NOVEL DRUG DELIVERY SYSTEM

 

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 18th and 19th 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

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