Next Issue
Previous Issue

Table of Contents

Pharmaceutics, Volume 2, Issue 4 (December 2010), Pages 321-431

  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
View options order results:
result details:
Displaying articles 1-6
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle Timing and Duration of Drug Exposure Affects Outcomes of a Drug-Nutrient Interaction During Ontogeny
Pharmaceutics 2010, 2(4), 321-338; doi:10.3390/pharmaceutics2040321
Received: 9 September 2010 / Revised: 5 October 2010 / Accepted: 12 October 2010 / Published: 14 October 2010
PDF Full-text (607 KB) | HTML Full-text | XML Full-text
Abstract
Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence
[...] Read more.
Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence of a significant drug-nutrient interaction (cefepime-carnitine) on the timing and duration of drug exposure relative to postnatal age. Rat pups were administered cefepime (5 mg/kg) twice daily subcutaneously according to different dosing schedules (postnatal day 1-4, 1-8, 8-11, 8-20, or 1-20). Cefepime significantly reduced serum and heart L-carnitine levels in postnatal day 1-4, 1-8 and 8-11 groups and caused severe degenerative changes in ventricular myocardium in these groups. Cefepime also altered the ontogeny of several key L-carnitine homeostasis pathways. The qualitative and quantitative changes in levels of hepatic γ-butyrobetaine hydroxylase mRNA and activity, hepatic trimethyllysine hydroxlase mRNA, intestinal organic cation/carnitine transporter (Octn) mRNA, and renal Octn2 mRNA depended on when during postnatal development the cefepime exposure occurred and duration of exposure. Despite lower levels of heart L-carnitine in earlier postnatal groups, levels of carnitine palmitoyltransferase mRNA and activity, heart Octn2 mRNA and ATP levels in all treatment groups remained unchanged with cefepime exposure. However, changes in other high energy phosphate substrates were noted and reductions in the phosphocreatine/ATP ratio were found in rat pups with normal serum L-carnitine levels. In summary, our data suggest a significant drug-nutrient transport interaction in developing neonates, the nature of which depends on the timing and duration of exposure relative to postnatal age. Full article
Open AccessArticle Enhanced Dissolution and Oral Bioavailability of Piroxicam Formulations: Modulating Effect of Phospholipids
Pharmaceutics 2010, 2(4), 339-350; doi:10.3390/pharmaceutics2040339
Received: 21 September 2010 / Revised: 20 October 2010 / Accepted: 26 October 2010 / Published: 27 October 2010
Cited by 18 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Several biologically relevant phospholipids were assessed as potential carriers/additives for rapidly dissolving solid formulations of piroxicam (Biopharmaceutics Classification System Class II drug). On the basis of in vitro dissolution studies, dimyristoylphosphatidylglycerol (DMPG) was ranked as the first potent dissolution rate enhancer for the
[...] Read more.
Several biologically relevant phospholipids were assessed as potential carriers/additives for rapidly dissolving solid formulations of piroxicam (Biopharmaceutics Classification System Class II drug). On the basis of in vitro dissolution studies, dimyristoylphosphatidylglycerol (DMPG) was ranked as the first potent dissolution rate enhancer for the model drug. Subsequently, the solid dispersions of varying piroxicam/DMPG ratios were prepared and further investigated. Within the concentration range studied (6.4-16.7 wt %), the dissolution rate of piroxicam from the solid dispersions appeared to increase as a function of the carrier weight fraction, whereas the cumulative drug concentration was not significantly affected by piroxicam/DMPG ratio, presumably due to a unique phase behavior of the aqueous dispersions of this carrier phospholipid. Solid state analysis of DMPG-based formulations reveled that they are two-component systems, with a less thermodynamically stable form of piroxicam (Form II) being dispersed within the carrier. Finally, oral bioavailability of piroxicam from the DMPG-based formulations in rats was found to be superior to that of the control, as indicated by the bioavailability parameters, cmax and especially Tmax (53 µg/mL within 2 h vs. 39 µg/mL within 5.5 h, respectively). Hence, DMPG was regarded as the most promising carrier phospholipid for enhancing oral bioavailability of piroxicam and potentially other Class II drugs. Full article
Open AccessArticle Small Volume Dissolution Testing as a Powerful Method during Pharmaceutical Development
Pharmaceutics 2010, 2(4), 351-363; doi:10.3390/pharmaceutics2040351
Received: 12 October 2010 / Revised: 26 October 2010 / Accepted: 28 October 2010 / Published: 1 November 2010
Cited by 8 | PDF Full-text (184 KB) | HTML Full-text | XML Full-text
Abstract
Standard compendia dissolution apparatus are the first choice for development of new dissolution methods. Nevertheless, limitations coming from the amount of material available, analytical sensitivity, lack of discrimination or biorelevance may warrant the use of non compendial methods. In this regard, the use
[...] Read more.
Standard compendia dissolution apparatus are the first choice for development of new dissolution methods. Nevertheless, limitations coming from the amount of material available, analytical sensitivity, lack of discrimination or biorelevance may warrant the use of non compendial methods. In this regard, the use of small volume dissolution methods offers strong advantages. The present study aims primarily to evaluate the dissolution performance of various drug products having different release mechanisms, using commercially available small volume USP2 dissolution equipment. The present series of tests indicate that the small volume dissolution is a useful tool for the characterization of immediate release drug product. Depending on the release mechanism, different speed factors are proposed to mimic common one liter vessel performance. In addition, by increasing the discriminating power of the dissolution method, it potentially improves know how about formulations and on typical events which are evaluated during pharmaceutical development such as ageing or scale–up. In this regard, small volume dissolution is a method of choice in case of screening for critical quality attributes of rapidly dissolving tablets, where it is often difficult to detect differences using standard working conditions. Full article
(This article belongs to the Special Issue Recent Developments and Future Perspectives in Dissolution Testing)
Open AccessArticle The Influence of Milling on the Dissolution Performance of Simvastatin
Pharmaceutics 2010, 2(4), 419-431; doi:10.3390/pharmaceutics2040419
Received: 2 December 2010 / Revised: 13 December 2010 / Accepted: 16 December 2010 / Published: 17 December 2010
Cited by 6 | PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit
[...] Read more.
Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit altered properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed by scanning electron microscopy (SEM) and image analysis. Process induced disorder was determined by partial least squares (PLS) regression modeling of respective X-ray powder diffractograms (XRPD) and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were milling frequency, milling time and ball quantity at a set drug load, out of which milling frequency was found to be the most important factor for particle size as well as process induced disorder. Milling frequency and milling time exhibited an interaction effect on the responses. The optimum milling settings using the maximum number of milling balls (60 balls with 4 mm diameter) was determined to be at a milling frequency of 21 Hz and a milling time of 36 min with a resulting primary particle size of 1.4 μm and a process induced disorder of 6.1% (assessed by Raman spectroscopy) and 8.4% (assessed by XRPD), at a set optimization limit of < 2 μm for particle size and < 10% for process induced disorder. This optimum was tested experimentally and the process induced disorder was determined to be 6.9% (± 2.2) by Raman spectroscopy and 7.8% (± 2.3) by XRPD. Subsequent intrinsic dissolution testing revealed that the process induced disorder was negligible with regard to the dissolution rate. The predicted primary particle size of 1.4 μm could be confirmed experimentally, but due to agglomeration of the primary particles a dissolution rate advantage was not shown, highlighting the importance of dissolution testing at an early stage of drug development. Full article
(This article belongs to the Special Issue Recent Developments and Future Perspectives in Dissolution Testing)

Review

Jump to: Research

Open AccessReview Drug Development for Pediatric Populations: Regulatory Aspects
Pharmaceutics 2010, 2(4), 364-388; doi:10.3390/pharmaceutics2040364
Received: 15 October 2010 / Revised: 18 November 2010 / Accepted: 24 November 2010 / Published: 29 November 2010
Cited by 24 | PDF Full-text (160 KB) | HTML Full-text | XML Full-text
Abstract
Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in
[...] Read more.
Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted—including the regulatory basis—and examples of the use of M&S are illustrated to support pediatric drug development. Full article
Open AccessReview Pediatric Dosing and Body Size in Biotherapeutics
Pharmaceutics 2010, 2(4), 389-418; doi:10.3390/pharmaceutics2040389
Received: 26 October 2010 / Revised: 9 December 2010 / Accepted: 15 December 2010 / Published: 16 December 2010
Cited by 5 | PDF Full-text (284 KB) | HTML Full-text | XML Full-text
Abstract
Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m2), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion
[...] Read more.
Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m2), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion (ADME) of biologics in pediatrics. The complexity of the factors involved in pediatric pharmacokinetics lends to the reconsideration of body size based dose adjustment. A proper dosing adjustment for pediatrics should also provide less intersubject variability in the pharmacokinetics and/or pharmacodynamics of the product compared with no dose adjustment. Biological proteins and peptides generally share the same pharmacokinetic principle with small molecules, but the underlying mechanism can be very different. Here, pediatric and adult pharmacokinetic parameters are compared and summarized for selected biotherapeutics. The effect of body size on the pediatric pharmacokinetics for these biological products is discussed in the current review. Full article

Journal Contact

MDPI AG
Pharmaceutics Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
pharmaceutics@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Pharmaceutics
Back to Top