William H. Doub

Lack of Significant Dermal Penetration of Titanium Dioxide from Sunscreen Formulations Containing Nano- and Submicron-Size TiO2 Particles

Titanium dioxide (TiO(2)) is included in some sunscreen formulations to physically block ultraviolet radiation. A dermal penetration study was conducted in minipigs with three TiO(2) particles (uncoated submicron sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized) applied 5% by weight in a sunscreen. These and control formulations were topically applied to minipigs at 2 mg cream/cm(2) skin (4 applications/day, 5 days/week, 4 weeks). Skin (multiple sites), lymph nodes, liver, spleen, and kidneys were removed, and the TiO(2) content was determined (as titanium) using inductively coupled plasma mass spectroscopy. Titanium levels in lymph nodes and liver from treated animals were not increased over the values in control animals. The epidermis from minipigs treated with sunscreens containing TiO(2) showed elevated titanium. Increased titanium was detected in abdominal and neck dermis of minipigs treated with uncoated and coated nanoscale TiO(2). Using electron microscopy-energy dispersive x-ray analysis, all three types of TiO(2) particles were found in the stratum corneum and upper follicular lumens in all treated skin samples (more particles visible with coated nanoscale TiO(2)). Isolated titanium particles were also present at various locations in the dermis of animals treated with all three types of TiO(2)-containing sunscreens; however, there was no pattern of distribution or pathology suggesting the particles could be the result of contamination. At most, the few isolated particles represent a tiny fraction of the total amount of applied TiO(2). These findings indicate that there is no significant penetration of TiO(2) nanoparticles through the intact normal epidermis.

Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies: Sponsored by the American Association of Pharmaceutical Chemists, U.S. Food and Drug Administration, Fédération Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists

Abstract This is a summary report of the conference on ‘Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies.’ The conference was held from December 3 to 5, 1990, in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration, Federation Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. This report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: (1) to reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; (2) to determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; and (3) to develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic. bioavailability, and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselectivc determinations, were also deliberated.

The state of nano‐sized titanium dioxide (TiO2) may affect sunscreen performance

In the past several years, there has been a trend in the sunscreen/cosmetics industry to replace micron‐sized titanium dioxide (TiO2) particles with nanoscale materials. The increased use of nanoscale TiO2 has resulted in questions about these and other nanoproducts. This study examines the effects of using nanoscale TiO2 on ultraviolet (UV) attenuation in simple to complex sunscreen formulations. UV light attenuation, product stability, and potential damage to the skin barrier were examined with both nanoscale and microscale TiO2 particles. Results indicate that none of the formulations decreased the barrier function of the skin and the best UV attenuation occurs when the TiO2 particles are stabilized with a coating and evenly distributed such as with non‐agglomerated coated nanoscale materials. This indicates that nanoscale TiO2 may have better efficacy while lacking toxicity.

Equivalence considerations for orally inhaled products for local action-ISAM/IPAC-RS European Workshop report.

The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified.

Particle size determination of sunscreens formulated with various forms of titanium dioxide

Background: There has been some apprehension expressed in the scientific literature that nanometer-sized titanium dioxide (TiO2) and other nanoparticles, if able to penetrate the skin, may cause cytotoxicity. In light of a lack of data regarding dermal penetration of titanium dioxide from sunscreen formulations, the Food and Drug Administration Center for Drug Evaluation and Research initiated a study in collaboration with the National Center for Toxicology Research using minipigs to determine whether nanoscale TiO2 in sunscreen products can penetrate intact skin. Four sunscreen products were manufactured. Method: The particle size distribution of three TiO2 raw materials, a sunscreen blank (no TiO2) and three sunscreen formulations containing uncoated nanometer-sized TiO2, coated nanometer-sized TiO2 or sub-micron TiO2 were analyzed using scanning electron microscopy (SEM), laser scanning confocal microscopy (LSCM), and X-ray diffraction (XRD) to determine whether the formulation process caused a change in the size distributions (e.g., agglomeration or deagglomeration) of the TiO2. Results: SEM and XRD of the formulated sunscreens containing nanometer TiO2 show the TiO2 particles to have the same size as that observed for the raw materials. This suggests that the formulation process did not affect the size or shape of the TiO2 particles. Conclusion: Because of the resolution limit of optical microscopy, nanoparticles could not be accurately sized using LSCM, which allows for detection but not sizing of the particles. LSCM allows observation of dispersion profiles throughout the sample; therefore, LSCM can be used to verify that results observed from SEM experiments are not solely surface effects.

Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3: Final report on a statistical procedure for determining equivalence

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test’s limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.

Effects of Device and Formulation on In Vitro Performance of Dry Powder Inhalers

The study examined the sensitivity of DPI in vitro performance to formulation and device changes. Rotahaler/Rotacaps was selected as the reference DPI drug product, and Aerolizer was selected as the test device. Since the test device was recognized to have much greater efficiency of dispersion, simple modifications to both formulation and device were made in an effort to provide a closer match to the in vitro performance of the reference product. The modifications included varying the drug and lactose particle sizes and/or lactose fine particle content in the test formulations, as well as lowering the specific resistance of the test device. These modifications were intended to address variables important for drug product performance for a defined experimental design and were not intended to mimic the extensive formulation and device design strategies that are employed in an industrial setting. Formulation and device modifications resulted in a modified test product that approached the reference product in the in vitro performance.

Gauge repeatability and reproducibility for accessing variability during dissolution testing: a technical note.

ConclusionsIn this study, the gauge R&R method was used to analyze sources of variability for the paddle apparatus (USP apparatus 2). An initial evaluation of gauge R&R dissolution testing results using the amount dissolved at 30 minutes for a 10-mg prednisone tablet showed no instrument or operator contributions to variability but did highlight some vessel differences within an instrument. Based on this finding, a new mechanical calibration step was developed to improve the performance of the measurement system.Gauge R&R analysis is useful for determining the sources of variability in a measurement system. In addition, the extensive characterization and variability knowledge obtained during gauge R&R testing of a product can be used to develop the mean and SD information necessary to set up an internal standard for dissolution testing.

Evaluation of substrates for 90° peel adhesion—A collaborative study. II. Transdermal drug delivery systems

In a previous study on peel adhesion for medical tapes, it was shown that a stainless steel (SS) substrate better discriminated among medical tapes than a high-density polyethylene (HDPE) substrate. The objective of this study was to determine if a SS substrate would also better distinguish among transdermal drug delivery systems (TDDSs). Five TDDSs (Vivelle Dot, Climara, Catapres-TTS, Duragesic, and Mylan Fentanyl) were evaluated on three different substrates (SS, HDPE, and human cadaver skin). All measurements were made using a dwell time of approximately 3 min, a peel angle of 90 degrees, and a peel speed of 300 mm/min. Differences among TDDSs were greater for SS than for HDPE, using the F statistic for testing for differences among TDDSs means as a measure of heterogeneity, thereby indicating greater discrimination by SS.

Evaluation of substrates for 90° peel adhesion—A collaborative study. I. Medical tapes

As part of a method development for peel testing, an interlaboratory comparison among Food and Drug Administration-Center for Drug Evaluation and Research, Food and Drug Administration-Center for Devices and Radiological Health and Southwest Research Institute was conducted using medical tapes. The aim was to determine which readily available substrate [stainless steel (SS), high density polyethylene (HDPE) or Vitro-Skin(R)] would best distinguish among various medical tapes. Five medical tapes (3M 1523, 3M 1525L, 3M 1776, Mepiform(R) and Mediderm(R) 3505) were evaluated on four different substrates (SS, HDPE, Vitro-Skin, and human cadaver skin) using the following peel parameters: approximately 3 min dwell time, 90 degrees peel angle, and 300 mm/min peel rate. No substrate mimics cadaver skin for all five tapes. SS had the best ability to distinguish among the medical tapes. Overall, for quality control purposes (yielding good discrimination and precision), SS would be the optimal substrate.