Recent advances in materials for extended-release antibiotic delivery system

The Journal of Antibiotics (2011) 64, 625–634 & 2011 Japan Antibiotics Research Association All rights reserved 0021-8820/11 $32.00 www.nature.com/ja REVIEW ARTICLE Recent advances in materials for extended-release antibiotic delivery system Ping Gao, Xin Nie, Meijuan Zou, Yijie Shi and Gang Cheng To maintain antimicrobial activity, frequent administration of conventional formulations of many antibiotics with short half-life is necessary. Otherwise, concentration under MIC occurs frequently in the course of anti-infective treatment, which induces antibiotic resistance. By maintaining a constant plasma drug concentration over MIC for a prolonged period, extended-release dosage forms maximize the therapeutic effect of antibiotics while minimizing antibiotic resistance. Another undoubted advantage of extended-release formulation is improved patient compliance. For better release properties, many materials have been introduced into the matrix and coating extended-release system in the past few years. Materials that have been widely used in industry are hydrophilic matrix materials such as hydroxypropylmethylcellulose. The excellent biocompatibility and extensive laboratory studies provide biodegradable polymers great potential for industrial applications. In addition, it seems like the researches on tailored materials that are obtained by chemical modification of the existing materials or combination of different carriers in physical mixtures have a long way to go. Meanwhile, with the development of polymers and inorganic porous nanocarriers, nanotechnology is applied increasingly for the extended delivery of antibiotics. This review highlights the development of materials used in extended-release formulation and nanoparticles for antibiotic delivery. We also provide an overview of the antibiotic extended-release products that have provided clinical benefit or are undergoing the clinical trial. The Journal of Antibiotics (2011) 64, 625–634; doi:10.1038/ja.2011.58; published online 3 August 2011 Keywords: antibiotic resistance; coating material; complex; extended release; matrix material; nanoparticles INTRODUCTION Since Alexander Fleming discovered penicillin in 1928, hundreds of antibacterial drugs have been introduced into clinical use and many infectious diseases have been overcome. However, with their extensive application, one of the most serious problems of current medicine— antimicrobial resistance—arises, which limits the therapeutic effect of conventional therapy. Many researchers are making efforts to discover new antibiotics, whereas some other studies are focused on improving the clinical outcomes of currently available antibacterial drugs by using new formulations. Extended-release delivery system is one of the investigations that is being carried out to decrease the induction of antibiotic resistance. The terms ‘sustained release’, ‘prolonged release’ and ‘slow release’ are synonymous with ‘extended release’. As antiinfection treatments often involve a long course of therapy, sufficient antibiotic exposure is needed to ensure the eradication of the microorganism. However, many patients tend to interrupt treatment once they feel better, and thus the incomplete treatment may aggravate the development of antibiotic resistance. Besides, many antibiotics have short half-life values and need to be administered frequently, which also contributes to patient incompliance. The poor compliance often leads to treatment failure or increases the cost of health-care resources such as the requirement for additional agents and hospital admission. It is recognized that extended-release preparation is advantageous to improve patient compliance, as frequent administration can be reduced by maintaining a constant plasma drug concentration over a prolonged period of time.1 For example, for azithromycin, a long serum half-life (B68 h) antibiotic, the conventional preparation allows for a short 3-day (500 mg day–1 for 3 days) or 5-day (500 mg on day 1 followed by 250 mg on days 2–5) course of therapy, whereas azithromycin sustained-release microsphere for oral suspension (Zmax) permits a single-dose administration. Clinical applications have demonstrated the undoubted advantages of improved compliance and convenience of the single-dose regimen.1 Furthermore, sustained-release formulations can improve the therapeutical index of antibiotics. Antimicrobial agents are commonly divided into two major categories on the basis of their pharmacodynamics: time-dependent and concentration-dependent antibiotics. The time-dependent antibiotics, such as b-lactams, macrolides (except for azalides), tetracyclines and clindamycin, exert bactericidal effect when drugs are maintained above the MIC.2 For these agents, the time that therapeutic drug concentrations are above the MIC (T4MIC) is the primary parameter and should be kept for a minimum standard to achieve the desired clinical outcomes.3 In addition, dosage under the threshold may promote the development of antibiotic resistance.4 Therefore, continuous infusion has been proposed and its clinical advantage against antibiotic resistance over intermittent bolus for School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China Correspondence: Dr G Cheng, School of Pharmacy, Shenyang Pharmaceutical University, PO Box 32, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, China. E-mail: Received 3 April 2011; revised and accepted 7 June 2011; published online 3 August 2011 Antibiotic material extended-release DDS P Gao et al 626 time-dependent antimicrobials has been confirmed.5–7 Nevertheless, this approach has certain limitations, such as low physicochemical stability and patient inconvenience. For obtaining all the advantages of continuous infusion while avoiding the limitations, sustained-release preparation is a good substitute. For instance, amoxicillin/clavulanic acid extended-release formulation (Augmentin XR) has been demonstrated to extend amoxicillin exposure and killing time for a greater proportion of the dosing interval than that achieved by conventional formulations. Clinical trials have also indicated that the pharmacokinetic-enhanced formulation provided higher treatment success when compared with its immediate-release preparations with lower cost.8 Another example is clarithromycin extended-release tablets (Biaxin), the release profile of which is shown in Figure 1. Compared with clarithromycin immediate release, the extended-release preparation remained T4MIC for a longer duration and achieved better clinical cure.9 Concentration-dependent antibiotics include aminoglycosides, quinolones, azalides (azithromycin), ketolides and vancomycin. Different from the time-dependent antibiotics, these agents achieve increased bacteria killing with increased levels of drugs. In addition, these agents have an associated concentration-dependent postantibiotics effect. The peak concentration (Cmax) and area under (...truncated)