Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films.

In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients.

Testing the disintegration and texture-related palatability predictions for orodispersible tablets using an instrumental tool coupled with multivariate analysis: Focus on process variables and analysis settings.

Orodispersible tablets (ODTs) represent a growing category of dosage forms intended to increase the treatment acceptability for special groups of patients. ODTs are designed to rapidly disintegrate in the oral cavity and to be administered without water. In addition, ODTs are easy to manufacture using standard excipients and pharmaceutical equipment. This study adds to previously published research that developed an instrumental tool to predict oral disintegration and texture-related palatability of ODTs with different formulations. The current study aimed to challenge the predictive capacity of the models under variable process conditions. The studied process parameters with potential impact on the pharmaceutical properties, texture profiles, and palatability were the compression pressure, punch shape and diameter. Subsequently, for all the placebo and drug-loaded ODTs, the in vivo disintegration time and texture-related palatability were determined with healthy volunteers. Previously developed regression models were applied to predict the formulation's disintegration time and texture-related palatability characteristics of ODTs obtained under different experimental conditions. The influence of process variables on the predictive performance of the models was estimated by calculating the residuals as the difference between the predicted and observed values for the investigated response. Increasing the speed of the analyser`s probe from 0.01 mm/s to 0.02 mm/s led to an improved differentiation of the texture profiles. The in vivo disintegration time and texture-related palatability scores were only influenced by the mechanical resistance and the tablet shape. Lower score was observed for the larger diameter tablets (10 mm). Overall, the prediction of the disintegration time at 0.02 mm/s was more accurate, except for stronger tablets. The best prediction of texture-related palatability was achieved for the 10 mm tablets, tested at 0.01 mm/s speed. The same model achieved good predictions of the oral disintegration time for all API-loaded formulations, which confirmed the ability of the texture analysis to capture process-related variability. Drug loading decreased the predictive capacity of the texture-related palatability because of the taste effect.

Texture analysis - A versatile tool for pharmaceutical evaluation of solid oral dosage forms.

In the past few decades, texture analysis (TA) has gained importance as a valuable method for the characterization of solid oral dosage forms. As a result, an increasing number of scientific publications describe the textural methods that evaluate the extremely diverse category of solid pharmaceutical products. Within the current work, the use of texture analysis in the characterization of solid oral dosage forms is summarised with a focus on the evaluation of intermediate and finished oral pharmaceutical products. Several texture methods are reviewed regarding the applications in mechanical characterization, and mucoadhesion testing, but also in estimating the disintegration time and in vivo specific features of oral dosage forms. As there are no pharmacopoeial standards for pharmaceutical products tested through texture analysis, and there are important differences between reported results due to different experimental conditions, the choice of testing protocol and parameters is challenging. Thereby, this work aims to guide the research scientists and quality assurance professionals involved in different stages of drug development into the selection of optimal texture methodologies depending on the product characteristics and quality control needs.

Curcumin-Loaded Microspheres Are Effective in Preventing Oxidative Stress and Intestinal Inflammatory Abnormalities in Experimental Ulcerative Colitis in Rats.

Curcumin's role in the treatment of ulcerative colitis (UC) has been proven by numerous studies, but its preventive administration, with the aim of reducing the remission episodes that are characteristic of this disease, must be further investigated. This study investigates the effects of a novel curcumin-loaded polymeric microparticulate oral-drug-delivery system for colon targeting (Col-CUR-MPs) in an experimental model of UC. Male Wistar rats (n = 40) were divided into five groups (n = 8), which were treated daily by oral gavage for seven days with a 2% aqueous solution of carboxymethylcellulose sodium salt (CMCNa) (healthy and disease control), free curcumin powder (reference), Col-CUR-MPs (test) and prednisolone (reference) prior to UC induction by the intrarectal administration of acetic acid (AA), followed by animal sacrification and blood and colonic samples' collection on the eighth day. Col-CUR-MPs exhibited an important preventive effect in the severity degree of oxidative stress that resulted following AA intrarectal administration, which was proved by the highest catalase (CAT) and total antioxidant capacity (TAC) levels and the lowest nitrites/nitrates (NOx), total oxidative status (TOS) and oxidative stress index (OSI) levels. Biochemical parameter analysis was supported by histopathological assessment, confirming the significant anti-inflammatory and antioxidant effects of this novel colon-specific delivery system in AA-induced rat models of UC. Thus, this study offers encouraging perspectives regarding the preventive administration of curcumin in the form of a drug delivery system for colon targeting.

Development of a Curcumin-Loaded Polymeric Microparticulate Oral Drug Delivery System for Colon Targeting by Quality-by-Design Approach.

The purpose of this study was to apply the quality-by-design (QbD) approach for the development of colon-targeted curcumin-loaded polymeric microparticles (Col-CUR-MPs). The proportion of the enterosoluble polymer (Eudragit® FS) in the polymeric matrix, curcumin concentration, and the concentration of the polymer mixture (Eudragit® FS-polycaprolactone) were identified as potential risk factors for the quality of the final product following risk assessment. The influence of these variables on the critical quality attributes (CQAs) of Col-CUR-MPs was investigated. Therefore, a central composite face experimental design was used in order to determine the functional relationships between variables and product CQAs. The obtained regression model and contour plots were used to establish the design space. Finally, the model was validated by preparing two microparticulate formulations, one corresponding to the robust setpoint from within the design space and one outside the established design space, and calculating the percentage bias between the experimental and predicted values. The in vivo study, which was conducted on a fluorescein-loaded formulation that corresponded to the robust setpoint determined by QbD and that contained a mixture of polycaprolactone and Eudragit® FS (60:40, w/w), confirmed the colon-targeting qualities of this formulation.

A quality by design (QbD) study on enoxaparin sodium loaded polymeric microspheres for colon-specific delivery.

The aim of this study was to apply quality by design (QbD) for pharmaceutical development of enoxaparin sodium microspheres for colon-specific delivery. The Process Parameters (CPPs) and Critical Quality Attributes (CQAs) were identified. A central composite experimental design was used in order to develop the design space of microspheres for colon-specific delivery that have the desired Quality Target Product Profile (QTPP). The CPPs studied were Eudragit® FS-30D/Eudragit® RS-PO ratio, poly(vinyl alcohol) (PVA) concentration and sodium chloride (NaCl) concentration. The encapsulation efficiency increased with NaCl concentration increase, the percentages of enoxaparin sodium reaching 94% for some formulations. Increasing the ratio Eudragit® FS-30D/Eudragit® RS-PO ensured a relatively complete release of enoxaparin sodium in the environment simulating the colonic pH. Based on these results, the optimum conditions were decided and the optimum formulation was prepared. The results obtained for the latter in terms of in vitro enoxaparin sodium release were good, the microparticles releasing only 9.42% enoxaparin sodium in acidic environment and 15.16% in the medium which simulated duodenal pH, but allowing the release of up to 89.24% in the medium which simulated colonic pH. The in vitro release profile of enoxaparin sodium was close to the ideal one, therefore the system was successfully designed using QbD approach.

Formulation, preparation and in vitro - in vivo evaluation of compression-coated tablets for the colonic-specific release of ketoprofen

ABSTRACT The aim of this study was to formulate and prepare compression-coated tablets for colonic release (CR-tablets), and to evaluate the bioavailability of ketoprofen following the administration of a single dose from mini-tablets with immediate release (IR-tablets) compared to CR-tablets. CR-tablets were prepared based on time-controlled hydroxypropylmethylcellulose K100M inner compression-coating and pH-sensitive Eudragit® L 30D-55 outer film-coating. The clinical bioavailability study consisted of two periods, in which two formulations were administered to 6 volunteers, according to a randomized cross-over design. The apparent cumulative absorption amount of ketoprofen was estimated by plasma profile deconvolution. CR-tablets were able to delay ketoprofen's release. Compared to IR-tablets used as reference, for the CR-tablets the maximum plasma concentration (Cmax) was lower (4920.33±1626.71 ng/mL vs. 9549.50±2156.12 ng/mL for IR-tablets) and the time needed to reach Cmax (tmax) was 5.33±1.63 h for CR-tablets vs. 1.33±0.88 h for IR-tablets. In vitro-in vivo comparison of the apparent cumulative absorption amount of ketoprofen showed similar values for the two formulations. Therefore, the obtained pharmacokinetic parameters and the in vitro-in vivo comparison demonstrated the reliability of the developed pharmaceutical system and the fact that it is able to avoid the release of ketoprofen in the first part of the digestive tract.

Development of enoxaparin sodium polymeric microparticles for colon-specific delivery.

BACKGROUND AND AIMS: Recent studies have shown that low molecular weight heparins are effective in the treatment of inflammatory bowel disease. Therefore, there is considerable interest in the development of an oral colonic delivery pharmaceutical system allowing targeted release of heparin in the inflamed tissue. The objective of this study was to prepare microparticles for the oral administration and colonic release of enoxaparin and to evaluate the influence of certain formulation factors on their characteristics. METHODS: Microparticles were prepared by water/oil/water double emulsion technique followed by solvent evaporation. The influence of several formulation factors on the characteristics of microparticles were evaluated. The formulation factors were alginate concentration in the inner aqueous phase, polymer (Eudragit(®) FS 30D and Eudragit(®) RS PO) concentration in the organic phase and ratios between the two polymers. The microparticles were characterized in terms of morphology, size, entrapment efficiency and enoxaparin release. RESULTS: The results showed that increasing sodium alginate percentage reduced the encapsulation efficiency of enoxaparin and accelerated enoxaparin release. Regarding the influence of the two polymers, reducing polymer concentration in the organic phase led to a smaller size of microparticles, a lower entrapment efficiency and an important retardation of enoxaparin release. The formulation prepared with Eudragit(®) FS 30D limited the release to a maximum of 3% in gastric simulated environment, a specific characteristic of oral systems for colonic delivery, and fulfilled our objective to delay the release. CONCLUSIONS: Microparticles prepared with Eudragit(®) FS 30D represent a suitable and potential oral system for the colonic delivery of enoxaparin.