Hypercholesterolaemia plays a crucial role in the development of atherosclerotic diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerotic process to coronary heart disease increases progressively with increasing levels of total serum cholesterol or low density lipoprotein (LDL) cholesterol at both the individual and the population level. The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoAto mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by statins decreases intracellular cholesterol biosynthesis, which then leads to transcriptionally upregulated production of microsomal HMG-CoA reductase and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance. There are no simple methods to investigate the concentration-dependent inhibition of HMG-CoA reductase in human pharmacodynamic studies. The main clinical variable is plasma LDL-cholesterol, which takes 4 to 6 weeks to show a reduction after the start of statin treatment. Consequently, a dose-effect rather than a concentration-effect relationship is more appropriate to use in describing the pharmacodynamics. Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins. The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDLcatabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins. Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised. The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (>90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.

Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.

Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs

Formulation aspects in the development of osmotically controlled oral drug delivery systems.

The cyclodextrins have a wide range of applications in different areas of drug delivery and pharmaceutical industry due to their complexation ability and other versatile characteristics. The most common pharmaceutical application of cyclodextrin is to enhance the solubility, stability, safety and bioavailability of drug molecules. The purpose of this review is to discuss and summarize some of the findings and applications of cyclodextrin (CD) and their derivatives in different areas of drug delivery. This article highlights the molecular structure, properties like complexation, solubility etc. of cyclodextrins and focuses on its use for parenteral, oral, ophthalmic and nasal drug delivery. Other routes including dermal, rectal, sublingual and pulmonary delivery are also briefly addressed. The objective of this contribution is to focus on the potential use of chemically modified cyclodextrins as high-performance drug carriers in drug delivery systems with emphasis on the more recent developments. Thus cyclodextrins, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.

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Cyclodextrins as Drug Carrier Molecule: A Review

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limit...

Osmotically Controlled Oral Drug Delivery

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem.HCl as a model drug. Diltiazem.HCl has an aqueous solubility greater than 590 mg/ml (37 degrees C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ml; 37 degrees C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of greater than 80% of an initial diltiazem.HCl load. Devices were prepared with cores that contained diltiazem.HCl and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of approximately 75% of the initial diltiazem.HCl load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.

The solubility-modulated osmotic pump: in vitro/in vivo release of diltiazem hydrochloride.

Controlled porosity solubility- and resin-modulated osmotic drug delivery systems for release of diltiazem hydrochloride

Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.

Steven C. Sutton

Papers

The solubility-modulated osmotic pump: in vitro/in vivo release of diltiazem hydrochloride.

Controlled porosity solubility- and resin-modulated osmotic drug delivery systems for release of diltiazem hydrochloride

Evaluation of Sustained/Controlled-Release Dosage Forms of 3-Hydroxy-3-methylglutaryl–Coenzyme A (HMG-CoA) Reductase Inhibitors in Dogs and Humans