Mangal S. Nagarsenker

Parenteral microemulsions: An overview

Parenteral delivery of the hydrophobic drugs is a very challenging task. The conventional approaches such as use of co-solvents, oily vehicles and modern approaches such as mixed micelles, liposomes, complexation with cyclodextrins and emulsions have several limitations. Microemulsions have evolved as a novel vehicle for parenteral delivery of the hydrophobic drugs. Their interesting features such as spontaneity of formation, ease of manufacture, high solubilization capacity and self-preserving property make them the vehicle of choice. The review focuses on the excipients available for formulation of the parenteral microemulsions and describes the investigations reported for the various classes of therapeutic agents.

Influence of preparation methodology on solid-state properties of an acidic drug-cyclodextrin system.

We have investigated the influence of processing variables on the solid‐state of a model drug, flurbiprofen, in cyclodextrin‐based systems and its effect on dissolution behaviour of the drug. The interaction between flurbiprofen and hydroxypropyl β‐cyclodextrin (HP‐β‐CyD) was studied by NMR spectroscopy and phase solubility studies. Binary systems containing flurbiprofen and HP‐β‐CyD or povidone (polyvinylpyrrolidone) K30, prepared by various processes, were characterized by FTIR, DSC, XRD and dissolution studies. HP‐β‐CyD enhanced the solubility of flurbiprofen and increased dissolution rates from binary systems. It was found to be superior to povidone K30 in producing higher dissolution rates. The method of preparation of the binary systems and the agents used were found to have a major influence on the final solid‐state of flurbiprofen. Solvents and processing conditions favouring greater interaction between flurbiprofen and the cyclodextrin during the preparation process resulted in greater extent of drug‐cyclodextrin association and/or greater amorphization of the drug. Use of ammonia during the preparation of binary systems yielded solids from which very rapid drug dissolution was achieved, due to a higher extent of molecular dispersion of the drug. Processing variables therefore could significantly influence the solid‐state of a drug in cyclodextrin‐based formulations and thereby affect its dissolution behaviour. This could lead to significant effects on the in‐vivo performance of the formulation.

Potential of Cyclodextrin Complexation and Liposomes in Topical Delivery of Ketorolac: In Vitro and In Vivo Evaluation

The objective of this investigation was to evaluate the effect of delivery strategies such as cyclodextrin complexation and liposomes on the topical delivery of ketorolac acid (KTRA) and ketorolac tromethamine. Ketorolac acid–hydroxypropyl-β-cyclodextrin solid dispersions (KTRA-CD) were prepared by kneading method. The liposomes containing ketorolac tromethamine (KTRM) and KTRA-CD were prepared. The in vitro permeation of KTRM solution, KTRA solution, KTRA-CD, and liposomes containing KTRM or KTRA-CD through guinea pig skin was evaluated. The anti-inflammatory activity of the topically applied KTRA-CD gel (containing 1% w/w KTRA) was compared to that of orally delivered KTRM solution. The KTRA-CD demonstrated significantly higher transdermal transport of ketorolac as compared to all other systems whereas liposomes significantly reduced the transport of ketorolac. The anti-inflammatory activity of the topically applied KTRA-CD gel was similar to that of the orally administered KTRM. Thus, cyclodextrin complexation enabled effective transdermal delivery of the ketorolac.

Novel delivery systems of atorvastatin should be evaluated for pharmacodynamics instead of pharmacokinetics

Sir, This letter is written in response to the recent investigation entitled ‘Preparation and evaluation of self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin’ authored by Shen & Zhong published in September 2006 issue. The letter tries to highlight the importance of assessment of novel delivery systems of atorvastatin, such as SMEDDS, for their pharmacodynamic effect instead of pharmacokinetics. Atorvastatin, like all other statins, is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in sterol biosynthesis (Malhotra & Goa 2001). The low oral bioavailability (~14%) of atorvastatin is mainly due to presystemic clearance by CYP3A4 in gastrointestinal mucosa and hepatic first-pass metabolism and, to some extent, P-glycoproteinmediated efflux (Lennernas 2003). These problems necessitate design of novel delivery strategies, such as self-microemulsifying drug delivery systems (SMEDDS), to improve the oral bioavailability of atorvastatin. The SMEDDS described by Shen & Zhong resulted in a 1.4to 1.5-fold improvement in the various pharmacokinetic parameters, such as Cmax, AUC and bioavailability, as compared to the conventional tablets. It is important to understand the potential mechanism for the improvement in the pharmacokinetic parameters of atorvastatin observed with SMEDDS although these reasons are not discussed in detail by the authors. The improvement in bioavailability of the therapeutic agent observed with SMEDDS is considered to be an interplay of several factors, such as inhibition of CYP3A4 or P-glycoprotein efflux, improvement in the lymphatic transport, increasing membrane fluidity to facilitate transcellular absorption and opening of tight junctions to increase paracellular transport (Porter & Charman 1997; O’Driscoll 2002; Holm etal 2003). As atorvastatin is completely absorbed after oral administration (Lennernas 2003), the main factors that would have been responsible for the increase in its bioavailability by SMEDDS are inhibition of CYP3A4 and improvement in the lymphatic transport. The SMEDDS described by Shen & Zhong include Cremophore RH 40 (polyethoxylated castor oil derivative), Labrafil 1944 CS, Labrafac (medium chain triglycerides) and propylene glycol. Cremophores (polyethoxylated castor oil derivatives) are known to inhibit the metabolism of CYP3A4 susbtrates like midazolam (Gonzalez et al 2004). Cremophore RH 60-based microemulsions (analogue of Cremophore RH 40) are known to improve the oral bioavailability of CYP3A4 substrates like nitrendipine (Kawakami et al 2002). Recently, Labrafil 1944 CS-based SMEDDS have been shown to improve the oral bioavailability of carvedilol, a CYP2D6 and CYP3A4 substrate (Wei et al 2005). Medium-chain triglycerides are known to improve the lymphatic transport of therapeutic agents (Porter & Charman 1997; O’Driscoll 2002; Holm et al 2003). Hence, we believe that the improvement in the pharmacokinetic parameters of atorvastatin SMEDDS could be a combined effect of inhibition of CYP3A4-induced presystemic metabolism and improved lymphatic transport. However, it should be noted that atorvastatin, like all the other statins, acts in the liver to demonstrate its lipid-lowering action (Stancu & Sima 2001). It is also noteworthy that plasma concentrations of atorvastatin acid and its metabolites do not correlate with the reduction in LDL cholesterol, indicating that there is a poor pharmacokinetic–pharmacodynamic relationship. This issue has adequately been discussed by Lennernas (2003). Therefore, to improve the therapeutic efficacy of atorvastatin, it is imperative that the effective concentration of atorvastatin be increased in the liver instead of the plasma. Thus, in the case of atorvastatin, increase in the Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E.), Mumbai-400098, India

Basic drug--enterosoluble polymer coevaporates: development of oral controlled release systems.

Precipitation of basic drugs within oral prolonged release systems, at the higher pH values of the intestine, would affect drug release. Coevaporates of a model basic drug verapamil HCl, in single or mixed polymer systems, containing Eudragit L100 (L100) and ethyl cellulose or Eudragit RS100, were prepared from ethanolic solution. XRD and DSC indicated loss of crystallinity of the drug in the coevaporates. The presence of the enterosoluble polymer in the system was found to aid in faster dissolution of the drug at higher pH values. This was affected by the presence and type of retarding polymer present in the system. Compression of the coevaporates resulted in either very slow release of the drug or undesirable changes in the release profile. Pelletization of a coevaporate containing drug and L100 yielded systems, which released the drug uniformly when studied by the buffer change method in simulated gastric (SGF) and intestinal (SIF) fluids. The presence of L100 in intimate contact with the drug was found to be essential for the desirable drug release properties of the system. The drug release occurred predominantly by diffusion in SGF and by a combination of diffusion and polymer dissolution/erosion in SIF. Appropriate choice of release modifiers and formulation variables and development of suitable formulations can yield systems which compensate for the reduced solubility of the drug in the higher pH environments of the intestine.