8
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Depot injectable atorvastatin biodegradable in situ gel: development, optimization, in vitro, and in vivo evaluation

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          This study aimed to develop an optimized depot injectable atorvastatin (ATR) biodegradable in situ gel (ISG) system with minimum initial burst using a central composite design. The factors selected were poly ( d, l-lactide-co-glycolide) (PLGA) concentration (X 1), molecular weight of polyethylene glycol (PEG) (X 2), and PEG concentration (X 3). The independent variables were the initial burst of ATR after 2 (Y 1) and 24 hours (Y 2). The optimized formulation was investigated using scanning electron microscopy, Fourier transform infrared spectroscopy, and in vitro drug release in phosphate-buffered saline of pH 7.4 for 72 hours. The in vivo pharmacokinetic study of the optimized ATR-ISG and the corresponding PEG-free ATR-ISG were conducted by intramuscular injection of a single dose (2 mg/kg) of ATR in male New Zealand White rabbits. A double-blind, randomized, parallel design was used in comparison with those of the marketed ATR tablet. Statistical analysis revealed that PLGA concentration and the molecular weight of PEG have pronounced effects on both Y 1 and Y 2. The optimized formulation was composed of 36.10% PLGA, PEG 6000, and 15.69% PEG, and exhibited characteristic in vitro release pattern with minimal initial burst. Incorporation of PEG in the formulation causes a slight decrease in the glass transition temperature value of PLGA, leading to a slight change in Fourier transform infrared spectroscopy spectrum due to possible interaction. Moreover, scanning electron microscopy photomicrograph showed smooth surface with disappearance of the cracks which characterize the surface of PEG-free formulation. The pharmacokinetic data for the optimized depot injectable ATR-ISG showed a significant ( P<0.05) decrease in maximum plasma concentration from 547.62 to 346.84 ng/mL, and increasing time to reach the maximum plasma concentration from 12 to 72 hours in comparison with the marketed tablet. The optimized ATR-ISG formulation has shown minimal initial drug burst which confirms the suitability of the ISG system in the prolongation of drug release in patients with chronic long-term therapy.

          Related collections

          Most cited references 32

          • Record: found
          • Abstract: found
          • Article: not found

          Novel injectable neutral solutions of chitosan form biodegradable gels in situ.

           A Chenite,  C Chaput,  D. Wang (2000)
          A novel approach to provide, thermally sensitive neutral solutions based on chitosan/polyol salt combinations is described. These formulations possess a physiological pH and can be held liquid below room temperature for encapsulating living cells and therapeutic proteins; they form monolithic gels at body temperature. When injected in vivo the liquid formulations turn into gel implants in situ. This system was used successfully to deliver biologically active growth factors in vivo as well as an encapsulating matrix for living chondrocytes for tissue engineering applications. This study reports for the first time the use of polymer/polyol salt aqueous solutions as gelling systems, suggesting the discovery of a prototype for a new family of thermosetting gels highly compatible with biological compounds.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems--a review.

            Poly(D,L-lactic-co-glycolic acid) (PLGA) is the most frequently used biodegradable polymer in the controlled release of encapsulated drugs. Understanding the release mechanisms, as well as which factors that affect drug release, is important in order to be able to modify drug release. Drug release from PLGA-based drug delivery systems is however complex. This review focuses on release mechanisms, and provides a survey and analysis of the processes determining the release rate, which may be helpful in elucidating this complex picture. The term release mechanism and the various techniques that have been used to study release mechanisms are discussed. The physico-chemical processes that influence the rate of drug release and the various mechanisms of drug release that have been reported in the literature are analyzed in this review, and practical examples are given. The complexity of drug release from PLGA-based drug delivery systems can make the generalization of results and predictions of drug release difficult. However, this complexity also provides many possible ways of solving problems and modifying drug release. Basic, generally applicable and mechanistic research provides pieces of the puzzle, which is useful in the development of controlled-release pharmaceuticals. Copyright © 2011 Elsevier B.V. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Clinical pharmacokinetics of atorvastatin.

              Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.
                Bookmark

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                20 January 2016
                : 10
                : 405-415
                Affiliations
                [1 ]Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
                [2 ]Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
                [3 ]Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, Egypt
                Author notes
                Correspondence: Khalid M El-Say, Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, PO Box 80260, Jeddah 21589, Saudi Arabia, Tel +966 12 640 0000, Email kelsay1@ 123456kau.edu.sa
                Article
                dddt-10-405
                10.2147/DDDT.S98078
                4725642
                26855565
                © 2016 Ahmed et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Comments

                Comment on this article