Design of Oral Sustained-Release Pellets by Modeling and Simulation Approach to Improve Compliance for Repurposing Sobrerol

Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.

A Pharmacokinetic Study of Mix-160 by LC-MS/MS: Oral Bioavailability of a Dosage Form of Citroflavonoids Mixture

This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes’ activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product.

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

Flux-Based Formulation Development—A Proof of Concept Study

The work aimed to develop the Absorption Driven Drug Formulation (ADDF) concept, which is a new approach in formulation development to ensure that the drug product meets the expected absorption rate. The concept is built on the solubility-permeability interplay and the rate of supersaturation as the driving force of absorption. This paper presents the first case study using the ADDF concept where not only dissolution and solubility but also permeation of the drug is considered in every step of the formulation development. For that reason, parallel artificial membrane permeability assay (PAMPA) was used for excipient selection, small volume dissolution-permeation apparatus was used for testing amorphous solid dispersions (ASDs), and large volume dissolution-permeation tests were carried out to characterize the final dosage forms. The API-excipient interaction studies on PAMPA indicated differences when different fillers or surfactants were studied. These differences were then confirmed with small volume dissolution-permeation assays where the addition of Tween 80 to the ASDs decreased the flux dramatically. Also, the early indication of sorbitol’s advantage over mannitol by PAMPA has been confirmed in the investigation of the final dosage forms by large-scale dissolution-permeation tests. This difference between the fillers was observed in vivo as well. The presented case study demonstrated that the ADDF concept opens a new perspective in generic formulation development using fast and cost-effective flux-based screening methods in order to meet the bioequivalence criteria.

Testing the Fit of Regression Models Estimated with Extremely Small Samples: Application in Pharmaceutical Stability Studies

Pharmaceutical stability studies are conducted to estimate the shelf life, i.e. the period during which the drug product maintains its identity and stability. In the evaluation of process, regression curve is fitted on the data obtained during the study and the shelf life is determined using the fitted curve. The evaluation process suggested by ICH considers only the case of the true relationship between the measured attribute and time being linear. However, no method is suggested for the practitioner to decide if the linear model is appropriate for their dataset. This is a major problem, as a falsely selected model may distort the estimated shelf life to a great extent, resulting in unreliable quality control. The difficulty of model misspecification detection in stability studies is that very few observations are available. The conventional methods applied for model verification might not be appropriate or efficient due to the small sample size. In this paper, this problem is addressed and some developed methods are proposed to detect model misspecification. The methods can be applied for any process where the regression estimation is performed on independent small samples. Besides stability studies, frequently performed construction of single calibration curves for an analytical measurement is another case where the methods may be applied. It is shown that our methods are statistically appropriate and some of them have high efficiency in the detection of model misspecification when applied in simulated situations which resemble pre-approval and post-approval stability studies.

A comprehensive synopsis on cognizance of Regulatory Affairs in different sectors of Pharmacy

A pharmaceutical drug regulatory Affairs is mainly involved in registration process parameters of different pharmaceutical products and new drug application. Regulatory affairs (RA) professionals play vital roles in a pharmaceutical field as, it is related to healthcare products. It provides strategic, operational direction and support for working within regulations to expedite the development of pharmaceutical, biological and medical devices. Also, it is principally concern with safety and efficacy, low risk/high benefit and quality assessment of healthcare drug products throughout the world. Regulatory system of each and every country has different regulatory agencies which govern certification and good manufacturing practices. Regulatory Affairs also has a very specific importance within the formulation and marketing of drug product in pharmaceutical industries. Current abstract reports for the first time and emphasizes on studies concerning awareness and knowledge testing in regulatory affair field by the various pharma professionals. This is completely certified online survey of quiz questionnaire based on important concepts in RA and circulated via google form to different social medias to more than 1000 pharma professionals (Academics, Students, Industrials area). The systematic analysis of received responses reveals awareness and knowledge of the participants about RA in selected pharma professionals. It shows that, participants form industrial area having more knowledge than academics and students. This survey comes out with conclusion that, there is more need to raise RA information sources by the inclusion of this subject in syllabus for academics via various courses to fulfill more RA professional demands in future.