Good manufacturing practice- and good distribution practice-compliant cold storage and refrigerated transport of allergen products: what is important?

Background All currently available products for diagnosis and therapy of type I allergies are protein extracts from allergenic source material. The extracted proteins have different properties and their structure is differently labile to temperature variations. Despite various pharmaceutical formulations to increase product stability, with few exceptions, allergen products must be refrigerated to ensure that their quality and native protein structure do not change during storage and transport. Maintaining quality is a challenge in complex distribution chains. Methods Regulatory requirements and guidelines that apply to cold storage and transport of allergen products are summarized and the responsibilities of the stakeholders are explained. Results The storage conditions determined in stability studies correspond to the transport conditions. These stability data can also be used to assess tolerable conditions during transport. According to a good distribution practice (GDP) contracts must be concluded between the responsible pharmaceutical entrepreneur and the qualified distribution service provider that regulate storage and transport in accordance with the product requirements. Conclusion Monitoring of storage and transport conditions is achieved by transport in qualified means of transport (e.g. truck). Alternatively, qualified transport packaging with active or passive cooling (e.g. cold packs) and qualified “data loggers” that record the transport temperatures can be used. Regardless of the system used, it must be demonstrated—by validating the transport conditions, routes and packaging at different times of the year and over the entire duration of transport—that regulatory requirements are met and that the quality of the products is maintained during shipment.

Subcutaneous Dihydrocodeine Tartrate: Compatibility in a Syringe Pump With Other Drugs Frequently Prescribed for the Management of Symptoms Associated With Brain Tumors

Background Dihydrocodeine can be more effective in the management of headache due to brain tumor than other opioids. It can be used as a subcutaneous infusion, but at present, there is little available data to support its use in combination with other medicines in a syringe pump. Aim This project aimed to establish physical stability data for the use of dihydrocodeine with other drugs when combined in a syringe pump. Design: Dihydrocodeine was combined in a syringe pump with either cyclizine, midazolam, or hyoscine butylbromide at different doses chosen to represent routine clinical practice. Each drug combination was repeated twice—with 0.9% sodium chloride and with water for injections. Setting: The project was conducted in an independent hospice after seeking appropriate approvals to use the drugs for this purpose. Results Dihydrocodeine and midazolam appear compatible at when 0.9% sodium chloride is used as the diluent. Dihydrocodeine and cyclizine appeared compatible when either 0.9% saline or water for injections was used as the diluent. Dihydrocodeine and hyoscine butylbromide appeared compatible with either diluent at 24 hours. Conclusions Physical stability data has been described that will support the use of dihydrocodeine and other drugs that are commonly used to manage symptoms due to brain tumors at the end of life. This information will benefit patients and ensure that one syringe pump can be used where possible. Future work could expand on this data and explore the physical stability of three drug combinations in each syringe.

Mixed Poloxamer Nanomicelles for the Anticonvulsant Lamotrigine Drug: Solubility, Micellar Characterization, and In-Vitro Release Studies

Recently the applications of Poloxamers in drug development is promising as it facilitated the drug molecule for delivering to the correct place, at the correct time and in the correct amount. Poloxamers can form nanomicelles to encapsulate hydrophobic drugs in order to increase solubility, stability and facilitate delivery at target. In this context, the solubilization of anticonvulsant lamotrigine (LMN) drug in a chain of Poloxamers containing different polyethylene oxide and polypropylene oxide noieties were examined. The results showed better solubilization of LMN in Poloxamers contain low CMTs while poor with Poloxamers having high CMTs. Systematic investigation of two mixed Poloxamer nanomicelles (P407:P403 and P407:P105) for LMN bioavailability at body temperature (37 °C) were investigated. The solubility of LMN was enhanced in mixed P407:P403 nanomicelles with the amount of P403 and reduced in mixed P407:P105 nanomicelles with the amount of P105. LMN encapsulated mixed Poloxamer nanomicelles were found spherical in shape with ~25 nm Dh sizes. The In-Vitro release profiles of mixed Poloxamer nanomicelles demonstrated the biphasic model with initial burst release and then slowly release of LMN. Better biocompatibility of LMN in the mixed P407:P403 nanomicelles was confirmed with stability data. The results of this work were proven the mixed P407:P403 nanomicelles as efficient nanocarriers for LMN.

Stability of Olmesartan Medoxomil Extemporaneous Suspensions

Background: Olmesartan medoxomil (OLM) is only available in the United States as tablets. The United States Pharmacopoeia (USP) has placed OLM on its priority list of preparations that require stability data to support practitioner compounding. Objective: The purpose of the study was to develop a stability-indicating assay and then determine the beyond-use date (BUD) for an extemporaneous OLM suspension. Methods: A reverse-phase high-performance liquid chromatography (HPLC) assay was developed and validated according to guidelines for USP official compounded monographs. OLM 2 mg/mL suspensions were compounded with Ora-Sweet and Ora-Plus and stored at room temperature or in a refrigerator. Suspensions were assayed periodically over 90 days for OLM concentration and observed for physical stability. The pH was measured at the beginning and end of the study. Results: The OLM concentration remained above 97% of the starting concentration for 90 days when stored in the refrigerator and above 94% of the starting concentration for 90 days when stored at room temperature. The suspension pH did not change and indicators of physical stability were unchanged for 90 days. Conclusion: OLM 2 mg/mL suspensions were chemically and physically stable at room temperature and in the refrigerator for 90 days. The BUD may be set at 90 days under either storage condition.

Development of Curcumin-Loaded Polymeric Mixed Micelle for Skin Moisturizing Antioxidant Formulation

The aim of this study was to fabricate curcumin-loaded polymeric mixed micelle which was a new nanocarrier of therpeutic agent for skin uses. Curcumin was extracted from dried turmeric rhizomes using ethanol and recrystallized. The purity of curcumin was 79±3.6 %w/w. Six curcumin-loaded polymeric micelles (PM1-PM6) were prepared by simple dissolution method using poloxamer 407 (5% and 10%) as a main core structure. PEG-40 hydrogenated castor oil (PEG-40HCO) was incorporated at two percentages (2.5% and 5.0%) to study the effect on the nanoparticle characteristics. The average particle sizes of PM1-PM6 were in the range of 33.3±6.6 nm to 171.3±52.8 nm. The entrapment efficiency and the loading capacity of curcumin were in the range of 47.45%-77.35% and 0.048%w/w-0.078%w/w, respectively. When PEG-40HCO was incorporated in to the polymeric micelles, the particle size decreased and the entrapment efficiency increased. Thus, PM4 and PM5 were selected for further study. Moisturizing antioxidant creams containing 0.005%w/w of curcumin loaded in PM4, PM5 and curcumin simply dissolved in propylene glycol (PG) were formulated. The resulted formulations showed good spreadability and good characteristics. After being subjected to accelerated test, all of the formulations remained with characteristic color, pH and showed no phase separation. The stability data showed that the moisturizing antioxidant creams were stable for the whole 3 months after storage at accelerated temperature (45°C/75%RH). The study demonstrated that polymeric mixed micelle spontaneously encapsulated a poorly water-soluble curcumin and increased the solubility up to 250 folds. The developed moisturizing cream containing 0.005%w/w of curcumin resulted a greenish-yellow color preparation. It had tolerable physicochemical properties based on curcumin content, pH and viscosity under the harsh condition. The cream also had satisfactory antioxidant activity, which can be regarded as an effective and acceptable therapeutic or skincare products for topical uses.

PredMS: a random Forest model for predicting metabolic stability of drug candidates in human liver microsomes

Motivation Poor metabolic stability leads to drug development failure. Therefore, it is essential to evaluate the metabolic stability of small compounds for successful drug discovery and development. However, evaluating metabolic stability in vitro and in vivo is expensive, time-consuming, and laborious. Additionally, only a few free software programs are available for metabolic stability data and prediction. Therefore, in this study, we aimed to develop a prediction model that predicts the metabolic stability of small compounds. Results We developed a computational model, PredMS, which predicts the metabolic stability of small compounds as stable or unstable in human liver microsomes. PredMS is based on a random forest model using an in-house database of metabolic stability data of 1,917 compounds. To validate the prediction performance of PredMS, we generated external test data of 61 compounds. PredMS achieved an accuracy of 0.74, Matthew’s correlation coefficient of 0.48, sensitivity of 0.70, specificity of 0.86, positive predictive value of 0.94, and negative predictive value of 0.46 on the external test dataset. PredMS will be a useful tool to predict the metabolic stability of small compounds in the early stages of drug discovery and development. Availability and implementation The source code for PredMS is available at https://bitbucket.org/krictai/predms, and the PredMS web server is available at https://predms.netlify.app. Supplementary information Supplementary data are available at Bioinformatics online.

Measurement of progesterone in sheep using a commercial ELISA kit for human plasma

Determination of serum or plasma progesterone (P4) concentrations is important to recognize pregnant and non-pregnant ewes, and also to predict the number of carried lambs. The 2 most common methodologies for the detection of plasma P4 are radioimmunoassay (RIA) and enzyme immunoassay (EIA). RIA is very expensive, and not all laboratories are equipped to perform this test; EIA is commercially available for human use, but only a few companies produce species-specific kits, which are expensive. We verified for ovine plasma a less expensive and easily available ELISA kit (DiaMetra) designed to quantify P4 in humans. Pools of ovine and human plasma were used to compare repeatability, accuracy, sensitivity, and stability of P4 measured by the DiaMetra kit. Repeatability data were within 15%, and accuracy values were ~90% for both plasma matrices. Stability data showed a loss of <20% for freeze–thaw and <30% for 30-d storage. All parameters were acceptable under international guidelines for method validation. The human ELISA kit was used successfully to quantify plasma P4 in 26 ewes during pregnancy until delivery. P4 concentrations were also correlated with the number of carried lambs.

Stability testing of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine: a translational study in UK vaccination centres

ObjectiveThe roll-out of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine has brought many logistical challenges, such as the absence of comprehensive stability data leading to strict handling instructions during dilution and administration. Accidental mishandling therefore presents challenging clinical dilemmas, which often led vaccine providers to err on the side of caution and discard mishandled vials rather than risk administering ineffective vaccine. This study aims to answer key questions about the vaccine’s stability to allow for a more informed decision-making process should a non-conformity occur.MethodsResidual vaccine in freshly used, but appropriately stored vials collected from vaccination centres in Brighton, UK, were tested after exposure to various handling conditions and analysed by dynamic light scattering to determine the size of the lipid-mRNA nanoparticles, and gel electrophoresis to visualise the mRNA integrity and separation from the lipid formulation.ResultsKnocking or dropping vaccine samples from small heights resulted in lowest levels of instability, indicating low risk of compromising clinical efficacy. However, repeated drawing and injecting through 23 G needles at high speed and, more significantly, shaking and vortexing led to progressive increase in the size and polydispersity index of the lipid-mRNA nanoparticles, coupled with or caused by up to ~50% release of mRNA from the lipid formulation. This is thought to impact the vaccine’s efficacy due to lack of free mRNA protection and cellular internalisation.ConclusionsThese results reiterate the importance of adhering to the manufacturer’s instructions on handling, especially with regard to shaking and exposing the vaccine to excessive vibration.