivered throughout the body. Depending on the polymer, the rate of drug diffusion out of the shell can be controlled. The size of the polymer shell pores determines the rate of diffusion. Polymer chains that act as lock-and-key receptors can attach to the encapsulation, providing some drug release control. For some types of polymer encapsulation, the polymer degrades to release the drug. A potential hazard of polymer use for drug delivery is uneven degradation one area can degrade more quickly than intended, leading to rapid drug release that can cause a toxic overdose.

(slide 13) Most drugs are crystals—solid materials with an ordered pattern in all directions. Some drugs are very efficacious, but have poor solution properties. To improve the properties of a drug molecule and retain the efficacy of the molecule, cocrystals are produced. Cocrystals are crystals composed of two or more different molecules, ions or atoms in a specific stoichiometric ratio. Cocrystals are used to alter/improve drug molecule solution properties, improving solubility while maintaining high efficacy.

(slide 14) The inspiration for new drug delivery devices can come from other engineering design feats, such as contraceptive microchips that merge birth control with controlled-release chemical microchips. For some women, including those without continuous access to medical resources, it can be inconvenient or difficult to continuously take oral birth control. A new, chip-like device with thousands of pharmaceutical-filled wells was designed to implant underneath the skin where it administers contraceptive pharmaceuticals for years. The well coverings degrade when a small electrical current is directed to the well. The chips can be turned on and off, enabling women to start or stop birth control at any time.

(slide 15) Medical drug delivery devices are devices implanted inside the human body to slowly release drugs at specific times or release drugs when directed. Medical devices can cause problems, including blood surface interactions resulting in infections, blood clotting, antibiotic resistance leading to device failure. These problems are caused because a foreign object is placed inside the body. The surface of the device may have had bacteria on it before implantation or the body may attempt to remove the device because it senses that it is not natural. Blood surface interactions are how the body and the surface of a device react when in contact with each other. To combat this, artificial surfaces are designed to negate these interactions. One method is a drug-eluting surface in which the surface releases a drug over time. In a drug-eluting surface, the drug is made catalytically—that means the drug is produced inside the body via a chemical reaction.

(slide 16) For example, metal organic frameworks (MOFs) are compounds composed of metals ions that connect to organic molecules creating frameworks. These frameworks can vary greatly from one dimensional to three dimensional. Three-dimensional frameworks make porous channels where chemical reactions can occur. Specifically for drugs, nitric oxide can be produced. For chronic wound treatment, nitric oxide helps neurotransmission, which is the exchange of signals between neurons in the body. If a signal is blocked, it can cause problems. For example, if the signals for pain are blocked, how would you know that you have a life-threatening injury? The sustained nitric oxide release of these metal organic frameworks has the capability to last for two to 12 weeks.

"Smart materials" inventions like MOFs have the potential use for targeted transport of drugs in the body. Endless possibilities exist for future drug delivery systems. Future research will help determine which technologies will be implemented sooner rather than later. Inventions and innovations are the result of specific, goal-directed research. What problem do you want to solve? What ideas do you have?

Associated Activities

  • Proof of Concept: Miracle Drug Encapsulation - Students follow the steps of the engineering design process as they make large-size shell encapsulation prototypes for oral drug delivery using household materials. Teams each encapsulate a Wiffle® ball containing colored drink mix powder, which represents a porous shell containing a new miracle drug. They submerge their prototypes into buckets of water for timing tests. Teams go through at least three design/test iterations, aiming to achieve solutions that meet the drug release delay and duration requirements.

Lesson Closure

Over the years, pharmaceuticals have developed from simple herbal infusions in teas and pastes made by apothecaries to complex injections and implants. In the future, we can expect new pharmaceuticals, devices and methods of drug delivery to be invented.

Vocabulary/Definitions

absorption: The process of a molecule being absorbed or soaked up into another region or part, such as a drug being soaked up by the digestive tract into the bloodstream.

bioavailability: The extent to which a medication can be used by the body. How a drug interacts with the body. If a drug has good bioavailability, its physical properties enable it to be used readily.

catalyst: A substance that helps improve a chemical reaction in the body in order to produce more of a drug or chemical.

cocrystal: A crystal comprised of two or more components, such as ions, molecules or atoms, in a specific stoichiometric ratio.

crystal: A solid material that consists of an ordered pattern in all directions.

degradation: The process of decay or breakdown of an object in which it becomes unusable.

diffusion: The movement of molecules in a random fashion to create an evenly concentrated environment.

drug administration: As refers to pharmaceuticals, the method of drug delivery into the human body.

drug delivery: A method of transporting a pharmaceutical to a desired body location.

drug-eluting: An object that releases a drug over a period of time.

duration: The length of time something continues to exist, such as a drug release.

efficacy: The capacity for producing a desired result. For example, how much a drug is able to inhibit if it causes 100% inhibition, it has a high efficacy.

encapsulation: As refers to pharmaceuticals, a shell-like method of coating drug molecules to enable release at specific times using diffusion.

inhalation: As refers to pharmaceuticals, a method of drug administration using the lungs to transfer medicine into the bloodstream.

injection (medicine): As refers to pharmaceuticals, a method of drug administration that uses some type of needle to push the drug into the bloodstream, skin or muscle. Three types: intravenous, subcutaneous and intramuscular. Also called a "shot."

intramuscular injection: A method of drug administration by inserting a needle directly into the muscle.

intravenous injection: A method of drug administration using an infusion directly into the bloodstream.

neurotransmission: The exchange of signals between neurons in the body that help relay information throughout the body, such as pain recognition.

oral administration: A method of drug administration using the mouth and digestive tract to achieve adsorption into the bloodstream.

pharmaceutical: A drug used for medical purposes, such as to diagnose, cure, treat or prevent disease.

polymer: A large macromolecule that is composed of repeating subunits.

solubility: The property of a substance to dissolve into solution.

subcutaneous injection: A method of drug administration by inserting a needle directly into the cutis layer of the skin.

suppository: A method of drug administration using the rectum, vagina or urethra to absorb pharmaceuticals.

topical: As refers to pharmaceuticals, a method of drug administration directly to the affected site, such as eye drops, lotion on the skin or transdermal patch.

toxicity: The degree of harmfulness of a substance to humans.

Assessment

Challenge Question: As presented on slide 2, pose the following challenge question to the class. Have students brainstorm ideas in small groups for five minutes. Then have groups share their ideas in a class discussion.

  • Imagine that you are a doctor, physician assistant or nurse practitioner. Your patient has a condition that requires her to keep constant levels of a medication in her body, but she is unable to swallow. She needs to take her medication at least twice a day for the rest of her life. What other method(s) can you use to administer her medication? To ensure patient compliance and safety, the drug delivery method must be as simple as possible. (Expect suggestions such as injections/shots, inhalers, ointments, etc.)

Conclude by making the point that new technologies are born by first identifying the criteria and constraints necessary to solve a problem, and then creating, developing and testing solutions that address those requirements. This specific, goal-directed research is what biomedical researchers are doing to make advances in medical care.

Presentation Worksheet: During the PowerPoint ® presentation, have students complete the Drug Delivery Worksheet. Review their answers to assess their comprehension of the presented content.

Lesson Summary Assessment

Technology Research: Assign students to complete the Pharmaceutical Research Worksheet, which requires them to use computers with Internet access to research new drug delivery methods (examples, how they work, method considerations) and future drug delivery methods (student ideas, nanotechnology possibilities, tissue engineering). Review their answers to gauge their depth of investigation and comprehension.

Additional Multimedia Support

Biomaterials and Biotechnology: The development of controlled drug delivery systems and the foundation of tissue engineering (part 3) by Robert S. Langer, MIT (26:50-minute video) really interesting information from 22:14 to 25:55, at https://www.youtube.com/watch?v=ZOgobBrGYVM

Amazing drug delivery system an animation shows an example long-duration drug delivery system (1:26-minute video): https://www.youtube.com/watch?v=MmGCJEqZkOY

New drug-delivery capsule may replace injections (1:35-minute video): https://www.youtube.com/watch?v=PBCa5bM3zjg

Drug Delivery Technology: Present and Future (part 2) by Robert S. Langer, MIT (35:11-minute video) at https://www.youtube.com/watch?v=o4moymWepUg

References

Falcaro, Paolo and Buso, Dario. (2011) Scanning electron microscope image of the seed inside the MOF crystals (photograph with caption). The Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia. Accessed January 27, 2016. http://www.scienceimage.csiro.au/image/11637

Copyright

Contributors

Supporting Program

Acknowledgements

This digital library content was developed by the University of Houston's College of Engineering under National Science Foundation GK-12 grant number DGE 0840889. However, these contents do not necessarily represent the policies of the NSF and you should not assume endorsement by the federal government.


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