Why Drug Delivery is a Crucial Part to Pharmaceuticals and How Nanotechnology is Advancing Drug Delivery
''The importance of nanotechnology in drug delivery is in the concept and ability to manipulate molecules and supramolecular structures for producing devices with programmed functions." Kinam Park
For a drug to be successful it must satisfy the pharmacokinetic and pharmacodynamic requirements. Pharmacokinetic requirements are that it must be absorbed, distributed, metabolised, excreted sufficiently and non-toxic. Pharmacodynamic requirements are that the drug must have sufficient efficacy (ability to carry out the desired effect) and selectivity. |
When a drug enters the body there are certain biological barriers that the drug molecule must first pass to get to its target organ. For example, when a drug is taken orally it must pass barriers in the stomach, the small intestine, the blood and the liver before it reaches the target organ. Barriers which must be overcome in these regions are cell membranes, metabolic enzymes, efflux transporters and binding proteins. Needless to say, there are many criteria which a drug must possess in order to reach its target region.
About 70% of drugs today are taken orally. Most pharmaceutical companies aim to develop an oral dosage form of their drug with a dosing regimen of once per day. Drugs of this type have reasonable manufacturing and storage costs and high patience compliance. Drug delivery for drugs administered orally usually involves encapsulating the drug using polymers. Liposomes are the main drug delivery system used today in oral administration. Drugs administered by parenteral routes (those which do not encounter the stomach or the GI tract) must also cross certain barriers. However, the basis of drug release from drug delivery systems is the same for all routes. Drug release is from: diffusion, degradation, swelling, and affinity-based mechanisms.
About 70% of drugs today are taken orally. Most pharmaceutical companies aim to develop an oral dosage form of their drug with a dosing regimen of once per day. Drugs of this type have reasonable manufacturing and storage costs and high patience compliance. Drug delivery for drugs administered orally usually involves encapsulating the drug using polymers. Liposomes are the main drug delivery system used today in oral administration. Drugs administered by parenteral routes (those which do not encounter the stomach or the GI tract) must also cross certain barriers. However, the basis of drug release from drug delivery systems is the same for all routes. Drug release is from: diffusion, degradation, swelling, and affinity-based mechanisms.
Most common types of administration
· Oral · Topical (skin) · Transmucosal- Nasal, buccal, vaginal, ocular, rectal · Inhalation Liposomes, polymeric micelles, nanoparticles, dendrimers and nanocrystals are a remaining portion of conventional drug delivery systems that happen to be on the nano-scale. Nanotechnology and its effects on drug delivery refers more correctly to the current drug delivery systems which include microchips, microneedle-based transdermal therapeutic systems, layer-by-layer assembled systems, and various microparticles produced by ink-jet technology. |
To appreciate the true meaning of nanotechnology in drug delivery, it may be beneficial to classify drug delivery systems based on the time period representing before and after the nanotechnology revolution.
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The main problems with the current methods are the low drug loading capacity, low loading efficiency, and poor ability to control the size distribution. Utilizing nanotechnologies, such as nanopatterning, could allow manufacturing of nano/micro particles with high loading efficiency and highly homogeneous particle sizes. The pharmaceutical industry has been slow to utilize the new drug delivery systems if they include components (also called excipients) that are not generally regarded as safe. Going through clinical studies for FDA approval of a new chemical entity is a long and costly process; there is resistance in the industry to adding any untested materials that may require seeking approval. Nanotechnology for drug delivery will mature faster and become more useful if it’s appreciated that the real potential of nanotechnology in drug delivery is based on utilization of nano/micro fabrication and manufacturing, rather than on dealing with delivery systems in the nano/micro scale. [31]
To describe what nanotechnology can do to manufacture nano/micro drug delivery systems, one can use manufacturing of nano/micro particles (or capsules) as an example. Imagine that the current soft gelatin capsules, which are in the centimeter scale, are manufactured at the nano/micro scale. The following are among the important technological advantages of nanoparticles as drug carriers: high stability (i.e., long shelf life); high carrier capacity (i.e., many drug molecules can be incorporated in the particle matrix); feasibility of incorporation of both hydrophilic and hydrophobic substances; and feasibility of variable routes of administration, including oral administration and inhalation. These carriers can also be designed to enable controlled (sustained) drug release from the matrix. [32]
Example of where Drug Delivery by a nanostructure is required: Small interfering RNA’s is a potential new universal drug for treatment of a variety of human diseases but efficient delivery into diseased cells remains a major challenge. Polymeric nanocarriers containing the drugs may solve the problem. Within the body, naked siRNA is degraded by enzymes. To avoid this they have incorporated siRNA in nanoparticles able to reach target cells intact. Microencapsulation technology has been used to surround nanoparticles in a bio-degradable coat for sustained release delivery. After release the nanoparticles bind to receptors in the cell membrane and are subsequently transported into the cell. Inside the cytoplasm, the nanoparticle matrix dissolves and the drug is released. [33]
To describe what nanotechnology can do to manufacture nano/micro drug delivery systems, one can use manufacturing of nano/micro particles (or capsules) as an example. Imagine that the current soft gelatin capsules, which are in the centimeter scale, are manufactured at the nano/micro scale. The following are among the important technological advantages of nanoparticles as drug carriers: high stability (i.e., long shelf life); high carrier capacity (i.e., many drug molecules can be incorporated in the particle matrix); feasibility of incorporation of both hydrophilic and hydrophobic substances; and feasibility of variable routes of administration, including oral administration and inhalation. These carriers can also be designed to enable controlled (sustained) drug release from the matrix. [32]
Example of where Drug Delivery by a nanostructure is required: Small interfering RNA’s is a potential new universal drug for treatment of a variety of human diseases but efficient delivery into diseased cells remains a major challenge. Polymeric nanocarriers containing the drugs may solve the problem. Within the body, naked siRNA is degraded by enzymes. To avoid this they have incorporated siRNA in nanoparticles able to reach target cells intact. Microencapsulation technology has been used to surround nanoparticles in a bio-degradable coat for sustained release delivery. After release the nanoparticles bind to receptors in the cell membrane and are subsequently transported into the cell. Inside the cytoplasm, the nanoparticle matrix dissolves and the drug is released. [33]
Liposomes ('Old' Nanotechnology)
Liposomes are nano sized artificial vesicles of spherical shape that can be produced from natural phospholipids and cholesterol. The properties of liposomes in addition to the general properties of surfactants those make them useful for different applications are
Liposomes is extensively studied for encapsulation of drugs. When lipid self assemble to liposomes water-soluble drugs will be trapped inside the liposomal cavity; fat-soluble drugs are incorporated within phospholipid bi-layer. The lipid bilayer of the liposome can fuse with other bilayers (e.g. cell membrane), thus delivering the liposome contents. Liposomal formulations are the first NanoPharmaceuticals introduced to market, Doxil® PEGylated liposomal formulation for doxorubicin is the first product based on liposomes. Theses liposomes are called as “Stealth” liposomes with size <200nm which are long circulation with hydrophilic (PEG) surface. These long circulating liposomes found to target to tumour tissue by a mechanism known as enhanced permeation and retention (EPR). Hence liposomal formulation of doxorubicin considerably reduced the cardio-toxicity of drug. Many lipososmal products are under various phases of clinical trials. Liposomes are currently investigated for a variety of additional therapeutic agents; anticancer drugs such as paclitaxel, camptothecin, cisplatin; antibiotic such as amikacin, vancomysin, ciprofloxacin; biologics such as antisense oligonucleotides, DNA
- Structural stability on dilution
- Varying permeability of the bilayer to different molecules.
- Ability to entrap both water soluble and insoluble substances and deliver them into desired environments.
Liposomes is extensively studied for encapsulation of drugs. When lipid self assemble to liposomes water-soluble drugs will be trapped inside the liposomal cavity; fat-soluble drugs are incorporated within phospholipid bi-layer. The lipid bilayer of the liposome can fuse with other bilayers (e.g. cell membrane), thus delivering the liposome contents. Liposomal formulations are the first NanoPharmaceuticals introduced to market, Doxil® PEGylated liposomal formulation for doxorubicin is the first product based on liposomes. Theses liposomes are called as “Stealth” liposomes with size <200nm which are long circulation with hydrophilic (PEG) surface. These long circulating liposomes found to target to tumour tissue by a mechanism known as enhanced permeation and retention (EPR). Hence liposomal formulation of doxorubicin considerably reduced the cardio-toxicity of drug. Many lipososmal products are under various phases of clinical trials. Liposomes are currently investigated for a variety of additional therapeutic agents; anticancer drugs such as paclitaxel, camptothecin, cisplatin; antibiotic such as amikacin, vancomysin, ciprofloxacin; biologics such as antisense oligonucleotides, DNA
Transdermal Micro-Array Patch ('New-ish' Nanotechnology)
A MicroArray Patch technology is being developed for the transdermal delivery of large molecule drugs, without the use of injections. The patch is in a band-aid format, and the surface of the patch is structured with polymer microneedles, from which the drug is delivered. The drugs can be attached to the external surface of the polymer microneedles, integrated into the polymer, or both.
When the patch is applied, the microneedles cross the stratum corneum and penetrate into the epidermis. The microneedles do not penetrate deep enough to enter blood capillaries or nerves, hence the delivery is non-invasive and pain-free. The drugs for delivery are present in a nanostructured form, facilitating uptake into the body. The microneedles are made of a polymer that is biocompatible and biodegradable. This reduces the risk of trauma to the skin and infection. The MicroArray Patches have been designed for the delivery of peptides, proteins, hormones, vaccines and skin repair agents. The use of MicroArray Patches will enable a wide range of medications to be effectively delivered to humans in a safe and non-invasive manner.[34] |
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Nanoparticles that act Like Red Blood CellsIn the short clip on the right we see particles which measure 6micrometers in length passing through membranes half their width. They mimic red blood cells shape and consistency in that they are flexible and fold-able. Basically in this experiment it was proven that the more flexible the molecules are the longer they last in the circulatory system. It was also seen that molecules with different flexibility ended up in different organs. This may prove to be a very beneficial advancement in drug delivery. De Simone, the chemist who worked on this says with regards to these findings that hopefully 'applications for the delivery of cancer drugs could be in early clinical trial stages within four years.' UNC ChapelHill.
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Heart Disease
Building on their previous work delivering cancer drugs with nanoparticles, MIT and Harvard researchers have turned their attention to cardiovascular disease, designing new particles that can cling to damaged artery walls and slowly release medicine. The particles, dubbed “nanoburrs,” are coated with tiny protein fragments that allow them to stick to damaged arterial walls. Once stuck, they can release drugs such as paclitaxel (taxol), which inhibits cell division and helps prevent growth of scar tissue that can clog arteries.[35]
Lab-on-a-Chip Implant for Osteoporosis Drug
About 15 years ago, MIT professors Robert Langer and Michael Cima had the idea to develop a programmable, wirelessly controlled microchip that would deliver drugs after implantation in a patient’s body. The MIT researchers and scientists from MicroCHIPS Inc.reported that they have successfully used such a chip to administer daily doses of an osteoporosis drug normally given by injection. The results, published in the Feb. 16 online edition of Science Translational Medicine, represent the first successful test of such a device and could help usher in a new era of telemedicine — delivering health care over a distance, Langer says.
“You could literally have a pharmacy on a chip,” says Langer, the David H. Koch Institute Professor at MIT. “You can do remote control delivery, you can do pulsatile drug delivery, and you can deliver multiple drugs.” [38]
“You could literally have a pharmacy on a chip,” says Langer, the David H. Koch Institute Professor at MIT. “You can do remote control delivery, you can do pulsatile drug delivery, and you can deliver multiple drugs.” [38]
Nanoengineered Surfaces Enhance Drug Loading and Adhesion
To circumvent the barriers encountered by macromolecules at the gastrointestinal mucosa, sufficient therapeutic macromolecules must be delivered in close proximity to cells.1 Previously, we have shown that silicon nanowires penetrate the mucous layer and adhere directly to cells under high shear.2 In this work, we characterize potential reservoirs and load macromolecules into interstitial space between nanowires. We show significant increases in loading capacity due to nanowires while retaining adhesion of loaded particles under high shear. [36]
Drug Delivery on a Larger Scale: The Pharmaceutical Industry and the Counterfeiting Problem is being helped by Nanotechnology
Nanotechnology protects capsules from counterfeiting and diversion. 'Employing nanotechnology-based encryption onto pharmaceutical capsules before they’re filled adds overt, covert, and forensic-level protection for Pfizer’s Capsugel division. When it comes to pharmaceutical brand authentication/protection, track-and-trace, and anti-counterfeiting, exciting new technologies continue to emerge at the packaging level. But capsule manufacturer Capsugel, a div. of Pfizer Inc., is providing authentication, anti-counterfeiting, and diversion protection beyond packaging. Those benefits are delivered via NanoGuardian's NanoEncryption™, an on-dose, brand-protection technology that serves to trace and authenticate every dose from plant to patient.' -Jim Butschli, Features Editor of Packaging World. [37]
Latest Developments in Anti-Cancer Treatment: 'Nano-Sized Protein Clusters Address Major Challenge of Drug Delivery'- (2012)o-Sized Protein Clusters Address Major Challenge of Drug Delivery
AUSTIN, Texas — A new form of proteins discovered by researchers at The University of Texas at Austin could drastically improve treatments for cancer and other diseases, as well as overcome some of the largest challenges in therapeutics: delivering drugs to patients safely, easily and more effectively. Aim? To deliver the proteins in high concentration intravenously by self injection like insulin.[39] Problem? Delivering proteins in high concentrations as they tend to form aggregates that can be dangerous to patients and impossible to inject. Solution? The Cockrell School research team has introduced a new physical form of proteins, whereby proteins are packed into highly concentrated, nanometer-sized clusters that can pass through a needle into a patient to treat disease. The novel composition avoids the pitfalls of previous attempts because drug proteins are clustered so densely that they don’t unfold or form dangerous aggregates.
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