Pharmaceutical sciences encompass a wide range of scientific disciplines that play a role in the design, development and delivery of drugs. The integration of these fields underpins the many medical advances that have helped to ensure the optimal clinical use of medicines.
Pharmaceutics involves the development of stable and sophisticated dosage forms for administration to humans. Drug formulation design and delivery technologies can used to improve the efficacy of drugs so as to optimise therapeutic outcomes. The formulation of drugs takes into account the route of administration and the physical and chemical properties of the active agent (e.g. solubility, flow properties and stability). In transdermal drug delivery, for example, the melting point of the drug is major consideration, since drugs with high melting points have lowered solubility and thus reduced penetration through the skin. The melting point can be lowered by formulation of a eutectic mixture, a mixture of two compounds that, at a certain ratio, inhibit the crystalline process of each other, such that the melting point of the mixture is less than that of each component alone. EMLA cream, a dermal anesthetic consisting of lignocaine and prilocaine, is an example of a eutectic mixture. In combination the local anesthetics possess greater thermodynamic activity for enhanced permeation through the stratum croneum, which is the main barrier for these substances. In addition, the 1:1 eutectic mixture is formulated as an oil-in-water emulsion to further maximise its activity.
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The knowledge and application of pharmacokinetic principles also influences the process drug formulation. Pharmacokinetics is a branch of pharmacology that looks at what the body does to a drug by examining the processes of absorption, distribution, metabolism and elimination of a compound. The use of pharmacokinetic data was central in producing suitable formulations for glyceryl trinitrate (GTN), a potent vasodilator that is used for relief of angina. When administered orally GTN is well absorbed from the gastrointestinal tract, but it is subject to extensive hepatic metabolism. In fact, almost 96% of the drug is destroyed by the liver, which significantly reduces its bioavailability and produces no therapeutic effect. For this reason, GTN is formulated for sublingual and buccal administration, since these routes bypass the liver.
Chemical modification of an active drug to form a prodrug is a way of improving the pharmacokinetic profile of a drug. Prodrugs are derivatives of drug molecules that undergo enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. Valaciclovir, the prodrug (esterified) form of acyclovir, is an antiviral drug used in the management of herpes simplex (cold sores) and herpes zoster (shingles). It increases the absorption of aciclovir and this has a greater oral bioavailability (55%) than aciclovir (10-20%).
The use of excipients (inert additives) is important for enhancing the micrometric properties of a drug. In modern pharmaceutical dosage forms, excipients can have specialised functions including improving the bioavailability of the active ingredient or controlling its release.
Nimodipine (NMD) is a dihydropyridine calcium channel blocker that has been shown to selectively regulate calcium channels to increase blood flow in cerebrovascular disorders. However, NMD is a poorly soluble (hydrophobic) drug with low bioavailability and limited clinical efficacy. By simply preparing a solid dispersion consisting of NMD and the polymers Eudragit-E100 and Plasdone-S630, the dissolution of the drug can be dramatically increased due to the disintegrant properties of the excipients.
Controlled drug delivery occurs when a polymer is astutely attached to a drug in such a way that the active agent is released in a predesigned manner. There are several advantages of controlled release systems including reduced dosing frequency, less fluctuation of plasma drug levels and reduced side effects. A classic example is the enteric coating of aspirin, which improves gastric tolerance of the drug. The enteric coating is stable in the highly acidic environment of the stomach, which prevents the release of aspirin in the stomach and reduces gastric mucosal injury.
Another drug that utilises a controlled drug delivery system is the night-dosed antihypertensive drug Veleran® (Verapamil). This implements a system known as CODAS (Chronotherapeutic Oral Drug Absorption System). The release-controlling coating is a combination of water-soluble and water insoluble polymers. As water from the gastrointestinal tract comes in contact with coated, drug loaded beads, the water-soluble polymer slowly dissolves and the drug diffuses through the resultant pores in the coating. The water insoluble polymer continues to act as a barrier and maintains the controlled release of the drug. This is designed to overcome problems associated with the increased blood pressure surge in morning waking hours of hypertensive patients.
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Drug delivery systems are also being developed for controlled release of insulin. These glucose- sensitive systems are based on the reaction between glucose in the blood and glucose oxidase, which can be immobilised on polymers within the system. The reaction lowers the pH in the microenvironment of the delivery system, causing an increase in the swelling of the polymers and leads to increased release of insulin. Currently, there are several formulations of insulin available for the management of diabetes. Short, fast acting preparations yield an elevated blood insulin concentration quickly after administration, while slow acting formulations enter circulation more slowly. By complexing insulin with zinc and/or protamine, the crystallinity of the compound is modified, thus causing prolonging its action.
Protein drugs (e.g. insulin, erythropoietin (EPO), growth hormone and interferon) have become increasing important as lead compounds in medicinal chemistry. However, there are several practical problems that limit the usefulness of these agents. Many of these drugs are large, unstable molecules with short circulating half-lives and susceptibility to inactivation by enzymatic degradation. They can be rapidly eliminated by the kidneys and are also poorly soluble, which can lead to aggregation and phlebitis (inflammation of the veins). Another failing of these drugs is their tendency to elicit an immunogenic reaction leading to the generation of neutralising antibodies. To overcome the problems associated with protein drugs researchers have attempted to improve the clinical properties of these polypeptides.
Pegylation, which is the chemical attachment of polyethylene glycol (PEG) chains to proteins, is a method of overcoming the shortcomings of polypeptide drugs. PEG is a non-toxic, hydrophilic, uncharged polymer that increases the molecular mass of the polypeptides. Pegylation (1) increases circulating half-life of the protein (2) reduces or eliminates immune responses to the proteins (3) increases solubility and stability (4) reduces enzymatic degradation through shielding, and (4) reduces kidney clearance. Pegylation can have dramatic effects on compounds, for example the pegylation of the cytokine interleukin-6 (IL-6), increases its half-life by a 100-fold, which in turn results in a 500-fold rise in its thrombopoietic potency.
Interferon-ï¡ (INF-ï¡) is a prime example of the usefulness of pegylation. INF-ï¡ is an endogenous protein that has antiviral and immunomodulatory properties, and is produced commercially in treatment of hepatitis C virus (HCV) infection. If left untreated, HCV infection can become chronic and lead to liver cancer, cirrhosis or death. Native interferon therapy had several limitations including short serum half-life (2-5 hours), high volume of distribution and rapid renal clearance of the drug. Pegylated interferons produce more constant and longer-lasting plasma levels of interferon, which results in the better suppression of viral replication. As a result, the pegylated drug can be administered once weekly unlike its unpegulated equivalent, which has to given three times a week. This improves patient compliance due to the reduction of dosing injections. Two forms of pegylated interferon, PEG-Intron (linear 5kDa PEG) and Pegasys (second-generation branched 40kDa PEG), are currently available.
Liposomes can also be pegylated to improve the delivery of encapsulated drugs. Doxil®, the pegylated liposomal form of the anticancer agent doxorubicin, is used in the treatment of several cancers. Peglyation increases the plasma half-life of the liposome and prevents leakage of the drug in circulation, thus reducing toxicity. Moreover, nanoparticles (e.g. PHDCA), which show promise as transporters of drugs across the blood brain barrier, have been revealed to penetrate into the brain to a greater extent when they are pegylated.
Nanotechnology-based medicine, in general, has attracted much attention in recent years, as a way of providing improvements in drug delivery and drug targeting. Nanoparticles are defined as particles less than 100nm. They are able to adsorb to and/or encapsulate drugs and in doing so minimise toxicity and improve efficacy of a drug.
Aurimune™, which is currently in clinical trials, is a gold nanoparticle coated with tumour necrosis factor (TNF-α). It is believed that this agent can weaken the blood vessels of a tumour, making follow-up chemotherapy more effective. If injected directly into the body, TNF-α would cause massive organ failure. The nanoshells conceal the drug to immediate immune detection and thus target delivery of TNF-α directly to tumour sites without affecting the rest of the body.
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Nanosuspensions are have been proposed to enhance the dissolution of water insoluble drugs. These are colloidal dispersions of crystalline drug particles, which are stabilized by surfactants. Budesonide, a poorly water-soluble corticosteroid, has been successfully prepared as a nanosuspension for pulmonary delivery.
The concept of targeted therapy was first conceived by Paul Ehrlich with the notion of 'magic bullets'. He sought after specific compounds that could selectively target the disease-causing organism and destroy it without harming other parts of the body. This is the promise that nanotechnology drug products of today offer for the treatment of disease.