Incorporation of HPMCAS during loading of glibenclamide onto mesoporous silica improves dissolution and inhibits precipitation.

Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies.

Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.

Calculation of drug-polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations.

Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realize the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realized.

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations - a PEARRL review.

OBJECTIVES: Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection. KEY FINDINGS: Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can be guided by molecular rationale. However, more work is required to see widespread application of such an approach for PI selection. SUMMARY: Precipitation inhibitors are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review.

OBJECTIVES: This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. KEY FINDINGS: Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid-based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. SUMMARY: Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.

Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs - a PEARRL review.

OBJECTIVES: Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water-soluble drugs. KEY FINDINGS: An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid-based delivery, solid dispersions and nano- or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. SUMMARY: In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early-stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour-intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations.

Biowaiver monographs for immediate release solid oral dosage forms: efavirenz.

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.

Residual neuromuscular blockade affects postoperative pulmonary function.

BACKGROUND: Residual neuromuscular blockade (RNMB) is known to be associated with respiratory complications in the postoperative period after muscle relaxant usage. The authors hypothesized that RNMB causes reductions in pulmonary function test (PFT) parameters in the immediate postoperative period. METHODS: An open-label prospective randomized cohort study was conducted comparing reductions in PFT parameters due to RNMB among different neuromuscular blocking agents. One hundred and fifty patients were randomized to receive vecuronium, atracurium, or rocuronium. After reversal of neuromuscular blockade and extubation, train-of-four ratio was measured every 5 min until the train-of-four ratio of 0.9 or greater was attained. PFTs were performed preoperatively and postoperatively when the patients were willing and fit. The train-of-four ratio, measured at PFT, was used to classify patients into "RNMB absent" and "RNMB present." RNMB was defined as a train-of-four ratio less than 0.9. RESULTS: Thirty-nine patients had RNMB at the time of performing PFT. There was no statistically significant difference in the postoperative reductions in PFT parameters in patients with RNMB among different neuromuscular blocking agents. Patients were regrouped as RNMB absent and RNMB present, irrespective of neuromuscular blocking agents. Postoperative PFT values for the RNMB-absent and RNMB-present groups were 62% and 49% of baseline forced vital capacity and 47% and 38% of baseline peak expiratory flow of the baseline, respectively. Postoperative forced vital capacity and peak expiratory flow values of RNMB-present patients were lower by 13% and 9% in absolute terms (P<0.008) and 21% and 19% in relative terms, respectively, compared with RNMB-absent patients. CONCLUSION: RNMB results in reductions in forced vital capacity and peak expiratory flow in the immediate postoperative period indicating impaired respiratory muscle function.

Biowaiver monographs for immediate release solid oral dosage forms: amodiaquine hydrochloride.

The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate release (IR) multisource solid dosage forms containing amodiaquine hydrochloride (ADQ) as the single active pharmaceutical ingredient (API). Both biopharmaceutical and clinical data of ADQ were assessed. Solubility studies revealed that ADQ meets the "highly soluble" criteria according to World Health Organization (WHO) and European Medicines Agency (EMA) but fails to comply with the United States Food and Drug Administration (US FDA) specifications. Although metabolism hints at high permeability, available permeability data are too scanty to classify ADQ inequivocably as a Class I drug substance. According to WHO and EMA guidances, ADQ would be conservatively categorized as a Class III drug, whereas according to the US FDA specifications, it would fall into Class IV. ADQ has a wide therapeutic index. Furthermore, no cases of bioinequivalent products have been reported in the open literature. As risks associated with biowaiving appear minimal and requirements for "highly soluble" API are met in the WHO and EMA jurisdictions, the biowaiver procedure can be recommended for bioequivalence (BE) testing of multisource IR products containing ADQ as the only API, provided the test product contains excipients used in ADQ products approved in International Conference of Harmonisation and associated countries, and in similar amounts. Furthermore, both comparator and test should conform to "very rapidly dissolving" product criteria (≥85% dissolution of the API in 15 min at pH 1.2, 4.5, and 6.8) and the labeling should specify that the product not be coadministered with high-fat meals. If the comparator and/or test product fails to meet these criteria, BE needs to be established by pharmacokinetic studies in humans.

Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid.

A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance.

Biowaiver monographs for immediate-release solid oral dosage forms: primaquine phosphate.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing the antimalarial drug primaquine phosphate as the only active pharmaceutical ingredient (API) are reviewed. On the basis of permeability data and solubility studies, primaquine phosphate was found to be "highly soluble" and "highly permeable" API, thus conforming to Class I of the Biopharmaceutical Classification System (BCS). It has a wide therapeutic index. BCS-conform dissolution studies showed the products to be rapidly dissolving. No data pertaining to BE or bioinequivalence of IR primaquine phosphate products could be located in open literature. On the basis of the available data, a biowaiver-procedure-based approval can be recommended for IR solid oral dosage forms of primaquine phosphate, provided the generic product contains excipients present in products already approved by the International Conference on Harmonisation or associated countries in similar amounts and the test and reference products meet the dissolution criteria for "rapidly dissolving" (>85% drug release in 30 min in standard media at pH 1.2, 4.5, and 6.8; similarity factor (f(2)) > 50) or "very rapidly dissolving" products (>85% drug release in 15 min in standard media at pH 1.2, 4.5, and 6.8).

Are counterfeit or substandard anti-infective products the cause of treatment failure in Papua New Guinea?

Counterfeit and substandard products present a big challenge to any national plan or policy devised to improve public health. Poor quality drug products are especially a problem in lower income countries where product information and drug regulation enforcement are scant or absent. The primary aim of the present study was to evaluate the quality of amodiaquine and amoxicillin formulations sold in Papua New Guinea (PNG) and to detect the presence of counterfeit or substandard drugs in circulation, if any. Fourteen samples, collected from five registered pharmacies in Port Moresby, PNG, were subjected to visual inspection, quality control tests, and verification of product authenticity. The quality control tests included weight variation, content uniformity, thin layer chromatography, and dissolution. None of the products complied with all of the evaluation criteria. Two products, one of which was purportedly distributed by a company which proved to be nonexistent, contained no detectable amodiaquine. The present study confirms that counterfeit and substandard amodiaquine and amoxicillin products are finding their way into the distribution chain in Port Moresby, PNG. This quality problem with anti-infective products is of great concern, as it not only exposes patients to poor quality products but also fosters the development of resistant bacterial strains.

Vitamin E ameliorates aflatoxin-induced alterations in the epididymis of mice.

The present investigation was an attempt to evaluate the effect of aflatoxin on biochemical and histopathological changes in the epididymis of mice and its possible amelioration on pre-treatment with vitamin E. Adult male albino mice were orally administered with 25 and 50 mg of aflatoxin/animal/day (750 and 1500 mg/kg body weight) for 45 days. Epididymis was isolated and processed for biochemical analysis. As compared with the control, absolute and relative epididymal weights were significantly reduced in aflatoxin-treated mice. Aflatoxin treatment caused significant, dose-dependent reduction in protein and sialic acid contents in caput and cauda epididymis than that of vehicle control. While activities of succinic dehydrogenase and adenosine triphosphatase were significantly reduced, acid phosphatase activity was significantly higher in caput and cauda epididymis of aflatoxin-treated mice than that of vehicle control. Pyknosis of epithelial cell nuclei, disorganization of epithelium, clumping of stereocilia and lumen devoid of sperms in caput and cauda epididymis were observed. Thus, pre-treatment with vitamin E (2 mg/0.2 mL olive oil/ animal/day) significantly ameliorated aflatoxin-induced changes, measured by biochemical and histopathological parameters.

Practice style traits: do they help explain practice behaviours of stroke rehabilitation professionals?

RATIONALE: The gap in knowledge translation from research to clinical practice is under scrutiny in stroke rehabilitation. One possible reason for this gap may be a poor understanding of clinicians' practice style traits and how they influence practice behaviours. OBJECTIVES: To identify the prevalence of practice style traits in physical therapists and occupational therapists working in stroke rehabilitation and, to explore associations between these traits and practice behaviours, where practice behaviours are defined as the clinicians' reasons for choosing assessments and interventions used in practice. The influence of more traditional personal and organizational factors on practice behaviours was also explored. DESIGN: Cross-sectional survey of a representative random sample of 243 clinicians (117 occupational therapists and 126 physical therapists) working across the continuum of stroke care in Ontario, Canada. METHODS: A telephone-administered validated clinical practice survey elicited information in 4 areas: practice style traits using the validated Practice Style Questionnaire, therapists' reasons for choosing assessments and interventions (practice behaviours), personal factors and organizational factors. RESULTS: For both disciplines, the most prevalent trait was pragmatist and the least prevalent was seeker. Seekers were the most likely to use evidence-based reasons for choosing assessments, but this finding did not reach significance (chi2 = 5.430, df = 3; p = 0.14). The most typical reason for choosing an intervention was that the clinician had learned it during professional training, an interesting finding given that approximately half of clinicians had more than 10 years of experience. Of the 21 potential explanatory variables examined, few explained clinicians' reasons for choosing assessments or interventions. CONCLUSION: While understanding practice traits is not going to be the single solution to closing the knowledge translation gap, it may help to guide best practice implementation strategies.

Occupational therapists' identification, assessment, and treatment of unilateral spatial neglect during stroke rehabilitation in Canada.

BACKGROUND AND PURPOSE: Unilateral spatial neglect (USN) is a disabling feature of stroke, and its identification and management are critical for optimizing patient outcomes. This study examined USN problem identification, assessment, and treatment among clinicians working in stroke rehabilitation. METHODS: This report was based on a Canada-wide survey of 253 occupational therapists providing inpatient stroke rehabilitation. RESULTS: Eighty percent (n=202) recognized USN as a potential problem, 27% (n=67) reported using standardized USN assessment tools, and 58% (n=147) indicated using USN interventions. Working on a stroke unit and younger age were among the variables explaining 7% to 19% of the variability in USN problem identification, assessment, and intervention use. CONCLUSIONS: Although USN problem identification was high, clinicians were unlikely to use standardized assessment tools or evidence-based interventions to effectively manage this serious impairment.

Assessment of unilateral spatial neglect post stroke in Canadian acute care hospitals: are we neglecting neglect?

OBJECTIVE: To estimate the prevalence, timing and frequency of use of standardized and non-standardized assessments to detect unilateral spatial neglect in acute care patients post stroke. DESIGN AND SETTING: Multicentred, retrospective study on medical charts from 10 randomly selected acute care hospitals in Ontario, Canada. SUBJECTS: Three hundred and twenty-four randomly selected medical charts of adult subjects with a primary diagnosis of stroke admitted in 2002 to the participating acute care hospitals. RESULTS: Out of 248 subjects who should have been assessed, 38% received some form of unilateral spatial neglect assessment. Only 13% were assessed with a standardized assessment and of these, 4% within 48 h post stroke or within 48 h of the patient regaining consciousness as recommended by clinical practice guidelines for stroke. Bivariate analysis found significant associations between severity of cognitive impairment and being ever assessed, as well as between the severity of motor deficits of the upper extremity and being ever assessed. CONCLUSION: Routine standardized assessment of unilateral spatial neglect during the acute care phase post stroke was not incorporated into daily practice in this study sample.

Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy.

We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe retinal dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of retinal dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle. A homozygous 677A-->G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic retinal dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with retinal dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C-->T (resulting in Q189X), each in the homozygous state, and 146C-->T (resulting in T49M) and 184C-->T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another retinal dehydrogenase. Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.

MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells.

PURPOSE: Mutations in the MERTK gene are responsible for retinal degeneration in the Royal College of Surgeons (RCS) rat and are a cause of human autosomal recessive retinitis pigmentosa (RP). This study reports the identification and functional analysis of novel MERTK mutations to provide information regarding whether they are causative of severe rod-cone degeneration in a young patient. METHODS: MERTK missense variants identified by single-strand conformational polymorphism (SSCP) and sequence analysis were introduced into expression constructs and used to transfect HEK293T cells. Recombinant protein expression was assayed with anti-MERTK and anti-phosphotyrosine antibodies. Protein turnover was assayed in pulse-chase studies of 35S-methionine incorporation. Transcript levels were determined by quantitative RT-PCR. RESULTS: Three MERTK sequence variants were identified in a patient with rod-cone dystrophy: R722X in exon 16 and R865W in exon 19 on the paternal allele and R844C in exon 19 on the maternal allele. The R844C sequence change affects an evolutionarily conserved amino acid residue and was not detected in unaffected individuals. In transfected HEK293Tcells, wild-type (wt) and W865 MERTK were expressed at equivalent levels and present in the plasma membrane, stimulated tyrosine phosphorylation, and induced significant rounding of the cell bodies. In contrast, C844 MERTK was expressed at low levels and did not stimulate tyrosine phosphorylation. In addition, the relative stability of C844 MERTK was significantly less than wt in assays of protein turnover. At age 13, the patient had 20/60 and 20/200 acuities, tunnel vision of 5 degrees centrally, and a far temporal peripheral crescent bilaterally, and ERGs were nondetectable. The fundi showed bull's-eye macular atrophy and widespread RPE thinning. CONCLUSIONS: The present study reports the identification of R844C, the first putative pathogenic MERTK missense mutation that results in severe retinal degeneration with childhood onset when in compound heterozygous form with a R722X allele. The loss of function of C844 MERTK is probably due to decreased protein stability.