Dosage Units Research Articles

Leveraging the Prescription Drug Monitoring Program to Curb Opioid Prescribing in Arkansas.

Effective means of accurately identifying problematic opioid prescribing are needed. Using an iterative approach with the Arkansas State Medical Board Pain Subcommittee, we modified existing opioid prescriber criteria to create seven metrics to be deployed in Arkansas. These included metrics of dose and days' supply, concomitant use of opioid and benzodiazepines, solid dosage units, and numbers of opioid patients and certain opioid prescriptions. Two of these metrics (average MME daily dose per prescription and total oxycodone 30mg or hydromorphone prescriptions) were weighted by 2, creating a maximum score of 9 of which each prescriber could receive. Twenty prescribers with a score of 7 or greater were identified and referred to the Arkansas State Medical Board Pain Subcommittee for review and subsequent investigation if deemed necessary. Of those 20 prescribers, four were previously investigated and under disciplinary action, and three were under current investigation for misconduct related to prescribing practices. Five prescribers had new investigations opened due to the findings from the metrics, and disciplinary action was taken. Therefore, 12 of the 20 prescribers referred to the Arkansas State Medical Board were deemed worthy of investigation and disciplinary action. The Arkansas opioid prescriber metrics are able to accurately identify prescribers with potentially problematic opioid prescribing.

Sales of Over-the-Counter Products Containing Codeine in 31 Countries, 2013-2019: A Retrospective Observational Study.

Opioid prescribing trends have been investigated in many countries. However, the patterns of over-the-counter purchases of opioids without a prescription, such as codeine combinations, are mostly unknown. We aimed to assess national sales and expenditure trends of over-the-counter codeine-containing products purchased in countries with available data over 6 years. We conducted a retrospective observational study using electronic point-of-sale data from the human data science company, IQVIA, for countries that had such data, including Argentina, Belgium, Brazil, Bulgaria, Canada, Croatia, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Japan, Latvia, Lithuania, Mexico, the Netherlands, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, Spain, Switzerland, Thailand, the UK, and the USA. We calculated annual mean sales (dosage units/1000 population) and public expenditure (£/1000 population) for each country between April 2013 and March 2019 and adjusted for data coverage reported by IQVIA. We quantified changes over time and the types of products sold. In total, 31.5 billion dosage units (adjusted: 42.8 billion dosage units) of codeine, costing £2.55 billion (adjusted: £3.68 billion), were sold over the counter in 31 countries between April 2013 and March 2019. Total adjusted sales increased by 11% (from 3911 dosage units/1000 population in 2013 to 4358 in 2019) and adjusted public expenditure increased by 72% (from £263/1000 in 2013 to £451/1000 in 2019). Sales were not equally distributed; South Africa sold the most (36 mean dosage units/person), followed by Ireland (30 mean dosage units/person), France (20 mean dosage units/person), the UK (17.2 mean dosage units/person), and Latvia (16.8 mean dosage units/person). Types of products (n = 569) and formulations (n = 12) sold varied. In many parts of the world, substantial numbers of people may be purchasing and consuming codeine in over-the-counter products. Clinicians should ask patients about their use of over-the-counter products, and public health measures are required to improve the collection of sales data and the safety of such products. STUDY PROTOCOL PRE-REGISTRATION: https://osf.io/ay4mc . The pre-print version of this work is available on medRxiv: https://doi.org/10.1101/2021.04.21.21255888 .

Superdisintegrants: Brief Review

Oral disintegrating tablets are a new trend in novel drug delivery systems that have seen a surge in popularity in recent decades. To improve the efficacy of solid dosage forms, super disintegrants are used. This is accomplished by reducing the disintegration time, which improves the rate of drug dissolution. Disintegrants are substances or combination of substances added to a drug formulation to aid in the breaking up or disintegration of tablet or capsule content into smaller fragments that dissolve more quickly than without them. Several newer agents known as ‘Superdisintegrants’ have been developed in recent years. Superdisintegrants classified as synthetic, semi-synthetic, natural, and co-processed blends have been used to create effective mouth dissolving tablets and overcome the limitations of traditional tablet dosage form. In the solid dosage form, superdisintegrants are typically used at a low level typically (1- 10%) relative to the total weight of the dosage unit. In present studies, includes all the information about Superdisintegrants, such as their types, advantage, selection criteria, incorporation methods, ideal properties and mechanism, which are used in the formulation to provide safer, more effective drug delivery while maintaining patient conformity.
 Keywords: Superdisintegrants, Disintegrants, Natural, Synthetic.

Pharmaceutical evaluation of compounded furosemide capsules and excipient performance

Compounding pharmacies play an important role not only in compounding personalized formulations, but also preparing drugs at the same concentration and dosage as those from commercial manufacturers. The excipients used in compounding are generally standardized for many drugs, however they do not consider the intrinsic properties, such as the poor water solubility, of each substance. The excipient performance of commercially available compounded furosemide capsules in 7 compounding pharmacies from Manaus was evaluated and compared them to the performance of the reference medicinal product (Lasix® tablets) and 2 batches of capsules made in-house (T2 and T4) with a standardized excipient. All batches were subjected to tests for weight variation, assay, uniformity of dosage units, disintegration and dissolution profile. Of the 7 different compound formulas acquired in the compounding pharmacies, only 2 passed all tests. Most formulas passed the tests for weight determination, disintegration time and assay, however batches from 2 establishments failed in regards to the uniformity of the content and 5 batches failed the dissolution test. The reference medicinal product was approved in all tests, as were the T2 capsules made in-house with drug-excipient ratio 1:2. These results confirm the importance of the excipient composition, especially for poorly soluble drugs.

Medicolegal Issues with Reference to NDPS and MHCA in Management and Rehabilitation of Persons with Substance Use Disorders.

Medicolegal Issues with Reference to NDPS and MHCA in Management and Rehabilitation of Persons with Substance Use Disorders.

Innovative derivative/zero ratio spectrophotometric method for simultaneous determination of sofosbuvir and ledipasvir: Application to average content and uniformity of dosage units

An innovative simple, rapid and sensitive spectrophotometric method was developed for the simultaneous analysis of sofosbuvir (SOF) and ledipasvir (LED) in their combined dosage forms. Sofosbuvir with ledipasvir (SOF/LED) as a combined dosage form was tried at the pandemic COVID 19 crisis. This technique has the advantages of both zero order and first order spectrophotometry. The zero and first derivative amplitudes were measured at 274.2 nm for SOF (zero crossing point of LED in first derivative spectrum) and 314 nm for LED (zero crossing point of SOF in first derivative spectrum) over the concentration range of 2.0–50.0 μg mL−1 with coefficients of determination (R2) > 0.9999 for both drugs and mean percentage recoveries of 100.25 ± 1.61 and 99.85 ± 0.99 for SOF and LED; respectively.This original method was validated according to ICH requirements and statistically compared to published comparison methods. This method was applied to estimate the average content and the uniformity of dosage units of SOF/LED combined dosage form according to British Pharmacopeia requirements.

The Sustainability of Price Dynamics in Precision Hematology

Background:Despite the promise of targeted agents in hematology, the high price of cancer therapies is a rapidly evolving problem. Until now, the increase in price of targeted anti-cancer treatments used in common hematological malignancies has not been evaluated. Here, we report patterns in price changes from 2015-2019 for multiple in-class anticancer medications for common hematologic malignancies.Methods:We utilized the publicly available Medicare Part D provider utilization and payment database from 2015 to 2019. We extracted drug prices (using generic names) for commonly used targeted anticancer agents for acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell lymphomas, and multiple myeloma. The primary outcome was the correlation of average change in Medicare spending per dosage unit among the multiple brand-name medications within each class available. We additionally calculated compound annual growth rates (CAGRs) [i.e. mean annual growth rates over a specified period of time] for medication costs within each class, and compared it with the consumer price index (CPI) (a measure of the average change over time in the prices of consumer items) and inflation rate. Agents without in-class competitor were excluded. CPI and inflation rates came from U.S. Bureau of Labor Statistics.Results:The study included 6 BCR-ABL inhibitors (1 generic), 2 BTK inhibitors, 2 IDH inhibitors, 2 FLT3 inhibitors, 3 IMIDs, 3 PI, 2 PI3K inhibitors, and 5 anti-CD20 monoclonal antibodies.The median (range) Pearson correlation coefficient values for drugs within each class were -0.155 (-0.984-0.992) for BCR-ABLi, -0.362 for BTKi, 0.234 (0.215-0.999) for IMIDs, 0.899 (-0.034-0.988) for PIs, and 0.954 (0.847-0.999) for anti-CD20 antibodies. The median correlation coefficient for BCR-ABLi was 0.751 if generic imatinib was excluded. The correlation coefficient between 2 nd and 3 rd generation IMIDs was 0.999. Non-generic BCR-ABLi and anti-CD20 antibodies showed strong linear association in price increase between two drugs within the same class. Due to drug novelty, coefficient could not be calculated for therapies with 2 or fewer data points (midostaurin, gilteritinib, enasidenib, ivosidenib, idelalisib, duvelisib). There was no significant correlation between expenditure for BTKi, PIs, and IMIDs.The median CAGRs in costs over this 5-year period were: were 6.29% for BCR-ABLi, 18.36% for BTKi, 2.69% for IDHi, 4.23% for FLT3i, 10.63% for IMIDs, 5.11% for PIs, 5.79% for PI3Ki, and 5.85% for anti-CD20s. The median CAGR in costs for modern precision-driven cancer therapeutic classes outpaced CPI (2.26%/year), and the average inflation rate (1.90%/year).Conclusions:Increase in cost within the same class should be weighed against incremental clinical benefit for the patients. For non-generic BCR-ABLi and anti-CD20 antibodies, despite there being several agents, the rise in drug expenditures correlated closely, calling into question the true value of within-class competition. There is an urgent need for drug pricing reform given the average expenditure of Medicare part D, and ultimately out-of-pocket costs for our patients with cancer continues to trend upwards. Increased advocacy efforts are needed to ensure precision therapeutics remains an attainable and sustainable goal. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Data-Enriched Edible Pharmaceuticals (DEEP) with Bespoke Design, Dose and Drug Release.

Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study was to fabricate DEEP with a patient-tailored dose, modify drug release and design to meet patients’ preferences. It also aimed to investigate physical stability in terms of the readability of QR code patterns of DEEP during storage. Cannabinoids, namely, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were used as the model active pharmaceutical ingredients (APIs). Three different substrates and two colorants for the ink were tested for their suitability to fabricate DEEP by desktop inkjet printing. Flexible doses and customizable designs of DEEP were obtained by manipulating the digital design of the QR code, particularly, by exploring different pattern types, embedded images and the physical size of the QR code pattern. Modification of the release of both APIs from DEEP was achieved by applying a hydroxypropyl cellulose (HPC) polymer coating. The appearance and readability of uncoated and polymer-coated DEEP did not change on storage in cold and dry conditions; however, the HPC polymer layer was insufficient in preserving the readability of the QR code pattern in the extreme storage condition (40 °C and 75% relative humidity). To sum up, the DEEP concept provides opportunities for the personalization of medicines, considering also patients’ preferences.

The risk assessment of the combined medicine in the capsule dosage form at the pharmaceutical development stage

Aim. To determine the potential risk factors associated with the critical quality indicators of the combined medicine “Neuronucleos” in the capsule dosage form for the treatment of polyneuropathies using the general risk assessment methodology while planning the drug quality at the stage of pharmaceutical development (PD). Materials and methods. The series of the combined medicine “Neuronucleos” in the capsule dosage form, critical indicators of the drug quality, the flowchart of the drug production, critical control points of the drug manufacturing process were developed. The method of causality was used. The quantitative assessment of risk factors was carriedout using the FMECA methodology. Results and discussion. The main objective of this study was to apply the Quality-by-Design (QbD) approach to PD of the combined medicine in the capsule dosage form based on uridine-5 monophosphate disodium salt (UMP), cytidine-5-monophosphate disodium salt (CMF), vitamin B6, thioctic acid and magnesium lactate dihydrate. For better patient compliance and the product quality, a target quality profile as a base for PD planning, as well as critical quality attributes (CQA) related to the product safety and efficacy were determined. The criticality of each CQA was assessed using a special scale. It was shown that “Quantitative content”, “Uniformity of dosage units”, “Dissolution”, “Impurities” were defined as the most CQA due to the minimum amount of UMF and CMF in the capsule and the possibility of their decomposition and increase in the quantity of impurities. The critical attributes of materials (CMA) were identified, and the characteristics required to control them were determined in order to ensure the expected product quality. The primary assessment of the quality indicator risks of the active ingredients was performed. It was found that the particle size affected the homogeneity, the quantitative content of API and dissolution in FPP, and it was shown that the solubility of active substances had a high risk when performing the “Dissolution” test. To determine the potential factors with a significant impact on the drug quality the maximum number of factors was found, and the Ishikawa diagram was constructed. The risk factors associated with the quality and compatibility of active substances and excipients, the quality of primary packaging, production conditions, the drug quality control and the technological process were identified. These factors are the causes of risk and can lead to a situation with negative consequences for the quality of a medicinal product. The FMECA process assessment allowed us to determine the impact of the manufacturing process on the CQA. Conclusions. At the stage of PD for the combined medicine in the capsule dosage form the potential critical indicators of the drug quality have been determined. The critical parameters of the quality of the initial components and the properties of the product have been assessed; the most probable risks for the drug quality have been identified, analyzed and assessed. Further research is advisable to focus on studying the effect of process parameters on critical parameters of the product quality and assessing risks for quality and creating a validation plan and its implementation.

Biosimilar uptake of filgrastim and impact on spending in Medicare Part D from 2015 to 2019.

67 Background: The introduction of a filgrastim biosimilar in 2014 was associated with substantial cost savings in Medicare Part B and Medicaid programs. However, Medicare Part D is unique since it is unable to directly negotiate prices with drug manufacturers. We sought to investigate the uptake of filgrastim biosimilars and impact on spending among Part D beneficiaries. Methods: We evaluated utilization trends for filgrastim (Neupogen), filgrastim-sndz (Zarxio), and tbo-filgrastim (Granix) using the 2015-2019 Medicare Part D Prescription Drug Event data. We conducted a retrospective cross-sectional review of annual spending, number of beneficiaries, number of claims, spending per beneficiary, and spending per dosage unit. We excluded filgrastim-aafi (Nivestym) due to recent approval and adjusted for inflation using 2019 dollars. Results: In 2019, total aggregate Part D spending on filgrastim products was $78 million. From 2015 to 2019, the biosimilar share of total aggregate spending increased from $1.8 million (2%) to $44 million (56%), with combined biosimilar spending (Zarxio and Granix) eclipsing originator Neupogen in 2018 (within 4 years of FDA approval of Zarxio). Total spending on Neupogen reduced 58% from 2015 to 2019. While biosimilar uptake progressively increased every year, total aggregate spending on all filgrastim forms reduced only 7% from 2015 to 2019 ($84 million to $78 million). For all 3 forms, from 2015 to 2019, trends in spending were: average spending per claim ($3193 to $2549, -20%), average spending per beneficiary ($5880 to $6722, +15%), and average spending per dosage unit of filgrastim ($583 vs $571, -2%). Detailed results in Table. Conclusions: We demonstrate that the significant uptake of biosimilar filgrastim products in Medicare Part D from 2015 to 2019 was associated with a small decrease in aggregate spending, essentially unchanged per unit spending, and increased spending per beneficiary on filgrastim products. Our findings contrast with experiences across Medicare Part B and Medicaid, that demonstrated significant cost savings with biosimilar filgrastim uptake. This may be due to inability of Medicare Part D to directly negotiate prices with manufacturers (in contrast to Medicare Part B and Medicaid), supporting ongoing Congressional policy being debated in the United States Senate (H.R. 3).[Table: see text]

Medicare Part D spending for the 10 costliest oral anticancer drugs.

52 Background: Novel oral targeted drugs are being used more frequently to treat many cancers and have substantially improved clinical and survival outcomes. Due to the long treatment durations of many of these medications, which are given continuously until patient progression, per-patient lifetime costs can be high. This study aimed to identify the ten oral anticancer therapies with the highest annual Medicare Part D spending. Methods: Descriptive statistics were performed on data obtained from the CMS Medicare Part D Drug Spending Dashboard and IBM Micromedex RED BOOK, from 2018-2019. Medicare Part D dashboard includes total and average drug spending, and number of beneficiaries utilizing the drug. RED BOOK provides current and historical average wholesale pricing (AWP) data for all prescription drugs. The wholesale acquisition cost (WAC) was calculated from the AWP to evaluate trends in price. We identified the ten anticancer brand-name medications in 2019 with the highest annual Part D spending and reported changes in average spending and number of unique beneficiaries for each drug from 2018-2019. Results: In 2019, Revlimid had the highest annual total Part D spending at $4.6 billion, followed by Imbruvica with $2.4 billion; these drugs also had the greatest number of beneficiary utilizers. From 2018-2019, change in average spending per dosage unit was greatest for Zytiga (34%), however among all drugs, average spending per beneficiary in 2019 was lowest for this medication ($58,074). From 2018-2019, WAC and average spending per dosage unit increased for all of the top ten drugs, as well as the number of total beneficiaries utilizing each drug, except for Zytiga and Sprycel. Conclusions: Oral anticancer therapies provide high value for patients, including improved quality of life and survival. Annual costs for these drugs are high, however spending on inpatient hospital services remains a greater share of total Medicare spending in aggregate and on a per beneficiary basis. Emerging one-time curative treatments for cancer may prove most cost-effective in the long-term by eliminating the need for continuous medication use and hospital care, while improving patient outcomes.[Table: see text]

The economic cost and sustainability of the precision oncology promise.

7 Background: Despite the promise of precision oncology, the cost-effectiveness of targeted treatments is debated. Until now, the increase in price of oral targeted anti-cancer treatments used in common malignancies has not been evaluated. Here, we report patterns in price changes from 2015-2019 for multiple oral anti-cancer medications for common solid tumor malignancies. Methods: We utilized the publicly available Medicare Part D provider utilization and payment database from 2015 to 2019. We extracted drug prices (using generic names) for commonly used targeted oral anticancer agents for lung, breast, and prostate cancer. The primary outcome was the correlation of average change in Medicare spending per dosage unit among the multiple brand-name medications within each class available. We additionally calculated compound annual growth rates (CAGRs) [i.e. mean annual growth rates over a specified period of time] for medication costs within each class, and compared it with the consumer price index (a measure of the average change over time in the prices of consumer items). Results: The study included 6 EGFR inhibitors (1 generic), 5 ALK inhibitors, 2 BRAF inhibitors, 3 hormonal agents (1 generic), 3 CDK4/6 inhibitors, 2 PARP inhibitors, and 7 anti-androgen agents (2 generic). The median (range) Pearson correlation coefficient values for drugs within each class were 0.967 (0.915-0.978) for EGFRi, 0.981 (0.966-0.989) for ALKi, 0.996 for BRAFi, 0.994 (0.992-0.999) for CDK4/6i, 0.855 for PARPi, and 0.442 (-0.522-0.962) for anti-androgens. Except for anti-androgens, all other drug classes showed strong linear association in price increase between two drugs within the same-class. A coefficient could not be calculated for therapies with 2 or fewer data points ( i.e., generic erlotinib, dacomitinib, generic abiraterone, apalutamide, and darolutamide). There was no significant correlation between expenditure for anti-estrogen agents. The median (range) CAGRs in costs over this 5-year period were: were 4.56% for EGFRi, 6.40% for ALKi, 2.58% for BRAFi, 5.48% for hormonal agents, 5.21% for CDK4/6i, 27.29% for PARPi, and 34.8% for anti-androgen agents. Conclusions: The median CAGR in costs for modern oral precision driven cancer therapeutic classes mostly outpaced CPI (2.26%/year), and the average inflation rate (1.90%/year). Increase in cost within the same class should be weighed against incremental clinical benefit for the patients. For most classes despite there being multiple agents, the rise in drug expenditures correlated closely, calling into question the true value of within class competition. There is an urgent need for drug pricing reform given the average expenditure of Medicare part D, and ultimately out of pocket costs for our patients with cancer continues to trend upwards. Increased advocacy efforts are needed to ensure precision therapeutics remains an attainable and sustainable goal.

Chronic use of the unfixed combination of ACE-inhibitors and beta-blockers in Italy from 2013 to 2019 through the healthcare administrative data.

The association between an ACE-inhibitor and a beta-blocker is recommended in case of complicated arterial hypertension and heart failure with reduced ejection fraction. This retrospective drug-utilization study has described its chronic use from the Italian National Healthcare Service perspective. From the ReS (Ricerca e Salute) database, collecting Italian healthcare administrative data, patients receiving an ACE-inhibitor or a beta-blocker from 2013 to 2019 were selected. The prevalence of use (patients treated/1000 inhabitants) and of continuous treatment (patients treated for ≥80% period from the supply to the end of the same year - by means of dosage units - per 1000 inhabitants) of each single active substance were assessed. Among patients continuously treated, those supplied with an ACE-inhibitor and a beta-blocker (unfixed and fixed combinations) were analyzed in terms of prevalence of continuous treatment. Subjects treated with the unfixed combination ramipril-bisoprolol in 2019 were characterized by gender and age. The prevalence of ACE-inhibitors' use increased from 49.7/1000 inhab. in 2013 to 50.2 in 2019: ramipril was the most supplied each year (28.9 to 31.6/1000 inhab.). The prevalence of continuous treatment increased from 27.4 to 28.3/1000 inhab.: ramipril the most continuously dispensed (16 to 18/1000 inhab.). The prevalence of beta-blockers' use increased from 61.0 to 90.4/1000 inhab.: bisoprolol the most supplied and with the highest increase (27.1 to 52.2/1000 inhab.). The prevalence of continuous treatment increased from 33.1 to 55.8/1000 inhab.: bisoprolol the most continuously dispensed (18 to 37/1000 inhab.). Among patients with continuous supplies, from 49,843 a 51,496 were treated with associations between an ACE-inhibitor and a beta-blocker on an ongoing basis. Half of them were continuously treated with the unfixed combination ramipril-bisoprolol (4.3 to 4.8/1000 inhab.). In 2019, subjects with continuous supplies of ramipril-bisoprolol were mainly males (63.4%) and elderly (mean age 71±12), and the prevalence of use increased with age. These findings, together with recommendations from the main international guidelines encourage to make available also ramipril and bisoprolol as fixed dose combination, in order to simplify the therapy administration and improve the adherence, especially among elderly and patients with multimorbidity.

Assessing the homogeneity of Actimask® acetaminophen and N-acetyl glucosamine mixture to predict further steps in the development of orodispersible tablets

One of the main problems in the production of tablets, which has significant negative consequences, is the segregation of the tablet mixture leading to inhomogeneity of dosage units, material losses in the manufacturing process and improperness of the specified pharmaceutical technical characteristics of the mixture.
 The aim of the research. This work aims at the pharmaceutical technical study of the substances N-acetyl-D-glucosamine and Actimask® Acetaminophen and determination the uniformity of the powder mixture of active pharmaceutical ingredients (APIs) to predict the optimal technology for obtaining a pharmaceutical formulation with the acceptable properties.
 Materials and methods. N-acetyl-D-glucosamine (Zhejiang Candorly Pharmaceutical, China) and Actimask® Acetaminophen (SpiPharma, USA) were used.
 Scanning probe microscope Solver P47N-PRO ("NT-MDT", Russia), optical microscope, flowability tester VP-12A, laser diffraction particle size analyzer SALD-2201 ("Shimadzu", Japan), liquid chromatograph Agilent 1260 Infinity II with Diode Array Detector (Agilent Technologies, USA), spectrophotometers Shimadzu UV-1800 ("Shimadzu", Japan) were used.
 The study of API pharmaceutical technical properties (microscopic characteristics, moisture absorption capacity, flowability, bulk volume and tapped volume, particle size distribution by sieve analysis and laser diffraction), as well as vibration simulation and following chromatographic study were carried out in this work.
 Results and discussion. The shape of the particles N-acetyl-D-glucosamine and Actimask® Acetaminophen, which was determined by microscopic analysis, demonstrated the possibility of N-acetyl-D-glucosamine particles to stick to Actimask® Acetaminophen ones. The experimental study allowed to reveal the hygroscopicity of both APIs; poor flowability, unsatisfactory Hausner ratio, and Carr index for N-acetyl-D-glucosamine; excellent flowability, Hausner ratio, and Carr index for Actimask®. Vibration caused segregation of the powder mixture. It was found that all layers do not meet the requirements and an excessive content of Actimask® is registered, which indicates the stratification of the powder mixture.
 Conclusions. The physical properties of the substances were determined and found to have significant differences in their particle size distribution. Segregation of the mixture after vibration was confirmed by laser diffraction and assay analysis. In order to solve the segregation problem, the granulation of N-acetyl-D-glucosamine may be proposed.

A Co-Processed API Approach for a Shear Sensitive Compound Affording Improved Chemical Stability and Streamlined Drug Product Processing.

The physical properties of active pharmaceutical ingredients (API) are critical to both drug substance (DS) isolation and drying operations, as well as streamlined drug product (DP) processing and the quality of final dosage units. High aspect ratio, low bulk density, API 'needles' in particular are a hindrance to efficient processing, with a low probability that conventional crystallization routes can modify the challenging morphology. The compound evaluated in this manuscript demonstrated this non-ideal morphology, with the added complexity of shear sensitivity. Modest shear exposure resulted in conversion of the thermodynamically stable crystalline phase to the amorphous phase, with the amorphous phase then undergoing accelerated chemical degradation. Slow filtration during DS isolation resulted in uncontrolled and elevated amorphous levels, while subsequent DP operations including blending, densification and compression increased amorphous content still further. A chemically stable final dosage unit would ideally involve a high bulk density, free flowing API that did not require densification in order to be commercialized as an oral dosage form with direct encapsulation of a single dosage unit. Despite every effort to modify the crystallization process, the physical properties of the API could not be improved. Here, an innovative isolation strategy using a thin film evaporation (TFE) process in the presence of a water soluble polymer alleviated filtration and drying risks and consistently achieved a high bulk density, free flowing co-processed API amenable to direct encapsulation. Characterization of the engineered materials suggested the lower amorphous levels and reduced shear sensitivity were achieved by coating surfaces of the API at relatively low polymer loads. This particle engineering route blurred conventional DS/DP boundaries that not only achieved improved chemical stability but also resulted in a optimized material, with simplified and more robust processing operations for both drug substance and drug product.

EVALUATION OF THE QUALITY OF DIFFERENT BRANDS OF ASCORBIC ACID IN FREETOWN, SIERRA LEONE

Objective: This study evaluates the registration status and the quality of nine brands of Vitamin C sold in Freetown, Sierra Leone, using official and non-official methods of analysis. Methods: The parameters taken into consideration during the study include non-official methods (friability and disintegration) and the official methods (identification test, uniformity of dosage unit, and assay by titrimetric and colorimetric tests). The different brands of vitamin C were selected and classified as registered and unregistered based on the data derived from the National Medicines Regulatory Authority. Results: One vitamin C product collected was unregistered at the National medicines regulatory authority (Pharmacy Board of Sierra Leone). All nine vitamin C products met the requirements for uniformity of dosage unit. The vitamin C products also conformed to the BP specification for friability and identification test (retention factor). The identification test showed that each brand contained vitamin C (ascorbic acid). The disintegration test was not applicable for chewable tablets. Three of the four non-chewable vitamin C products complied with the BP specification for disintegration, while one failed and did not meet the requirement. The assay results for ascorbic acid using titration and colourimetric method were comparable and appropriate for determining vitamin C. Out of a total of nine samples; seven met the requirement for BP specification (Passed) for assay. In contrast, one product did not meet the BP requirement (failed), and one sample had more vitamin C than the Pharmacopoeia limit. Conclusion: Periodic quality evaluation and routine checks for pharmaceutical products can ascertain the quality of products, their storage conditions and identify potential counterfeit medications.

Bayesian hierarchical modeling for online process monitoring and quality control, with application to real time image data

With the increasing availability of real-time process data, the Bayesian framework is an adaptable means for dealing with complex models and data structures which can provide readily interpretable outputs for first-principles and hybrid models. Applied to process monitoring and control scenarios, Bayesian models have the capability to provide informed decisions about quantities of interest derived from the online process measurements through the use of probability as a measure of uncertainty. This work presents one such application, wherein real-time image data is used to predict the content of pharmaceutical dose units produced by an additive manufacturing process; a probabilistic quality control strategy is therefore enacted at the level of each dosage unit. Utilizing a hierarchical modeling approach, we are able to draw upon a large historical database to model sources of uncertainty across a wide range of conditions, thus yielding more reliable predictions for future data at in-sample and out-of-sample conditions.

Statistical Inference of the Probability of Passing the USP Dissolution Test

In pharmaceutical manufacturing, dissolution test for immediate-release dosage forms is routinely performed to ensure the drug products conform to the quality standard specified in the United States Pharmacopeia and National Formulary (USP/NF). The USP dissolution test is a complex three-stage dissolution test involving the inference of individual dissolution measurement or/and sample mean of dissolution measurement of all dosage units. Passing the USP dissolution test once does not necessarily assure that the same batch of drug products would pass again if tested later. For the purpose of inferring the dissolution quality of a batch of drug products, a statistical inference based on acceptance limit is considered. The statistical inference assures a high probability of passing the USP dissolution test with a prescribed level of confidence. There is no closed-form expression of the true probability of passing the USP dissolution test. In the literature, the true probabilities of passing the USP dissolution test are usually approximated based on the lower probability bound. The available statistical inferential procedures based on the lower probability bound give an approximate and conservative inference. In this article, we propose the derivation of the true probability of passing the USP dissolution test based on the numerical computation. The probabilities of passing the USP dissolution test derived from the proposed numerical computation are no appreciable difference from the simulated true probabilities. The statistical inferential procedure via acceptance limits for various sample sizes of dissolution measurements and probabilities of passing the USP dissolution test is also provided.

Use of Box–Behnken design for optimization of compounded medication: acyclovir capsules report

Campus compounding pharmacies play an important role in public health. Herpes simplex is one of the most common viral diseases in humans, which generates a great demand for acyclovir capsules in compounding pharmacy. It is well known that the formulation's components influence the effectiveness of the drug. The objective of this study is to show the applicability of Box-Behnken design in optimization of a compounded formulation and to evaluate the effect of excipients on dissolution and drug content in acyclovir 200 mg capsules produced at UFF´s University Pharmacy (FAU). The formulations were prepared and evaluated for average weight test, uniformity of dosage units and in vitro dissolution, while meeting pharmacopoeial specifications. A statistical analysis showed that sodium starch glycolate, Aerosil®, influences drug content and dissolution results. Magnesium stearate shows no influence on the dissolution at different concentrations but influences the assay results. A numerical optimization was applied to adjust the formulation variables based on the foresaid responses, accomplishing the best formulation that will be prepared and dispensed at FAU upon medical prescription.

Identification of VEGFA-centric temporal hypoxia-responsive dynamic cardiopulmonary network biomarkers

AimsHypoxia, a pathophysiological condition, is profound in several cardiopulmonary diseases (CPD). Every individual's lethality to a hypoxia state differs in terms of hypoxia exposure time, dosage units and dependent on the individual's genetic makeup. Most of the proposed markers for CPD were generally aim to distinguish disease samples from normal samples. Although, as per the 2018 GOLD guidelines, clinically useful biomarkers for several cardio pulmonary disease patients in stable condition have yet to be identified. We attempt to address these key issues through the identification of Dynamic Network Biomarkers (DNB) to detect hypoxia induced early warning signals of CPD before the catastrophic deterioration. Materials and methodsThe human microvascular endothelial tissues microarray datasets (GSE11341) of lung and cardiac expose to hypoxia (1% O2) for 3, 24 and 48 h were retrieved from the public repository. The time dependent differentially expressed genes were subjected to tissue specificity and promoter analysis to filtrate the noise levels in the networks and to dissect the tissue specific hypoxia induced genes. These filtered out genes were used to construct the dynamic segmentation networks. The hypoxia induced dynamic differentially expressed genes were validated in the lung and heart tissues of male rats. These rats were exposed to hypobaric hypoxia (simulated altitude of 25,000 or PO2 - 282 mm of Hg) progressively for 3, 24 and 48 h. Key findingsTo identify the temporal key genes regulated in hypoxia, we ranked the dominant genes based on their consolidated topological features from tissue specific networks, time dependent networks and dynamic networks. Overall topological ranking described VEGFA as a single node dynamic hub and strongly communicated with tissue specific genes to carry forward their tissue specific information. We named this type of VEGFAcentric dynamic networks as “V-DNBs”. As a proof of principle, our methodology helped us to identify the V-DNBs specific for lung and cardiac tissues namely V-DNBL and V-DNBC respectively. SignificanceOur experimental studies identified VEGFA, SLC2A3, ADM and ENO2 as the minimum and sufficient candidates of V-DNBL. The dynamic expression patterns could be readily exploited to capture the pre disease state of hypoxia induced pulmonary vascular remodelling. Whereas in V-DNBC the minimum and sufficient candidates are VEGFA, SCL2A3, ADM, NDRG1, ENO2 and BHLHE40. The time dependent single node expansion indicates V-DNBC could also be the pre disease state pathological hallmark for hypoxia-associated cardiovascular remodelling. The network cross-talk and expression pattern between V-DNBL and V-DNBC are completely distinct. On the other hand, the great clinical advantage of V-DNBs for pre disease predictions, a set of samples during the healthy condition should suffice. Future clinical studies might further shed light on the predictive power of V-DNBs as prognostic and diagnostic biomarkers for CPD.