Pediatric drugs--a review of commercially available oral formulations

Pediatric oral formulations can be quite scientifically challenging to develop and the prerequisites for both a measurable dosage form to administer based upon bodyweight, and also taste-masking are two of the challenges unique for pediatric oral formulations. The physicochemical and organoleptic properties of the active drug substance such as solubility, chemical stability, and taste along with the intended dose can determine which formulations are feasible to develop. Oral pediatric formulations are available in 17 different varieties and can be either a ready-to-use formulation such as a solution, syrup, suspension, tablet, scored tablet, chewable tablet, orally disintegrating tablet, or thin strip, or can also be a formulation that requires manipulation such as a powder for constitution to a suspension, tablet for constitution to a suspension, powder for constitution to a solution, drops for reconstitution to a suspension, concentrated solution for dilution, effervescent tablet, bulk oral granules, bulk oral powder, or solid in a capsule to mix with food or drink. Recently there has been an increase in pediatric formulation development inspired by increased regulatory incentives. The intent of this review is to educate the reader on the various types of formulations administered orally to pediatrics, the rationale in deciding which type of formulation to develop, the excipients used, development challenges, the in-use handling of oral pediatric formulations, and the regulatory incentives.     

Photostability determination of commercially available nifedipine oral dosage formulations

Nifedipine (NIF), a 1,4-dihydropyridine calcium channel antagonist, undergoes photodegradation to dehydronifedipine (DNIF) upon exposure to ultraviolet (UV) light and to the nitroso analogue of dehydronifedipine (NDNIF) when exposed to sunlight. NIF photodegradation products do not contribute to clinical activity, thus the content of NIF must remain uniform between equipotent formulations. Large differences in light stability between bioequivalent NIF products could potentially result in the therapeutic failure of unstable preparations. Consequently, if large photostability differences do exist between NIF preparations, product substitution may not be warranted. The light stability of 10 intact immediate- or controlled-release oral NIF formulations, obtained from several European and North American manufacturers, was studied using direct continuous artificial sunlight exposure extending over a 12-week period. The content of both NIF and NDNIF for each product was measured to determine the extent of photodecomposition using a specific and sensitive reversed-phase high pressure liquid chromatographic (HPLC) method. In addition, NIF photodegradation was measured using both pure NIF powder and methanolic NIF solution to determine the effectiveness of the artificial sunlight source used in this study. After 12 weeks of artificial sunlight exposure, less than 3% of NDNIF (w/w initial NIF content) was present in each of the 10 tested dosage forms. Photodegradation was greater than 10% (w/w initial NIF content) in 5–10 min (mean t = 31 min), and in 24 h (mean t = 7.7 days) of artificial sunlight exposure for methanolic NIF solution and pure NIF powder samples, respectively. Therefore, the tested NIF formulations all appear to be photostable up to at least 12 weeks of continuous artificial sunlight exposure, compared with pure NIF powder and methanolic NIF solution. It is concluded that if therapeutic failures or pharmacodynamic differences between the tested NIF formulations were observed, photoinstability as a major contributory factor would be unlikely.     

Molecular and pharmacokinetic properties of 222 commercially available oral drugs in humans

This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDRI (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.     

林可霉素溶液剂和片剂的生物利用度比较

本文采用微生物法测定了12名健康志愿者交叉口服750mg林可霉素溶液剂和片剂后的血药浓度,经IBM计算机药动学程序PKBP—NI的拟合和统计程序POMS分析,评价比较了这两种制剂的药动学参数和生物利用度。结果表明:溶液剂的口服吸收稍快于片剂,而片剂的吸收略优于溶液剂,但两者的药动学参数均无显著差异(p>0.05)。两者的生物利用度是相似的,其相对生物利用度F(AUC_(0→∞)溶液剂/AUC_(0→∞)片剂)为92.3%。     

Derivatization of thiols under flow conditions using two commercially available propiolate esters

In the present study we report new data on the reaction of three representative thiols – captopril (CAP), cysteine (CYS) and N-acetylcysteine (NAC) – with two commercially available propiolate esters – methyl-propiolate (MP) and butyl-propiolate (BP) – under flow conditions. The reactions were investigated on-line using sequential injection analysis (SI) and the formed derivatives were monitored spectrophotometrically at 285 nm. The effect of critical parameters of the reaction such as the pH, the temperature and the amount concentration of the reagents were studied in detail including stopped-flow (SF) experiments. Both reagents were found to be suitable for the automated derivatization of thiols, although MP offered faster kinetics compared to BP. The applicability of the procedures was demonstrated by the development of SI methods for the dissolution studies of CAP tablets with satisfactory results.     

Adapting a commercially available software program to improve ADR reporting

To facilitate the long-term storage, retrieval, and analysis of adverse drug reaction (ADR) data, the drug information service at the University of Texas Health Science Center at San Antonio selected a computer software program with the capability to compile sets of relational databases. Five subsets were created to form the ADR database--patient demographics, medications, American Hospital Formulary Service classifications, adverse reactions, and case reports. This computerized system allows for quick information retrieval as well as the generation of monthly ADR reports. With such information, trends in ADRs can be identified and targeted for intervention programs to improve patient care and to comply with JCAHO requirements.     

Determination of residual erythrocytes in rat tissue homogenates using commercially available anti-red blood cell sera

A method to determine the residual erythrocyte content in rat tissue homogenates by means of radial immunodiffusion (Mancini et al., 1965) is described. The method makes use of commercially available antisera against rat erythrocytes. Tissues were homogenized after addition of digitonin and applied on Mancini plates. To measure within the linear part of the calibration curve, the tissue homogenates were diluted to concentrations between 0.062% and 2.5% wet weight content, depending on the type of tissue and on the degree of bleeding before the death of the animal. Recovery data of added blood as well as a comparison with results from organ distribution studies with ⁵⁹Fe-labeled erythrocytes demonstrated that this simple method is sufficiently reliable and sensitive.The present procedure is to control experiments in which drug tissue levels (e.g., antibiotics) are to be determined and in which the drug content of residual blood is likely to bias the results to an unknown extent. It can be used as well in organ distribution studies of substances with a high affinity for erythrocytes (e.g., Pb; As in rats). It is possible to individually control the success of procedures without the use of isotopes—such as exsanguination or vascular perfusion—that are performed in order to reduce the blood content in the organs under consideration.     

Correlation-based prediction of tissue-to-plasma partition coefficients using readily available input parameters

Abstract

1. Rationale: Tissue-to-plasma partition coefficients (K_p) that characterize the tissue distribution of a drug are important input parameters in physiologically based pharmacokinetic (PBPK) models. The aim of this study was to develop an empirically derived K_p prediction algorithm using input parameters that are available early in the investigation of a compound.

2. Methods: The algorithm development dataset (n?=?97 compounds) was divided according to acidic/basic properties. Using multiple stepwise regression, the experimentally derived K_p values were correlated with the rat volume of distribution at steady state (V_ss) and one or more physicochemical parameters (e.g. lipophilicity, degree of ionization and protein binding) to account for inter-organ variability of tissue distribution.

3. Results: Prediction equations for the value of K_p were developed for 11 tissues. Validation of this model using a test dataset (n?=?20 compounds) demonstrated that 65% of the predicted K_p values were within a two-fold error deviation from the experimental values. The developed algorithms had greater prediction accuracy compared to an existing empirically derived and a mechanistic tissue-composition algorithm.

4. Conclusions: This innovative method uses readily available input parameters with reasonable prediction accuracy and will thus enhance both the usability and the confidence in the outputs of PBPK models.     

Comparative human study of ibuprofen enantiomer plasma concentrations produced by two commercially available ibuprofen tablets

Twelve healthy male subjects participated in a two-way Latin square crossover study in which the treatments were a single 400 mg generic ibuprofen tablet (Tablet A) or a single 400 mg MOTRIN Tablet (Tablet B). Blood samples were drawn at various times through 12 h after dosing and plasma samples were assayed for ibuprofen enantiomers with a stereospecific capillary gas chromatographic procedure. Concentration-time data for both enantiomers were in agreement and indicated that drug was absorbed much more quickly from Tablet B than from the Tablet A; enantiomer Tmax values were less than 1.3 h from Tablet B but longer than 4 h from the Tablet A (p less than 0.001). Also, maximum enantiomer plasma concentrations from the Tablet B were about 50 per cent of the peak concentrations observed from Tablet A (p less than 0.001). The total extent of drug absorption appeared to be the same in both products. These data clearly indicate that the two tablets are not bioequivalent with respect to either ibuprofen enantiomer.     

TAP-binding peptides prediction by QSAR modeling based on amino acid structural information

The transporter associated with antigen processing (TAP) is essential for peptide delivery from the cytosol into the lumen of the endoplasmic reticulum (ER), where these peptides are loaded on a major histocompatibility complex (MHC) I molecules and form peptide-MHC complex. The peptide-MHC leaves the ER and displays their antigenic cargo on the cell surface to cytotoxic T cells. In this study, 89 physicochemical properties of amino acid were collected from AAIndex database, and used to characterize the peptides which were binding to TAP. Then, the stepwise regression (STR) was used to optimize the parameters which characterized the TAP binding peptides, and the multiple linear regression (MLR) was used to construct the quantitative structural activity relationship (QSAR) model based on optimized parameters. The quantitative models had good reliability and predictive ability: the Q2 of "leave one out" validation is 0.676 and R2 of test dataset is 0.722 respectively. Additionally, the standardized coefficients of the models could demonstrate the attributions for each position of epitope and determine which special amino acid is suitable at any position of the peptide. Therefore, the QSAR model constructed by STR-MLR has many advantages, such as, easier calculation and explanation, good performance, and definite physiochemical indication, which could be used to guide the design and modification of the TAP binding peptide.     

Inhibition of thiopurine S-methyltransferase activity by impurities in commercially available substrates: a factor for differing results of TPMT measurements

Objectives: Thiopurine S-methyltransferase (TPMT) activity, when measured in red blood cells (RBC) with a recently published TPMT activity assay using 6‐thioguanine (6-TG) as substrate, could not be reproduced in another laboratory. We investigated factors which could influence the results of the TPMT activity measurement. Methods: We tested twelve 6-TG and four 6-mercaptopurine (6-MP) compounds from different suppliers as substrates and determined the enzyme kinetic parameters K_m and V_max . Furthermore, we studied the influence of different 6-TG compounds on the affinity of the methyl donor S-adenosyl-l-methionine (SAM) to the TPMT enzyme. Results: All 6-TG products were of equal purity (declared >98% by the supplier); this was ascertained by HPLC. However, the rate of methylation obtained following incubation with 6-TG from different suppliers ranged from 10% to 100% when incubated with the same RBC lysate. The lowest apparent K_m value for a 6-TG was 22.3 μmol · l⁻¹, while the product with the highest methylation rate showed a K_m of 156 μmol · l⁻¹. From these results we assume that there is a contaminant in some 6-TG products, which acts as a strong inhibitor of TPMT activity. Compounds possibly used for the synthesis of 6-TG (guanine, pyridine, 6-chloroguanine) did not affect the methylation rate. Thioxanthine, which is known to be a strong inhibitor of TPMT when added to the assay system to give a 2% contamination, reduced TPMT activity from 100% to 72%. Using 6-MP from different suppliers as substrate resulted in K_m values ranging from 110 to 162 μmol · l⁻¹ and V_max values ranging from 54 to 68 nmol 6‐MMP · g⁻¹Hb · h⁻¹. The K_m value for the methyl donor SAM was similar to and independent from the thiopurine substrates tested (range 4.9–11 μmol · l⁻¹ SAM). In contrast to other investigators, we found non-enzymatic S-methylation, which was negligible under our assay conditions (3% with 128 μmol · l⁻¹ SAM), but could become relevant in experiments using higher SAM concentrations. Conclusions: TPMT enzyme activity determined with 6‐TG as substrate may be strongly inhibited by a contaminant in some of the 6-TG lots distributed. Received: 28 June 1998 / Accepted in revised form: 18 January 1999     

Presentation of a structurally diverse and commercially available drug data set for correlation and benchmarking studies

A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small, physicochemically diverse set of 24 drug compounds. Factors such as structural diversity, commercial availability, price, and a suitable analytical technique for quantification were considered in the selection. Lipophilicity, pKa, solubility, and permeability across human Caco-2 cell monolayers were measured for the compiled data set. The results show that, by use of a physicochemically diverse data set, experimental responses over a wide range were obtained. The paper also shows how experimental difficulties due to the diversity of the data set can be overcome. We anticipate that this data set can serve as a benchmark set for validation of new experimental techniques or in silico models. It can also be used as a diverse starting data set for the development of new computational models.