Compliance with Pregnancy Prevention Recommendations for Isotretinoin Following the Amendment of the European Union Pregnancy Prevention Program: A Repeat Study in Estonia.

BACKGROUND: Isotretinoin, indicated for severe acne, is a potent teratogen and therefore contraindicated in pregnancy. Thus, the pregnancy prevention program (PPP) for isotretinoin has been introduced. OBJECTIVES: The aim of this study was to assess the concomitant use of isotretinoin and effective contraception and the rate of potential isotretinoin-exposed pregnancies in females of childbearing age in 2017-2020 in Estonia. In addition, we aimed to evaluate whether compliance with the PPP has improved compared with the previous study conducted in Estonia covering the period of 2012-2016. METHODS: This retrospective, nationwide study using prescription and healthcare claims data included 2575 females aged 15-45 years who started using isotretinoin between 2017 and 2020. RESULTS: For 64.7% of females of childbearing age, no concurrent use of an effective contraceptive was detected while using isotretinoin. A moderately higher contraceptive coverage (35.3%) was observed compared with the previous study (29.7%) (p < 0.001). Complete contraception coverage was highest in females aged 30-39 years with an adjusted OR of 12.8 (p < 0.001) compared with the age group 15-19 years and 2.47 (p < 0.001) compared with the age group 20-29 years. 17 pregnancies coincided with the isotretinoin treatment-related period. The risk for potential isotretinoin-exposed pregnancy was 6.6 (95% CI 3.9-10.5) per 1000 treated females of childbearing age over the 4-year observation period. The risk for potential isotretinoin-exposed pregnancies per 1000 treated females was 1.0 in females aged 15-19 years, 11.6 in females aged 20-29 years, 8.8 in females aged 30-39 years, and 7.4 in females aged 40-45 years (p = 0.009). CONCLUSION: A slight improvement in complete contraceptive coverage during isotretinoin use has not resulted in a decrease in the risk of isotretinoin-exposed pregnancies. The contraceptive usage and risk for pregnancy vary greatly across age groups, suggesting the need for a more targeted approach to improve the effectiveness of the PPP.

Drying capacity of a continuous vibrated fluid bed dryer - Statistical and mechanistic model development.

The drying capacity of a continuous vibrated fluid bed dryer was studied using a DoE by varying microcrystalline cellulose content in the formulation, water amount in the twin-screw granulation, inlet air temperature, air flow rate and the acceleration of the horizontal fluid-bed. Temperature and humidity profiles were measured along the dryer using wireless sensors. For the parameter space explored in this study, acceleration was the most influential process parameter of the dryer regarding the resulting granule moisture content. An empirical model was developed that allowed for fast and accurate moisture content prediction that could be incorporated into an enhanced control strategy. In addition, a mechanistic model was formulated that allow for prediction of temperature and moisture profiles, and most importantly the moisture content of the granules inside the dryer. The mechanistic model can be integrated to other unit operation models to provide overall understanding of an integrated continuous process line. The mechanistic model also makes it possible to define the equipment design requirements (e.g., length of the dryer) to meet the specific needs in terms of drying capacity, temperature and moisture profile.

Could paper package leaflet be left out from hospital products?

Background: Package leaflet provides information about medicinal product to the user. Printed leaflet is familiar and available, however poorly legible, especially when containing multiple languages. It is resourceful to update, has potential to go missing or get damaged, and is environmentally burdensome. The pharmaceutical manufacturers in the Baltic countries have been granted permission to market selected hospital medicinal products without printed package leaflet. The industrial pilot project is expected to promote availability of medicinal products and patient safety via increased access to medicinal information. Objective: Only few countries in Europe have derogated from Article 58 of Directive 2001/83/EC. Knowledge about the effects of removal of paper package leaflet from the medicinal product is limited, and related publications are scarce. Current interview study is identifying the obstacles during the implementation of the industrial project, investigating the potential environmental impact, and searching for further opportunities for the package leaflet in development of medicinal products. Methods: Real-time person-to-person semi-structured interviews with relevant stakeholders were conducted, and transcripts were analysed by content analysis to identify themes. Results: Results demonstrated general support for removing package leaflet from selected hospital products. Main difficulties of the industrial project regarded the need for clear communication and practical disadvantages of project setup. Main benefits included educational aspect of increasing awareness about product information and strengthened collaboration. Majority of participants felt doubtful about the impact of the industrial project on people's awareness of ecological issues and they admittedly lacked sufficient information on the environmental impact of pharmaceutical packaging. Conclusion: The removal of paper leaflet could be extended to more products based on the positive feedback for the industrial pilot project. However, it is paramount that the format of electronic product information would need to be enhanced first to improve readability.

How to stop disproportionation of a hydrochloride salt of a very weakly basic compound in a non-clinical suspension formulation.

Our objectives were to stabilize a non-clinical suspension for use in toxicological studies and to develop methods to investigate the stability of the formulation in terms of salt disproportionation. The compound under research was a hydrochloride salt of a practically insoluble discovery compound ODM-203. The first of the three formulation approaches was a suspension prepared and stored at room temperature. The second formulation was stabilized by pH adjustment. In the third approach cooling was used to prevent salt disproportionation. 5 mg/mL aqueous suspension consisting of 20 mg/mL PVP/VA and 5 mg/mL Tween 80 was prepared for each of the approaches. The polymer was used as precipitation inhibitor to provide prolonged supersaturation while Tween 80 was used to enhance dissolution and homogeneity of the suspension. The consequences of salt disproportionation were studied by a small-scale in vitro dissolution method and by an in vivo pharmacokinetic study in rats. Our results show that disproportionation was successfully suppressed by applying cooling of the suspension in an ice bath at 2-8 °C. This procedure enabled us to proceed to the toxicological studies in rats. The in vivo study results obtained for the practically insoluble compound showed adequate exposures with acceptable variation at each dose level.

The effect of relative humidity and formulation variables on chewable xylitol-sorbitol tablets.

Changing relative humidity levels challenge the manufacturing of chewable xylitol-sorbitol based tablets. The aim of the study is to investigate how the formulation of chewable xylitol-sorbitol tablets affects the properties of the powder blends and the tablets in an environment of different relative humidity levels. In all, 30 batches containing different ratios of sorbitol, xylitol and magnesium stearate were prepared at three different relative humidity levels. Powder blends were made into tablets using an instrumented eccentric tableting machine. To demonstrate the effect of variables on powder blend and tablet properties, multiple linear regression analysis was performed. It was found that xylitol-sorbitol powder blends and tablets benefitted from the large amount of magnesium stearate, and the high lubricant level negatively affected the quality of the tablets only at high relative humidity. In the presence of high environmental humidity, the amount of sorbitol in the powder mixture must be limited in order to prevent sticking whereas at low relative humidity, higher content of sorbitol is needed to decrease the friability of tablets. Results indicate that alternating relative humidity levels truly challenge the production of xylitol-sorbitol based tablets and if the humidity is not controllable, there is a need for additional filler-binders.

Effect of colloidal silicon dioxide and moisture on powder flow properties: Predicting in-process performance using image-based analysis.

The effect of colloidal silicon dioxide (CSD) on powder flow properties of poor-flowing excipient lactose 200 M was investigated. Binary mixtures of different ratios of CSD as glidant were examined using a modern image-based flow measuring technique. Special attention was placed to subtle variations in powder flow from small changes in glidant concentration (0.025% w/w). Understanding the modes of interaction of particles and their effects on flowability using the method predicted the die filling performance during tablet manufacture. In addition, the importance of moisture content on powder flow properties was empirically underlined. A more efficient range of CSD was detected from 0.10 to 0.50% w/w in most of the tested conditions, which revealed a significant improvement in powder flow performance compared to higher amounts typically handled in the pharmaceutical industry.

Predicting the effect of prandial stage and particle size on absorption of ODM-204.

The prediction of absorption properties plays a key role in formulation development when the compound under development shows poor solubility and its absorption is therefore presumed to be solubility limited. In our work, we combined and compared data obtained from in vitro dissolution tests, transit intestinal model studies (TIM-1) and physiologically based pharmacokinetic modelling. Our aim was to determine the ability of these methods to predict performance of poorly soluble lipophilic weak base in vivo. The validity of the predictive methods was evaluated against the in vivo clinical pharmacokinetic (PK) data obtained after administration of the first test formulation, T1. The aim of our study was to utilize the models in evaluating absorption properties of the second test formulation, T2, which has not yet been clinically administered. The compound in the studies was ODM-204, which is a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. Owing to its physicochemical properties ODM-204 is prone to low or variable bioavailability. The models examined provided congruent data on dose dependent absorption, food effect at a dose of 200 mg and on the effect of API (active pharmaceutical ingredient) particle size on absorption. Our study shows that the predictive tools of in vitro dissolution, TIM-1 system and the PBPK (physiologically based pharmacokinetic) simulation, showed predictive power of different mechanisms of bioavailability and together provided valuable information for decision making.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100 mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d = 5 mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.

Prediction of drug dissolution from Toremifene 80 mg tablets by NIR spectroscopy.

The aim of our study was to justify substitution of dissolution analysis for NIR measurement of Toremifene 80 mg tablets. We studied implementation of a NIRS method by integrating the method development to discrimination power of the dissolution method. Hence, we analyzed 20 DoE tablet batches and studied which of the critical formulation factors affecting dissolution were statistically significant. To study if these factors can be detected by NIRS, PLS calibration models were developed. Finally, PLS model was built to correlate NIR data with the actual dissolution results to predict the released amount of toremifene in 30 min. To obtain the data the tablet batches were measured by NIR using diffuse reflectance technique and multivariate analysis tool was used to calibrate the NIRS models. Correlations between the critical formulation factors and the NIR spectra of Toremifene 80 mg tablet were shown and it was thus justified to develop a NIRS prediction model for dissolution. Variance (R2), standard error of estimate (SEE) and standard error of prediction (SEP) of the model were 90.0%, 4.3% and 5.9%, respectively. It was thus shown that multi-phased and time consuming dissolution procedure could be substituted for fast non-invasive NIRS method.

Predicting tablet tensile strength with a model derived from the gravitation-based high-velocity compaction analysis data.

In the present study, a model was developed to estimate tablet tensile strength utilizing the gravitation-based high-velocity (G-HVC) method introduced earlier. Three different formulations consisting of microcrystalline cellulose (MCC), dicalcium phosphate dihydrate (DCP), hydroxypropyl methylcellulose (HPMC), theophylline and magnesium stearate were prepared. The formulations were granulated using fluid bed granulation and the granules were compacted with the G-HVC method and an eccentric tableting machine. Compaction energy values defined from G-HVC data predicted tensile strength of the tablets surprisingly well. It was also shown, that fluid bed granulation improved the compaction energy intake of the granules in comparison to respective physical mixtures. In addition, general mechanical properties and elastic recovery were also examined for all samples. In this study it was finally concluded, that the data obtained by the method was of practical relevance in pharmaceutical formulation development.

Use of telephone and web interfaces of interactive response technology at clinical investigator sites in clinical trials.

BACKGROUND: Interactive response technologies are used in clinical trials to provide services such as automated randomization and medication logistics management. The objective of this article is to investigate the usage of telephone (Interactive Voice Response) and web (Interactive Web Response) interfaces of interactive response technologies at clinical investigator sites in clinical trials, to obtain information about the preferences of interactive response technology end users between the telephone and web interfaces, and to explore the relevance of the telephone interface in this setting. METHODS: The data consist of an online survey conducted in spring 2016 with clinical investigators, study nurses, and pharmacists in 13 countries. RESULTS: Ninety-eight percent of survey respondents preferred the web interface over the telephone interface, the most important reason being superior usability. However, the respondents indicated the usability of interactive response technology interfaces is not optimal, and lack of integration and consistency across systems is common. A vast majority of interactive response technology end users at clinical sites prefer to use the web interface over the telephone interface, but most also feel there would need to be a back-up system. CONCLUSIONS: Based on the results, it would be beneficial to improve the usability of the interactive response technology interfaces, and to increase consistency across systems from the current level. Support to and training of the users, as well as clarifying the responsibilities between sites and the sponsor should also be a focal point. Study sponsors should explore with interactive response technology service providers how removing the telephone interface would impact future studies, and whether there could be a more efficient means to achieve a reliable back-up to the web interface instead of a dedicated telephone interface.

The Use of Video Instructions in Patient Education Promoting Correct Technique for Dry Powder Inhalers: An Investigation on Inhaler-Naïve Individuals.

Introduction: The correct use of a prescribed inhaler device is crucial for achieving successful disease management in asthma. This study investigates non-verbal, demonstrational videos as a method of teaching inhaler naïve individuals how to use a dry powder inhaler (DPI). Methods: Video instructions for four DPIs were examined using a mixed methodology; 31 inhaler-naïve individuals participated in the study. Participants were each shown a demonstrational video of one the four inhalers, after each video the participant demonstrated how they would use the inhaler. After demonstrating the use, participants crossed over to the next inhaler. The demonstrations were videotaped. A common questionnaire was filled at the beginning of the study and four inhaler-specific questionnaires which were filled out by the participant after each inhaler demonstration. Results: The frequency of participant error varied between inhalers. When asked about how they perceived the video instructions, participants often stated they would have liked to receive feedback on their performance. The importance of feedback was further highlighted by the fact that participants tended to overestimate their own inhaler technique. Conclusion: Non-verbal videos may be more efficient for some DPIs than for others as a method for providing inhaler instructions. Lack of feedback on the participants' inhaler performance emerged as a clear shortcoming of this educational method. Some steps in the inhalation process may be harder for individuals to remember and therefore require extra emphasis in order to achieve correct inhaler technique.

Comparison of melibiose and trehalose as stabilising excipients for spray-dried ß-galactosidase formulations.

Spray-dried protein formulations commonly require stabilising excipients to prevent protein degradation during processing and storage, and trehalose has been commonly used. The purpose of this work was to evaluate melibiose in spray-dried protein formulations in comparison to trehalose. The protein-activity-preserving efficacy, process behaviour and storage stability were studied. Spray drying of ß-galactosidase was carried out using different process temperature, drying air flow and feed liquid atomisation settings. Both melibiose and trehalose reduced protein activity loss during drying. A decrease in activities was observed when the process temperature exceeded a threshold temperature. During storage (30 days at 18% RH and 20 or 40 °C), the formulations dried below this threshold temperature showed no further activity loss, and the stabilising efficacy of the two disaccharides was equal. With higher process temperatures, the remaining protein activities after storage trended higher with melibiose formulations. All formulations remained amorphous. The powder yields of melibiose formulations were similar to trehalose. There was a difference in residual moisture contents, with melibiose formulations giving drier products. In conclusion, protein formulations with melibiose could be spray dried into amorphous powders that were physically stable, contained lower moisture contents and protected protein activity at least as well as trehalose formulations.

Time-Gated Raman Spectroscopy for Quantitative Determination of Solid-State Forms of Fluorescent Pharmaceuticals.

Raman spectroscopy is widely used for quantitative pharmaceutical analysis, but a common obstacle to its use is sample fluorescence masking the Raman signal. Time-gating provides an instrument-based method for rejecting fluorescence through temporal resolution of the spectral signal and allows Raman spectra of fluorescent materials to be obtained. An additional practical advantage is that analysis is possible in ambient lighting. This study assesses the efficacy of time-gated Raman spectroscopy for the quantitative measurement of fluorescent pharmaceuticals. Time-gated Raman spectroscopy with a 128 × (2) × 4 CMOS SPAD detector was applied for quantitative analysis of ternary mixtures of solid-state forms of the model drug, piroxicam (PRX). Partial least-squares (PLS) regression allowed quantification, with Raman-active time domain selection (based on visual inspection) improving performance. Model performance was further improved by using kernel-based regularized least-squares (RLS) regression with greedy feature selection in which the data use in both the Raman shift and time dimensions was statistically optimized. Overall, time-gated Raman spectroscopy, especially with optimized data analysis in both the spectral and time dimensions, shows potential for sensitive and relatively routine quantitative analysis of photoluminescent pharmaceuticals during drug development and manufacturing.

Isomalt and its diastereomer mixtures as stabilizing excipients with freeze-dried lactate dehydrogenase.

The purpose of this research was to study isomalt as a protein-stabilizing excipient with lactate dehydrogenase (LDH) during freeze-drying and subsequent storage and compare it to sucrose, a standard freeze-drying excipient. Four different diastereomer mixtures of isomalt were studied. The stability of the protein was studied with a spectrophotometric enzyme activity test and circular dichroism after freeze-drying and after 21 days of storage at 16% RH. Physical stability was analyzed with differential scanning calorimetry and Karl Fischer titration. Statistical analysis was utilized in result analysis. LDH activity was almost completely retained after freeze-drying with sucrose; whereas samples stabilized with isomalt diastereomer mixtures had a considerably lower protein activity. During storage the sucrose-containing samples lost most of their enzymatic activity, while the isomalt mixtures retained the protein activity better. In all cases changes to protein secondary structure were observed. Isomalt diastereomer mixtures have some potential as protein-stabilizing excipients during freeze-drying and subsequent storage. Isomalt stabilized LDH moderately during freeze-drying; however it performed better during storage. Future studies with other proteins are required to evaluate more generally whether isomalt would be a suitable excipient for pharmaceutical freeze-dried protein formulations.

The effect of mechanical dry coating with magnesium stearate on flowability and compactibility of plastically deforming microcrystalline cellulose powders.

Mechanofusion is a dry coating method that can be used to improve the flowability of cohesive powder by coating host particles with a lubricant, for example magnesium stearate (MgSt). It has been shown previously that fragmenting material can under some circumstances be mechanofused with MgSt without impairing compactibility of the powder and without reducing the dissolution rate of the resulting tablets. However, the effects on material with viscoelastic behaviour, known to be sensitive for the negative effects of MgSt, is not known. Therefore, mechanofusion of microcrystalline cellulose (MCC) with MgSt was investigated in this study. Four MCC grades were mechanofused with different MgSt concentrations and process parameters, and the resulting flowability and compactibility were studied. Starting materials and low-shear blended binary mixtures were studied as a reference. Mechanofusion improved the flow properties of small particle size MCC powders (d50 < 78 µm) substantially, but increasing the MgSt content consequently resulted in weaker tablets. Larger particle size MCC grades, however, fractured under the shear forces during the mechanofusion process and hence their flow properties were decreased. Improvement of the flow properties but also the negative effects on compactibility of small particle size grades were observed even at relatively mild mechanofusion parameters and low lubricant concentrations.

Atomic layer deposition-A novel method for the ultrathin coating of minitablets.

We introduce atomic layer deposition (ALD) as a novel method for the ultrathin coating (nanolayering) of minitablets. The effects of ALD coating on the tablet characteristics and taste masking were investigated and compared with the established coating method. Minitablets containing bitter tasting denatonium benzoate were coated by ALD using three different TiO2 nanolayer thicknesses (number of deposition cycles). The established coating of minitablets was performed in a laboratory-scale fluidized-bed apparatus using four concentration levels of aqueous Eudragit® E coating polymer. The coated minitablets were studied with respect to the surface morphology, taste masking capacity, in vitro disintegration and dissolution, mechanical properties, and uniformity of content. The ALD thin coating resulted in minimal increase in the dimensions and weight of minitablets in comparison to original tablet cores. Surprisingly, ALD coating with TiO2 nanolayers decreased the mechanical strength, and accelerated the in vitro disintegration of minitablets. Unlike previous studies, the studied levels of TiO2 nanolayers on tablets were also inadequate for effective taste masking. In summary, ALD permits a simple and rapid method for the ultrathin coating (nanolayering) of minitablets, and provides nanoscale-range TiO2 coatings on porous minitablets. More research, however, is needed to clarify its potential in tablet taste masking applications.

Challenge of paediatric compounding to solid dosage forms sachets and hard capsules - Finnish perspective.

OBJECTIVES: The study evaluated the quality of compounded sachets and hard gelatine capsules and their feasibility in paediatric drug administration. METHODS: Commercial tablets were compounded to sachets and capsules in hospital environment, and the uniformity of content and simulated drug dose were determined. KEY FINDINGS: Compounded formulations were successfully obtained for a range of drug substances; dipyridamole, spironolactone, warfarin and sotalol formulations were within acceptable limits for uniformity of content, in most cases. However, some loss of drug was seen. The type and amount of excipients were found to affect uniformity of content; good conformity of capsules was obtained using lactose monohydrate as filler, whereas microcrystalline cellulose was a better choice in sachets. In capsules, content uniformity was obtained for a range of drug doses. If the drug is aimed to be administered through a nasogastric tube, solubility of the drug and excipients should be considered, as they were found to affect the simulated drug dose in administration. CONCLUSIONS: Compounded sachets and capsules fulfilled the quality requirements in most cases. In compounding, the choice of excipients should be considered as they can affect conformity of the dosage form or its usability in practice. Quality assurance of compounded formulations should be taken into consideration in hospital pharmacies.

A novel set of behavioural indicators for measuring perception of food by cats.

Behavioural indicators provide a promising approach for objective assessment of the perceptions of animals. In cats, the frequency of specific behaviours as indicators of perception has been studied in connection with food palatability. The aim of this study was to expand that knowledge by identifying behavioural indicators correlating with three degrees of palatability. Thirty-four pet cats were presented with three types of items: favoured food (FF), favoured food with a placebo mini-tablet hidden inside (TFF) and non-favoured food (NFF). The items were presented in a pseudo-randomised sequence, with six trials per item and 18 trials per cat. The behaviour of cats before, during and after eating, or refusing to eat, was video-recorded. Two trained observers, blinded to the types of food items, independently determined the frequency of 16 behavioural patterns on the video recordings. The data were analysed using a mixed logistic regression model. Five behavioural patterns differentiated FF from NFF; 'flick ears backwards', 'lick nose, not eaten', 'flick tail' and 'groom body' were more frequent with NFF, whereas 'lick lips' was more frequent with FF. One indicator, 'drop item', was more frequent with TFF than FF. These findings provide evidence of new behavioural indicators for objective assessment of food perception in cats. The findings also have practical applicability in designing a novel palatability test to be utilised in developing veterinary pharmaceuticals with improved palatability for cats.

Spray-dried amorphous isomalt and melibiose, two potential protein-stabilizing excipients.

The possibility of producing amorphous isomalt and melibiose by spray drying was studied. The impact of process parameters on yield and solid-state stability was compared to sucrose and trehalose. All powders remained amorphous during 2-3 weeks. Processing was challenging due to powder stickiness. Low-temperature and low-humidity drying processes generally performed best. Most isomalt and sucrose powder was retrieved when using 60°C inlet temperature, 800L/h atomizing rate, 1.4ml/min feed rate, 15% concentration and 100% aspirator rate, giving 42-43°C outlet temperature. Isomalt was the most problematic, because it had the lowest Tg and became sticky very easily, therefore process parameters needed to be precisely balanced. There was more freedom in designing processes for melibiose but best yields were obtained with low-temperature (50°C inlet temperature, 800L/h atomizing rate, 4.9ml/min feed rate, 10% concentration and 100% aspirator, 39°C outlet temperature). Trehalose was different in that higher temperatures resulted in better yields. Yet, trehalose generally contained the highest moisture contents. The possibility to produce amorphous isomalt and melibiose at low-temperature process conditions makes them promising considering spray drying applications for heat-sensitive proteins. Melibiose is a better candidate than isomalt because of easier processability and superior solid-state stability.