Controlled initial surge despite high drug fraction and high solubility.

Potential connections between release profiles and solvent evaporation rates alongside polymer chemistry were elucidated for the release of tetracycline hydrochloride from two different poly (d, l-lactide-co-glycolide) (PLGA) film matrices containing high drug fractions (50%, 30%, and 15%), and prepared at two distinct solvent evaporation rates. At highest tetracycline concentrations (50%), (i) the early release rates were ≤0.5 µg/min in all cases; (ii) release was linear from systems fabricated with lower lactic content and slower solvent evaporation rate and bimodal from systems fabricated with higher lactic content and faster evaporation rate; (iii) surface fractions covered by the drug were similar at both evaporation rates for 85:15 PLGA but very different for 50:50 PLGA, leading to unexpectedly reduced early release from 50:50 PLGA than from 85:15 PLGA when both the matrices were fabricated using a slower evaporation rate. These features remained unaffected in case of low drug concentration. Results suggested that during the formation of the drug-polymer microstructure, the combined effect of polymer chemistry and solvent evaporation rate sets apart the surface characteristics and the initial release profiles of systems containing high drug fraction, and an appropriate combination of these parameters may be utilized to control the early stage of drug release.

Comparative evaluation of the in vitro efficacy of lanthanum carbonate chewable tablets.

The aims of this study were to systematically evaluate the effects of pH levels, phosphate concentrations, and tablet integrity on the phosphate binding profiles of lanthanum carbonate chewable tablets, and to compare the in vitro phosphate binding efficacy of one reference and two test products of lanthanum carbonate chewable tablets. Langmuir equation was utilized to calculate the binding constants k1 and k2 . The phosphate binding to the tablets of lanthanum carbonate product was pH dependent, with a faster binding rate at low pH. The crushed tablets bind phosphate more rapid. Compared with the whole tablets, the kinetic binding profiles from the crushed tablets were less variable under all conditions for both test and reference products. The phosphate level has a significant impact on the phosphate binding for both whole and crushed tablets under all pH conditions, with more binding at higher phosphate concentration. The phosphate binding profiles displayed significant difference among the products. For a crushed tablet, the phosphate binding to lanthanum reached equilibrium within 8 h under all conditions. The 90% confidence interval for the k2 ratio (test/reference) was well within the 80%-125% under all pH conditions. However, the k1 ratio varies from 54% to 144%. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1370-1381, 2013.

Spontaneous carbonate formation in an amorphous, amine-rich, polymeric drug substance: sevelamer HCl product quality.

Spectral differences among multiple manufacturers/lots of sevelamer HCl were observed by Fourier transform infrared spectroscopy, and further characterization was performed to identify the cause for these differences. The drug substance is a polymer that possesses a large molecular weight, is amorphous, and is practically insoluble in both water and organic solvents. Thus, solid-state characterization methods (spectroscopic and thermal) were required to identify and characterize differences among the samples to assess possible differences in product quality. ¹³C cross-polarization-magic-angle-spinning nuclear magnetic resonance spectroscopy of sevelamer HCl substances demonstrated the presence of a carbonyl-containing species, which was attributed to a carbonate impurity among samples. Stability studies demonstrated that this carbonate impurity formed spontaneously upon exposure of the drug substance to atmospheric water vapor and carbon dioxide, even under ambient conditions. Mechanistically, this behavior likely arises from the large number of primary and secondary amine groups, the hygroscopicity of the HCl salt, and a high degree of molecular mobility due to the amorphous nature of the drug substance.

Comparative stability of repackaged metoprolol tartrate tablets.

The stability of metoprolol tartrate tablets packaged in original high density polyethylene containers and repackaged in USP Class A unit-dose blister packs was investigated. Studies were conducted at 25 degrees C/60% relative humidity (RH) for 52 weeks and at 40 degrees C/75% RH for 13 weeks. The potency, dissolution, water content, loss on drying and hardness of the drug products were analyzed. Results indicated no differences in the stability between the tablets in both packages stored under 25 degrees C/60% RH. No difference in potency was found in both packages under either condition. However, a significant weight increase due to moisture uptake was observed for the repackaged tablets stored under 40 degrees C/75% RH. The weight increase was accompanied by a decrease in tablet hardness (6.5-0 kp) and a increase in dissolution rate (51-92%) in 5 min. Near-infrared (NIR) chemical imaging also monitored moisture uptake of the tablet non-invasively through the package. The observed changes in product stability may adversely affect the products bioavailability profile, even though the potency of the active drug remained within USP specification range of 90-110%. Study results suggest product quality can be negatively impacted even when using USP Class A repackaging materials.

Participation of women in clinical trials for new drugs approved by the food and drug administration in 2000-2002.

OBJECTIVE: This study aimed to track the inclusion of women in clinical trials for new drugs approved by the Food and Drug Administration (FDA) between 2000 and 2002 and to evaluate the extent of analyses by sex. METHODS: Data were extracted from FDA reviewers' reports, summaries of clinical trials in New Drug Applications (NDAs), and product labeling and organized into a Microsoft Access database. The information collected includes subject enrollment by sex per clinical phase and sex differences in pharmacokinetics, safety, and efficacy as determined by either sponsors or reviewers. RESULTS: There were 67 New Molecular Entities (NMEs) approved by the FDA between 2000 and 2002. A total of 397,825 subjects were enrolled in 2,323 clinical trials. If 9 sex-specific NMEs are excluded, 297,697 subjects were enrolled in 1,974 clinical trials. Forty-seven percent of participants were male, 49% were female, and 4% of subjects were not specified. Of the 58 sex-nonspecific products in the study, 71% (41 of 58) of sex analyses were performed either by the sponsor or FDA reviewers. Twenty-five NMEs were found to have sex differences in pharmacokinetics, efficacy or adverse events. However, no recommendation was made to adjust dosage based on sex differences. CONCLUSIONS: The percentages of women and men participating in clinical trials varied by year, phase, and product type. However, the overall participation by women and men was comparable, suggesting an improvement in including more women in clinical trials when compared with the previous FDA study evaluating women's participation from 1995 through 1999. As with the previous study, however, a significant underrepresentation of women in early phase trials and in certain areas, such as cardiovascular products, was observed and continues to be an issue of concern. Lack of appropriate analyses by sex should also be noted as an issue of concern.

Feasibility studies of utilizing disk intrinsic dissolution rate to classify drugs.

The purpose of this report was to investigate the feasibility of using disk intrinsic dissolution rate (DIDR) to determine solubility class membership. We employed a VanKel dissolution apparatus fitted with a Wood's intrinsic dissolution die. To test the robustness of the method, variations of DIDR with compression force, dissolution volume, distance of the drug disk from the bottom of the dissolution vessel, and drug disk rotation speed were studied using furosemide and metoprolol in pH 4.5 acetate buffer as a model system. The DIDRs of six low solubility and nine high solubility model drugs were then determined at pH 1.2, 4.5, and 6.8 and compared to their BCS solubility class membership. It was found that the compression force, dissolution medium volume, and die position had no significant effect on DIDR for the system studied. The proposed compression force, dissolution volume, die position, and rotation speed are 2000 psi, 900 ml, 0.5 in., and 100 rpm, respectively. The test results obtained from 15 model BCS drugs show a good relationship between the DIDR and BCS solubility classification with 0.1 mg/min/cm(2) as a class boundary unless the dose is either extremely low or high where discrepancies may exist between the solubility and DIDR methods. Therefore, more scientific research and debates are needed before considered for regulatory purpose.