Robustness Optimization of an Existing Tablet Coating Process Applying Retrospective Knowledge (rQbD) and Validation

The objective of these studies is to verify and validate the improvement in the inter-tablet coating uniformity for an industrially commercialized coated tablet, without involving changes in the approved registration dossier. Using the CPP (critical process parameters) determined from previous retrospective statistical analysis, the recommended working ranges are identified. Retrospective analysis showed that the design of experiments (DoE) provided an improved process variable configuration. Therefore, it is decided to study two critical parameters: Product temperature and drum speed, with an additional 22 experimental design. The quality results of the samples analyzed show that the aesthetic defects of the batches made with the new working ranges have been reduced. These results have also been corroborated with the 42 industrial batches manufactured with the new ranges. With the optimized parameters, tablets have been coated and the suitability of the model determined. The results demonstrated the overall reliability and effectiveness of the proposed Quality by Design approach and provides a useful tool to help optimize the industrial coating process. This study confirms that it is possible to optimize and validate the manufacturing process of an existing commercial product by means of a DoE with retrospective data. Therefore, no variation in the dossier is required

Excipients in the Paediatric Population: A Review

This theoretical study seeks to critically review the use of excipients in the paediatric population. This study is based on the rules and recommendations of European and American drug regulatory agencies. On the one hand, this review describes the most frequent excipients used in paediatric medicine formulations, identifying the compounds that scientific literature has marked as potentially harmful regarding the side effects generated after exposure. On the other hand, this review also highlights the importance of carrying out safety -checks on the excipients, which, in most cases, are linked to toxicity studies. An excipient in the compilation of paediatric population databases is expected to target safety and toxicity, as in the STEP database. Finally, a promising pharmaceutical form for child population, ODT (Orally Disintegrating Tablets), will be studied

Palatability and stability studies to optimize a carvedilol oral liquid formulation for pediatric use

Carvedilol (CARV) is a blocker of α- and β- adrenergic receptors, used as an “off-label” treatment for cardiovascular diseases in pediatrics. Currently, there is no marketed pediatric-appropriate CARV liquid formulation, so its development is necessary. Palatability (appreciation of smell, taste, and aftertaste) is a key aspect to be considered during the development of pediatric formulations since only formulations with good palatability also have adequate acceptability in this population. Consequently, the aim of this research was to assess the palatability and acceptability of different CARV formulations using an in vivo taste assessment (ID Number PR103/22) in order to select the highest palatability-rated CARV formulation. The preparation of CARV formulations was based on a reference 1 mg/mL CARV solution, which contains malic acid as a solubilizing agent. Subsequently, sucralose and flavoring agents were added and mixed until complete dissolution to the corresponding formulations. Adult volunteers participated in this study and evaluated the taste and odor of various CARV formulations through a questionnaire and a sensory test. The mean palatability score, measured on a 10-point scale, increased from 1.60 for the unflavored control to 7.65 for the highest-rated flavored formulation. Moreover, the bitterness of the optimized CARV formulation was reduced from 66.67% to 17.86%, and the taste pleasantness was increased from 25/100 to 73/100. This optimized CARV formulation contains a sweetening agent, sucralose, in addition to two flavoring agents at appropriate concentrations for pediatrics. Furthermore, the physicochemical and microbiological stability of the optimized CARV formulation were evaluated for 6 months at 25, 30, and 40 °C, in addition to in-use stability for 15 days at 25 °C, whose results were confirmed. Thus, we successfully developed a palatable CARV liquid solution that contains excipients appropriate for pediatrics and is stable under the studied conditions.</span

Development of a Carvedilol oral liquid formulation for paediatric use

Carvedilol (CARV) is an 'off-label' β-blocker drug to treat cardiovascular diseases in children. Since CARV is nearly insoluble in water, only CARV solid forms are commercialized. Usually, CARV tablets are manipulated to prepare an extemporaneous liquid formulation for children in hospitals. We studied CARV to improve its aqueous solubility and develop an oral solution. In this study, we assessed the solubility and preliminary stability of CARV in different pH media. Using malic acid as a solubility enhancer had satisfactory results. We studied the chemical, physical, and microbiological stability of 1 mg/mL CARV-malic acid solution. A design of experiment (DoE) was used to optimize the CARV solution's preparation parameters. A 1 mg/mL CARV solution containing malic acid was stable for up to 12 months at 25 °C and 30 °C and 6 months at 40 °C. An equation associating malic acid with CARV concentrations was obtained using DoE. Microbiological data showed that the use of methylparaben was not necessary for this period of time. We successfully developed an aqueous CARV solution suitable for paediatrics and proven to be stable over a 12-month period

Development of a Standardized Method for Measuring Bioadhesion and Mucoadhesion That Is Applicable to Various Pharmaceutical Dosage Forms

Although some methods for measuring bioadhesion/mucoadhesion have been proposed, a standardized method is not yet available. This is expected to hinder systematic comparisons of results across studies. This study aimed to design a single/systematic in vitro method for measuring bioadhesion/mucoadhesion that is applicable to various pharmaceutical dosage forms. To this end, we measured the peak force and work of adhesion of minitablets, pellets, and a bioadhesive emulsion using a texture analyzer. Porcine tissue was used to simulate human stomach/skin conditions. The results of these formulations were then compared to those for formulations without the bioadhesive product. We conducted a case study to assess the stability of a bioadhesive emulsion. The results for the two parameters assessed were contact time = 60 s and contact force = 0.5 N at a detachment speed of 0.1 mm/s. Significant differences were observed between the bioadhesive and control formulations, thus demonstrating the adhesive capacity of the bioadhesive formulations. In this way, a systematic method for assessing the bioadhesive capacity of pharmaceutical dosage forms was developed. The method proposed here may enable comparisons of results across studies, i.e., results obtained using the same and different pharmaceutical formulations (in terms of their bioadhesion/mucoadhesion capacity). This method may also facilitate the selection of potentially suitable formulations and adhesive products (in terms of bioadhesive properties)

Optimization of the Cohesion Index in the SeDeM Diagram Expert System and application of SeDeM Diagram: an improved methodology to determine the Cohesion Index

In this study, we suggest optimizing the methodology to determine the Cohesion Index (Icd) in order to avoid mistaken characterizations due to powder bulk density. For this purpose, five different excipients, with different bulk densities and of different chemical nature, were compressed at different heights. Their compression and their tablet characterization enable establishing a powder weight for compression in accordance with its bulk density. Therefore, the resulting tablet will have a height within a defined range of heights where it has no critical effects on its hardness. Then, the impact of this optimization is shown in a formula development, one of the main SeDeM's applications. A mathematical equation was used to calculate the theoretical amount of excipient to formulate the API according to both methodologies. The compression results demonstrate that the characterization with the NM-Icd is more accurate than the previous one while preserving its simplicity

Formulation of Sustained Release Hydrophilic Matrix Tablets of Tolcapone with the Application of Sedem Diagram: Influence of Tolcapone's Particle Size on Sustained Release

Hydrophilic matrix tablets are a type of sustained release dosage form characterized by distributing a drug in a matrix that is usually polymeric. Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase. In recent years, it has been shown that tolcapone is a potent inhibitor of the amyloid aggregation process of the transthyretin protein, and acts by stabilizing the structure of the protein, reducing the progression of familial amyloid polyneuropathy. The main objective of this study was to obtain a sustained release tablet of tolcapone for oral administration with a preferred dosage regimen of 1 administration every 12 or 24 h and manufactured, preferably, by direct compression. The SeDeM Diagram method has been used for the formulation development of hydrophilic matrix tablets. Given the characteristics of tolcapone, the excipient selected for the formation of the polymeric matrix was a high viscosity hydroxypropylmethylcellulose (Methocel® K100M CR). A decrease in the particle size of tolcapone resulted in a slower dissolution release of the formulation when the concentration of the polymer Methocel® K100M CR was below 29%. These surprising and novel results have given rise to patent number WO/2018/019997

Validation of a titration method to determine chondroitin sulfate loaded to solid lipid nanoparticles in an experimental factorial design

Previous efforts at the Faculty of Pharmacy and Food Sciences of the University of Barcelona, have achieved to obtain cationic solid lipid nanoparticles (cSLN), with an average size of less than 200 nm, by the hot microemulsion method, which have been tested as a vehicle for pDNA and siRNA, in the transfection of cell lines. It is of scientific interest to evaluate the capacity of SLN transporting different types of biomolecules with pharmacological potential. Chondroitin sulfate (CHON) is a major component of the extracellular matrix of several connective tissues, including skin, bone, ligaments, tendons and cartilage. For that reason, CHON is a potential therapeutical agent in Osteoarthritis (OA), which is characterized by progressive structural and metabolic changes in joint tissues. Studies recommend topical administration in treating OA as first line therapy, and the development of topical systems with nanotechnology may introduce a new perspective for future treatment of OA. An experimental factorial design, to optimize the production of SLN of CHON, was employed. The variables were defined as Concentration (mg/ml), Stirring rate (rpm) and Reaction time (min). Different properties were tested, including entrapment efficiency of CHON, zeta potential and particle size. A titration method was validated to test entrapment efficiency of CHON. A calibration curve was obtained from 0.10 to 1.20 mg mL-1 (r > 0.9994). Withinday % RSD was 0.7 and between-day % RSD was 1.11. Specificity/ selectivity experiments revealed the absence of important interference from excipients, mean recovery from spiked samples for CHON was 93.6 %

Conventional inactivated bivalent H5/H7 vaccine prevents viral localization in muscles of turkeys infected experimentally with low pathogenic avian influenza and highly pathogenic avian influenza H7N1 isolates

Highly pathogenic avian influenza (HPAI) viruses cause viraemia and systemic infections with virus replication in internal organs and muscles; in contrast, low pathogenicity avian influenza (LPAI) viruses produce mild infections with low mortality rates and local virus replication. There is little available information on the ability of LPAI viruses to cause viraemia or on the presence of avian influenza viruses in general in the muscles of infected turkeys. The aim of the present study was to determine the ability of LPAI and HPAI H7N1 viruses to reach muscle tissues following experimental infection and to determine the efficacy of vaccination in preventing viraemia and meat localization. The potential of infective muscle tissue to act as a source of infection for susceptible turkeys by mimicking the practice of swill-feeding was also investigated. The HPAI virus was isolated from blood and muscle tissues of all unvaccinated turkeys; LPAI could be isolated only from blood of one bird and could be detected only by reverse transcriptasepolymerase chain reaction in muscles. In contrast, no viable virus or viral RNA could be detected in muscles of vaccinated/challenged turkeys, indicating that viral localization in muscle tissue is prevented in vaccinated birds

Development and Validation of a New High-Performance Liquid Chromatography Method for the Simultaneous Quantification of Coenzyme Q10, Phosphatidylserine, and Vitamin C from a Cutting-Edge Liposomal Vehiculization

A high-performance liquid chromatography (HPLC) method was developed to simultaneously quantify three widely used active substances such as coenzyme Q10, phosphatidylserine, and vitamin C. This new method optimizes current timing and costs in the analyses of these three active substances. Additionally, since the analyzed compounds were encapsulated on a cutting-edge liposomal formulation, further processing was necessary to be developed prior to HPLC analyses. The technique was studied and adequately validated in accordance with the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) regarding selectivity, linearity, accuracy, precision, and robustness. After data treatment of results, linear regressions for all active substances showed an optimal linearity with a correlation coefficient of >0.999 in the concentration range between 70 to 130% of the liposomal formulation and less than a 3% relative standard deviation (RSD) in accuracy and precision