recent advances in novel drug delivery

Manivannan R et al / IJRAP 2010, 1 (2) 316-326

International Journal of Research in Ayurveda & Pharmacy, 1(2), Nov-Dec 2010 316-326

Review Article Available online through

www.ijrap.net

RECENT ADVANCES IN NOVEL DRUG DELIVERY SYSTEMS

Manivannan Rangasamy* and Kugalur Ganesan Parthiban JKK Munirajah Medical Research Foundation, College of Pharmacy, Ethirmedu, Komarapalayam,

Namakkal – 638183, Tamilnadu, India

Received: 17-10-2010; Revised: 28-11-2010; Accepted: 30-11-2010

ABSTRACT

Drug delivered can have significant effect on its efficacy. Some drugs have an optimum concentration range with in which maximum benefit is derived and concentrations above (or) below the range can be toxic or produce no therapeutic effect. Various drug delivery and drug targeting systems are currently under development. The main goal for developing such delivery systems is to minimize drug degradation and loss, to prevent harmful side effects and to increase bioavailability. Targeting is the ability to direct the drug loaded system to the site of interest. Among drug carrier one can name soluble polymers, microparticles made of insoluble (or) biodegradable natural and synthetic polymers, microcapsules, cells, cell ghosts, lipoproteins, liposomes and micelles. Two major mechanisms can be distinguished for addressing the desired sites for drug release, (a) Passive and (b) Active targeting. Controlled drug carrier systems such as micellar solutions, vescicles and liquid crystal dispersions, as well as nanoparticle dispersions consisting of small particles of 10 – 400 nm show great promise as drug delivery systems. Hydrogels are three dimensional, hydrophilic, polymer networks capable of imbibing large amounts of water or biological fluids. Buckyballs, a novel delivery system with 60 carbon atoms formed in the shape of hollow ball. They are other type’s namely bucky babies, fuzzy balls, gadofullereness, and giant fullerenes. Nanoparticles can be classified as nano tubes, nano wires, nano cantilever, nanoshells, quantum dots, nano pores. Researchers at north western university using gold particles to develop ultra sensitive detection systems for DNA and protein markers associated with many forms of cancer, including breast and prostrate cancer. Drug loaded erythrocytes is one of the growing and potential systems for delivery of drugs and enzymes. KEYWORDS: Drug delivery system, Carriers, Nanoparticles, Colloidal drug carriers. *Author for Correspondence Rangasamy Manivannan Professor Department of Pharmaceutics, JKK Munirajah Medical Research Foundation, College of Pharmacy, Ethirmedu, Komarapalayam, Namakkal – 638183. Email: [email protected] Mobile: +91-099761-39446.



INTRODUCTION 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, bio-conjugate chemistry, and molecular biology. Dramatic changes have in introduced, with new technology and new devices now on market. In some cases traditional capsules and ointments have been replaced by osmotic pumps, wearable ambulatory pumps, electrically assisted drug delivery and host of other delivery methods based on various polymer technologies. In some cases the new drugs require new delivery systems because the traditional systems are inefficient and ineffective. Some therapies may become very site specific and require very high concentrations of drugs in selected sites of body, as more controlled drug delivery systems will be available very near future. New drug delivery system development is largely based on promoting the therapeutic effects of a drug and minimizing its toxic effects by increasing the amount and persistence of a drug in the vicinity of target cell and reducing the drug exposure of non target cells1,2,3&4.

Novel drug delivery systems can include those based on physical mechanisms and those based on biochemical mechanisms. Physical mechanisms also referred as controlled drug delivery systems include osmosis, diffusion, erosion, dissolution and electro transport. Biochemical mechanisms include monoclonal antibodies, gene therapy, and vector systems, polymer drug adducts and liposomes. Therapeutic benefits of some new drug delivery systems include optimization of duration of action of drug, decreasing dosage frequency, controlling the site of release and maintaining constant drug levels12,13&14. 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. 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 properties19&20. Liposomes

Tiny pouches made of lipids, or fat molecules surrounding a water core widely used for clinical cancer treatment. Several different kinds of liposomes are widely employed against infectious diseases and can deliver certain vaccines. During cancer treatment they encapsule drugs, shielding healthy cells from their toxicity, and prevent their concentration in vulnerable tissues such as those of patient kidneys and liver. Liposomes can also reduce or eliminate certain common side effects of cancer treatment such as nausea and hair loss.

They are form of vesicles that consist either of many, few or just one phospholipid bilayers. The polar character of liposomal core enables polar drug molecules to be encapsulated. Amphiphilic and



lipophilic molecules are solubilised within phospholipid bilayer according to their affinity towards phospholipids. 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 imprinting15. 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. 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 route8&10. Classification of nanomaterials Nanotubes

They are hollow cylinders made of carbon atoms. They can also be filled and sealed, forming test tubes or potential drug delivery devices. Nano wires

Glowing silica nano wire is wrapped around a single strand of human hair. It looks delicate. It is about five times smaller than virus applications for nano wires include the early sensing of breast and ovarian malignancies. Nanocantilever

The honey comb mesh behind this tiny carbon cantilever is surface of fly’s eye. Cantilevers are beams anchored at only one end. In nano world, they function as sensors ideal for detecting the presence of extremely small molecules in biological fluids. Nanoshells

Nanoshells are hollow silica spheres covered with gold. Scientists can attach antibodies to their surfaces, enabling the shells to target certain shells such as cancer cells. Nano shells one day also are filled with drug containing polymers. Quantum dots

Quantum dots are miniscule semiconductor particles that can serve as sign posts of certain types of cells or molecules in the body. They can do this because they emit different wavelengths of radiations depending upon the type of cadmium used in their cores. Cadmium sulfide for ultra violet to blue, cadmium selinide for most of the visible spectrum and cadmium telluride for far – infra red and near infra red. Nano pores

Nano pores have cancer research and treatment applications. Engineered into particles, they are holes that are so tiny that DNA molecules can pass through them one strand at a time, allowing for highly precise and efficient DNA sequencing. By engineering nanopores into surface of drug capsule that are



only slightly larger than medicines molecular structure, drug manufacturers can also use nanopores to control rate of drug’s diffusion in body. Gold Nanoparticles

These nanoparticles, seen in transmission electron micrograph image, they have solid core. Researchers at north western university are using gold particles to develope ultra sensitive detection systems for DNA and protein markers associated with many forms of cancer, including breast prostrate cancer. Bucky balls

Bucky ball is common name for a molecule called buckminsterfullerene, which is made of 60 carbon atoms formed in shape of hollow ball, discovered in 1985. Bucky balls and other fullerenes because of their chemistry and their unusual hollow, cage like shape extremely stable and can withstand high temperatures21,22&23.

Applications

Bucky balls may see widespread use in future products and applications, from drug delivery vehicles for cancer therapy to ultra hard coating and military harmor.

Bucky ball – antibody combination delivers antitumor drugs. v Bucky balls to fight allergy. v Bucky balls as powerful antioxidant and also inhibitor of HIV.

Demerits v Bucky balls hurt cells. v Bucky balls have high potential to accumulate in living tissue. v Difficulty of targeting drug delivery location24,25,26,27,28&29.

Carbon nanotubes

Carbon nanotubes can be modified to circulate well within the body. Such modifications can be accomplished with covalent or non – covalent bonding. Modifications can increase or decrease circulation time with in the body. Carbon nanotubes show no significant toxicity when they have modified so as to be soluble in aqueous, body type fluids. They enter readily into the cells. Cancer cells in tumors are larger than normal cells and also exhibit leakage. Large molecules which circulate slowly can leak into and accumulate in cancer cells. Carbon nanotubes carrying active agents have been demonstrated in animal studies to do this. Researchers have also used carbon tubes to deliver the precursors of active drug, which they call a prodrug, eg : Cisplatin46,47&48 Dendrimers

Dendrimers are precisely defined, synthetic nanoparticles that are approximately 5–10 nm in diameter. They are made up of layers of polymer surrounding a control core. The dendrimers surface contains many different sites to which drugs may be attach and also attachment sites for materials such as PEG which can be used to modified the way of dendrimer which interacts with body. PEG can be attached to dendrimer to ‘disguise’ it and prevent the body’s defense mechanism for detecting it, there by slowing the process of break down. This fascinating particle holds significant promise for cancer treatment. Its many branches allow other molecules to easily attach to its surface. Researchers have fashioned dendrimers into sophisticated anticancer machines carrying five chemical tools – a molecule designed to bind to cancer cells, a second that fluorescence upon locating genetic mutations, a third to assist in imaging tumor shape using x – rays, a fourth carrying drugs released on demand, and a fifth that would send a signal when cancerous cells are finally dead. The creators of these dendrimers had successful tests with cancer cells in culture and plan to try them in living animals soon35&36. Fast dissolving tablet

A novel tablet concept which offers ease of oral administration and benefits of increased patient compliance is fast dissolving tablet (FDT). This tablet format is designed to allow administration of oral



solid dosage form in absence of water or fluid intake. Such tablets readily dissolve or disintegrate in saliva generally within less than 60 seconds. When put on tongue, this tablet disintegrate instantaneously, release in the drug. Good in chemical stability. Suitable during traveling where water is may not be available30,31,32,33,34&35. Chronotherapeutics

Chronotherapeutics refers to a treatment method in which in–vivo drug availability, is timed to match rhythms of disease, in order to optimize therapeutic out comes and minimizes side effects. Controlled release formulation can be divided into subgroups such as rate controlled release, delayed release and pulse release formulations. Enteric coatings have traditionally been used as layer device in treatment of Parkinsonism patients using l–dopa / benzarazide39,40&41. Drug loaded erythrocytes

Drug loaded erythrocytes is one of the growing and potential systems for delivery of drugs and enzymes. Erythrocytes are biocompatible, biodegradable, posse’s long circulation half–life and can be loaded with variety of biologically active substances. Carrier erythrocytes are prepared by collecting blood sample from the organism of interest and separating erythrocytes from the plasma. By using various physical and chemical methods cells are broken and drug is entrapped into erythrocytes, finally they are resealed and resultant carriers are then called as “resealed erythrocytes”. Upon re injection the drug loaded erythrocytes serve as slow circulation depots, targets the drug to reticulo–endothelial system. Miniaturized drug delivery system for intra – corporeal use

Modern diagnostic and therapeutic procedures address the quality of patient care and aimed at reducing pain and discomfort. Research in micro endoscopy is devoted to miniaturization of devices and to integration of micro systems into tip of endoscope in order to increase its functionalities. Endoscopic wireless devices usually refer to as endoscopic pills37&38. Iontophoresis (IP)

Novel topical systems include iontophoresis and phonophoresis. It is an electro chemical method that enhances the transport of some solute molecule by creating a potential gradient through the skin with an applied electrical current or voltage. It induces increased migration of ionic drugs into skin by electrostatic repulsion at active electrode. Negative ions are delivered by cathode and positive ion by anode. Typical iontophoresis devices consist of battery, microprocessor controller, drug reservoir and electrodes13. Advantages of IP include,

a) Control of delivery rates by variations of current density, pulse voltage, drug concentration and ionic strength.

b) Eliminating gastro intestinal incompatibility, erratic absorption and first pass metabolism. c) Reducing side effects and variation among patients. d) Avoiding risks of infections, inflammation, and fibrosis associated with continuous injection and

infusion Phonophoresis

Phonophoresis (ultra sound, sonophoresis, ultra sonophoresis, ultra phonophoresis) is the transport of drugs through the skin using ultra sound. It is the combination of ultra sound therapy with topical drug therapy to achieve therapeutic drug concentrations at selected sites in the skin. It is widely used by physiotherapists. Today that product is applied to the skin and some time is allowed for drug to begin absorption into the skin. Then ultra sound unit is applied. The ultra sound emitted from the unit is actually a sound wave outside the normal human hearing range



Molecular imprinting technology The molecular imprinting technology has an enormous potential for creating satisfactory drug

dosage forms. Molecular imprinting involves forming a pre-polymerization complex between the template molecule and functional monomers or functional oligomers (or polymers) with specific chemical structures designed to interact with the template either by covalent, non-covalent chemistry (self-assembly) or both. Once the pre-polymerization complex is formed, the polymerization reaction occurs in the presence of a cross-linking monomer and an appropriate solvent, which controls the overall polymer morphology and macroporous structure. Once the template is removed, the product is a heteropolymer matrix with specific recognition elements for the template molecule.Examples of MIP-based drug delivery systems involve: (i) rate-programmed drug delivery, where drug diffusion from the system has to follow a specific rate profile, (ii) activation-modulated drug delivery, where the release is activated by some physical, chemical or biochemical processes and (iii) feedback-regulated drug delivery, where the rate of drug release is regulated by the concentration of a triggering agent, such as a biochemical substance, the concentration of which is dependent on the drug concentration in the body. Despite the already developed interesting applications of MIPs, the incorporation of the molecular imprinting approach for the development of DDS is just at its incipient stage. Nevertheless, it can be foreseen that, in the next few years, significant progress will occur in this field, taking advantage of the improvements of this technology in other areas. Among the evolution lines that should contribute more to enhance the applicability of imprinting for drug delivery, the application of predictive tools for a rational design of imprinted systems and the development of molecular imprinting in water may be highlighted16,16,17&18. 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. 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.

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).

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 drugs11.



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 carrier9.

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.

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.

Nanoparticles provide massive advantages regarding drug targeting, delivery and release and, with their additional potential to combine diagnosis and therapy, emerge as one of the major tools in nanomedicine. The main goals are to improve their stability in the biological environment, to mediate the bio-distribution of active compounds, improve drug loading, targeting, transport, release, and interaction with biological barriers. The cytotoxicity of nanoparticles or their degradation products remains a major problem, and improvements in biocompatibility obviously are a main concern of future research5. New drug delivery systems can provide improved or unique clinical benefits such as v Improvement in patient’s compliance. v Improved out comes. v Reduction of adverse effect. v Improvement of patient’s acceptance of treatment. v Avoidance of costly interventions such as laboratory services. v Allowing patients to receive medications as out patients and possibly. v Reduction in overall use of medicinal resources. v Nano-drug delivery systems that deliver large but highly localized quantities of drugs to specific

areas to be released in controlled ways; v Controllable release profiles, especially for sensitive drugs. v Materials for nanoparticles those are biocompatible and biodegradable. v Architectures / structures, such as biomimetic polymers, nanotubes. v Technologies for self-assembly. v Functions (active drug targeting, on-command delivery, intelligent drug release devices/

bioresponsive triggered systems, self-regulated delivery systems, systems interacting with the body, smart delivery).

v Virus-like systems for intracellular delivery. v Nanoparticles to improve devices such as implantable devices / nanochips for nanoparticle release,

or multi reservoir drug delivery-chips. v Nanoparticles for tissue engineering; e.g. for the delivery of cytokines to control cellular growth

and differentiation, and stimulate regeneration; or for coating implants with nanoparticles in biodegradable polymer layers for sustained release.



v Advanced polymeric carriers for the delivery of therapeutic peptide/proteins (biopharmaceutics) and also in the development of: Combined therapy and medical imaging, for example, nanoparticles for diagnosis and manipulation during surgery (e.g. thermotherapy with magnetic particles);

v Universal formulation schemes that can be used as intravenous, intramuscular or peroral drugs v Cell and gene targeting systems. v User-friendly lab-on-a-chip devices for point-of-care and disease prevention and control at home. v Devices for detecting changes in magnetic or physical properties after specific binding of ligands

on paramagnetic nanoparticles that can correlate with the amount of ligand. v Better disease markers in terms of sensitivity and specificity42,43,44&45.

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Figure 1: Drug Delivery carriers

Figure 2: Liposomes

Figure 3: Nanotubes

Figure 4: Quantum Dots



Figure 5: Bucky Balls

Figure 6: Dendrimers

Figure 7: Iontophoresis

Source of support: Nil, Conflict of interest: None Declared

recent advances in novel drug delivery

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