Prevalence and sequelae of penile lichen sclerosus in males presenting for circumcision in regional Australia: a multicentre retrospective cohort study.

Background: Lichen sclerosus (LS) in men commonly involves the external genitalia, with up to 20% of these patients developing urethral stricture disease, and a small group developing malignant transformation to penile squamous cell carcinoma (SCC). The objective of this study was to determine the prevalence of LS and its sequelae in males presenting for circumcision. Methods: A multicentre retrospective cohort study was conducted at 8 hospitals within 3 Australian regional centres. We identified males who underwent circumcision between January 2004 and November 2018 and obtained histological and clinical data. Histopathological confirmation of LS was the primary outcome. Development of urethral stricture disease and penile cancer were secondary outcomes. Results: Six hundred and eleven patients underwent circumcision, of which 313 (51.2%) had a specimen sent for histology. Of these, 199 (63.6%) had confirmed LS where the median age at diagnosis was 65 years [interquartile range (IQR), 40-77]. Even if the remainder of unsent specimens were free of LS, the prevalence would still be 32.6%. Amongst the patients with LS, 44 (22.1%) developed urethral strictures, 1 penile SCC (0.5%), and 1 penile intraepithelial neoplasia (0.5%). Conclusions: The prevalence of LS in patients undergoing circumcision where the foreskin was sent for histopathological review was 63.6%. In those with LS, the prevalence of urethral stricture disease was 22.1%.

Preparation of medicines for children - a hierarchy of classification.

There is some confusion about the types of paediatric pharmaceutical preparation (in a regulatory and pharmaceutical development context) that are acceptable for approval by medicines regulators. Some of the confusion relates to terminology which may mean different things to different stakeholders. It may not always be possible to provide authorised, commercially manufactured, age appropriate, ready-to-administer preparations. In terms of assurance of quality and bioavailability there is a continuum from this ideal through intermediate products through authorised compounding and manipulation of commercial dosage forms to ad hoc compounding using only the skills and experience of the individual pharmacist. Additionally, it is widely known that caregivers may manipulate medicines at home, for example by segmenting tablets and by addition to foods or liquids. The first intent of the manufacturer should be to provide for children an age appropriate, ready-to-administer preparation which is commercially manufactured and approved by the competent authorities. However, there will still be a place for providing other age appropriate preparations such as approved products that are 'intermediates' requiring reconstitution before use, or instructions for compounding or manipulation of a dosage form. If compounding or manipulation is likely to be required it is preferable that data are generated by Industry, approved by the competent authorities and provided in the Summary of Product Characteristics (SmPC). It is acknowledged however, that ad hoc compounding or manipulation may also take place in certain circumstances such as logistical difficulties or to satisfy the needs of the child who does not find the authorised product to be 'age appropriate'. This paper explores compounding and manipulation of medicines in relation to approval by medicines regulators and non-approved preparation to fulfil the needs of the individual patient. Definitions are proposed to provide a hierarchical classification based on assurances of quality and bioavailability.

Low dose lipid formulations: effects on gastric emptying and biliary secretion.

PURPOSE: Food stimulates changes to gastrointestinal secretion and motility patterns, however, the effect of smaller quantities of lipid, such as that contained in a lipid-based drug formulation, has not been detailed. This study aimed to examine the effects of small quantities of lipid on gastric emptying and biliary secretion. METHODS: The influence of oral administration of three lipid-based formulations and a negative control formulation on gastric emptying and biliary secretion was evaluated in 16 healthy male subjects using gamma scintigraphy, ultrasonography and duodenal aspiration. RESULTS: Low quantities (2 g) of long chain lipid stimulated gall bladder contraction and elevated intestinal bile salt, phospholipid and cholesterol levels. Changes in gastric emptying were also evident, although these did not reach statistical significance. Administration of a similar quantity of medium chain lipid, however, had little effect on gastric emptying and gallbladder contraction and did not stimulate appreciable increases in intestinal concentrations of biliary-derived lipids. CONCLUSIONS: The quantities of long chain lipid that might be administered in a pharmaceutical formulation stimulate gallbladder contraction and elevate intestinal levels of bile salt and phospholipid. This effect is a likely contributor to the ability of lipid based formulations to enhance the absorption of poorly water-soluble drugs.

Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds.

In this study, the importance of accurate simulation of fasting gastric environment for the assessment of the absorption process of two model lipophilic compounds, GR253035X (weak base) and atovaquone (non-ionizable), was assessed. Dissolution profiles were constructed in previously proposed simulated gastric fluids and in a new medium that comprises only of components that have been recovered from the fasting stomach. Dissolution data obtained in a more physiologically relevant medium led to better correlation between the simulated and actual intralumenal dissolution vs. time profiles for GR253035X. In contrast, accurate simulation of gastric environment did not affect the simulated plasma profile of atovaquone. Accurate simulation of the fasting gastric contents may be crucial for the assessment of the absorption profile of lipophilic weak bases.

Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts.

To better predict food effects on the bioavailability/bioequivalence of drugs and drug products from in-vitro data, a dissolution medium that simulates the initial composition of the postprandial stomach was developed. First, the physical parameters of two homogenized standard breakfasts often administered to assess food effects in pharmacokinetic studies were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Subsequently, the match of the physical parameters of several commercially available liquid meals, including long-life milk, Ensure and Ensure Plus to those of the breakfasts was evaluated. Of the three liquid meals studied, Ensure Plus had the closest physicochemical behaviour to that of homogenized standard breakfasts. By increasing the viscosity of Ensure Plus with 0.45% pectin, it was possible to obtain a medium that closely resembles the FDA standard breakfast.

Physical stability and enthalpy relaxation of drug-hydroxypropyl methylcellulose phthalate solvent change co-precipitates.

The poorly water-soluble drug GWX was co-precipitated with hydroxypropyl methylcellulose phthalate (HPMCP) using a solvent change method. The two co-precipitate formulations made, with drug-HPMCP ratios of 2:8 and 5:5, were analysed using modulated temperature differential scanning calorimetry. They were found to consist of completely amorphous solid solution and a mixture of amorphous solid solution, crystalline drug and amorphous drug, respectively. Stability with respect to crystallization of the two co-precipitates and pure amorphous drug made by quench cooling was compared by storing preparations at 25 degrees C and 40 degrees C, under vacuum over P(2)O(5), and at 75% relative humidity (r.h.). Humidity (75% r.h. compared with dry) had a larger influence on crystallization of the amorphous drug than temperature (25 degrees C compared with 40 degrees C). The solid solution phase in co-precipitates had a relatively higher stability than amorphous drug alone, with respect to crystallization, in presence of the plasticizer water, and crystalline drug. These findings were partly explained by evidence of decreased molecular mobility in the amorphous solid solution with respect to amorphous drug alone, using enthalpy relaxation measurements. At an ageing temperature of 65 degrees C, the calculated half-life for enthalpy relaxation of the 2:8 drug-HPMCP ratio coprecipitate was about 6 orders of magnitude greater than that of amorphous drug alone, indicating a large difference in relative molecular mobility.

Factors affecting incorporation of drug into solid solution with HPMCP during solvent change co-precipitation.

Drug-hydroxypropyl methylcellulose phthalate (HPMCP) mixtures were completely dissolved in acetone, and the resulting solution was added drop-wise into HCl(aq). Resulting co-precipitates were filtered, and then dried under vacuum at 45 degrees C, -800 mbar for 24 h. Modulated differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction and HPLC were used to detect and quantify different phases present in co-precipitates. A 1/8 factorial study followed by a circumscribed central composite (CCC) study of significant factors, were used to detect and quantify respectively, the effects that processing factors had on the percentage of drug present in co-precipitates which was incorporated into solid solution (the response). Robustness of the model obtained from the CCC study was tested. Statistically significant factors were found to be the percentage of drug added into solvent, stirrer speed, and antisolvent pH. The statistically significant mathematical model obtained from the CCC study predicted that the dominant factor influencing the response is the percentage of drug added into solvent. The effect of stirrer speed on the response includes a local maximum at stirrer speed approximately 700 rpm. Both stirrer speed and antisolvent pH showed interactions with the percentage of drug added into solvent. The model obtained from this study indicated the possibility of two opposing phenomena influencing the response: crystallization inhibition by HPMCP, and solvent-antisolvent plasticization. Testing of this model using eight experimentally determined points showed reasonable robustness, with six out of eight points lying inside 95% prediction intervals.

Solvent change co-precipitation with hydroxypropyl methylcellulose phthalate to improve dissolution characteristics of a poorly water-soluble drug.

Research compound GWX belongs to biopharmaceutical classification system type II, and hence shows dissolution-rate-limited absorption. To improve its dissolution performance, GWX was formulated as a co-precipitate with hydroxypropyl methylcellulose phthalate (HPMCP). Co-precipitates with various drug-HPMCP ratios were prepared and characterised using modulated differential scanning calorimetry (MDSC), X-ray powder diffraction, HPLC and dissolution testing. Co-precipitates with 1:9 and 2:8 drug-HPMCP ratios showed the highest extent of dissolution after both 5 and 90 min, followed by 3:7, 4:6, and 5:5 drug-HPMCP co-precipitates, in respective order. Co-precipitates with drug-HPMCP ratios of 6:4 and greater showed no significant improvement in dissolution over crystalline drug alone. The amounts of crystalline and amorphous drug in co-precipitates, as determined by MDSC, and HPLC quantification of the total amount of drug in co-precipitates were used to determine the amount of drug incorporated into solid solution. It was found that dissolution rate and extent was correlated to the amount of drug incorporated into amorphous solid solution for the 1:9 to 5:5 drug-HPMCP ratio co-precipitates. Amorphous drug alone and physical mixtures of drug and HPMCP showed very little and no significant improvement in dissolution rate or extent, respectively, above crystalline drug alone. Amorphous drug alone re-crystallized to a large extent within 1 min of contact with the dissolution medium, whereas 4:6 drug-HPMCP co-precipitate showed a lower degree of re-crystallization and 2:8 drug-HPMCP co-precipitate showed very little re-crystallization. It was concluded that the likely mechanisms of improved dissolution of low drug-HPMCP ratio co-precipitates were improved wetting or increased surface area for mass transfer, thermodynamically enhanced dissolution of a higher energy amorphous form and inhibition of re-crystallization, when drug was incorporated into solid solution.