Developing a quality by design approach to model tablet dissolution testing: an industrial case study

Abstract

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.     

Characterization of the geometric properties of the sclero-conjunctival structure: a review

AIM: To investigate the variation of IGSF3 gene in three families with congenital absence of lacrimal puncta and canaliculi, and to lay a foundation for further research on the pathogenic gene of congenital lacrimal duct agenesis. METHOD: The members of the three families were recruited. The ophthalmologic examinations in details, including slit-lamp biomicroscope, intraocular pressure and fundus examination, etc were carried out. All patients were checked with paracentesis of puncta membrane and lacrimal duct probing, as well as the CT-DCG (computed tomography-dacryocystography). Peripheral blood of 13 participants (3 normal) from three families were collected, 4 mL each, for genomic DNA extraction, and 11 exon fragments of IGSF3 gene were amplified and sequenced by polymerase chain reaction (PCR) to determine whether there were IGSF3 genetic variation. RESULTS: A total of 13 members from three families were screened for 4 synonymous variants: c.930C>T (p.Pro366=), c.1359T>C (p.Ser709=), c.1797G>A (p.Ser855=), c.1539G>A (p.Ser769=), and 6 missense variants: c.1507G>A (p.Gly759Ser), c.1783T>C (p.Trp851Arg), c.1952G>T (p.Ser 907Ile), c.3120C>G (p.Asp1040Glu), c.3123C>G (p.Asp1041Glu), c.3139_3140insGAC (p.Asp1046_Pro1047insAsp), and the latter three were only found in two patients with absence of lacrimal puncta and canaliculi combined with congenital osseous nasolacrimal canal obstruction from the first family. CONCLUSION: The same IGSF3 gene mutation c.3139_3140insGAC is found in the patients with congenital absence of lacrimal puncta and canaliculi combine with osseous nasolacrimal canal obstruction.     

Ambulatory Treatment of Multidrug-Resistant Staphylococcus-Infected Orthopedic Implants with High-Dose Oral Co-trimoxazole (Trimethoprim-Sulfamethoxazole)

We examined the effectiveness and safety of high-dose oral co-trimoxazole (trimethoprim-sulfamethoxazole) for the treatment of orthopedic implants infected with multidrug-resistant Staphylococcus species. The prospective study was conducted between 1989 and 1997 in a university medical center with ambulatory-care services. Patients eligible for the study consisted of those from whom multidrug-resistant Staphylococcus spp. organisms susceptible only to glycopeptides and co-trimoxazole were isolated from their orthopedic implants and for whom there was no contraindication to the treatment. All patients were treated orally with high-dose co-trimoxazole (trimethoprim, 20 mg/kg of body weight/day; sulfamethoxazole, 100 mg/kg/day). Patients with prosthetic hip infections were treated for 6 months, with removal of any unstable prosthesis after 5 months of treatment; patients with prosthetic knee infections were treated for 9 months, with removal of any unstable prosthesis after 6 months of treatment; and patients with infected osteosynthetic devices were treated for 6 months, with removal of the device after 3 months of treatment, if necessary. Monthly clinical evaluations were conducted until the completion of the treatment, and follow-up examinations were conducted regularly for up to 6 years. The overall treatment success rate was 66.7% (26 of 39 patients), with success rates of 62.5% for patients with prosthetic knee infections, 50% for those with prosthetic hip infections, and 78.9% for those with other device infections. Seventeen of the 28 (60.7%) patients who did not have any orthopedic material removed were cured. Eight patients stopped the treatment because of side effects, and one patient was not compliant. In three patients treatment failed because of the appearance of a resistant bacterium. Long-term oral ambulatory treatment with co-trimoxazole appears to be an effective alternative to the conventional medicosurgical treatment of chronic multidrug-resistant Staphylococcus-infected orthopedic implants which includes long-term intravenous antibiotic therapy combined with surgical debridement and removal of foreign material or its subsequent one- or two-stage replacement.     

High nevus counts confer a favorable prognosis in melanoma patients

A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5‐ and 10‐year melanoma‐specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21–0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08–0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi.