Application of Multiple Linear Regression and Artificial Neural Networks for the Prediction of the Packing and Capsule Filling Performance of Coated and Plain Pellets Differing in Density and Size

Plain or coated pellets of different densities 1.45, 2.53, and 3.61 g/cc in two size ranges, small (380–550 μm) and large (700–1200 μm) (stereoscope/image analysis), were prepared according to experimental design using extrusion/spheronization. Multiple linear regression (MLR) and artificial neural networks (ANNs) were used to predict packing indices and capsule filling performance from the “apparent” pellet density (helium pycnometry). The dynamic packing of the pellets in tapped volumetric glass cylinders was evaluated using Kawakita’s parameter a and the angle of internal flow θ. The capsule filling was evaluated as maximum fill weight (CFW) and fill weight variation (FWV) using a semi-automatic machine that simulated filling with vibrating plate systems. The pellet density influenced the packing parameters a and θ as the main effect and the CFW and FWV as statistical interactions with the coating. The pellet size and coating also displayed interacting effects on CFW, FWV, and θ. After coating, both small and large pellets behaved the same, demonstrating smooth filling and a low fill weight variation. Furthermore, none of the packing indices could predict the fill weight variation for the studied pellets, suggesting that the filling and packing of capsules with free-flowing pellets is influenced by details that were not accounted for in the tapping experiments. A prediction could be made by the application of MLR and ANNs. The former gave good predictions for the bulk/tap densities, θ, CFW, and FWV (R-squared of experimental vs. theoretical data >0.951). A comparison of the fitting models showed that a feed-forward backpropagation ANN model with six hidden units was superior to MLR in generalizing ability and prediction accuracy. The simplification of the ANN via magnitude-based pruning (MBP) and optimal brain damage (OBD), showed good data fitting, and therefore the derived ANN model can be simplified while maintaining predictability. These findings emphasize the importance of pellet density in the overall capsule filling process and the necessity to implement MLR/ANN into the development of pellet capsule filling operations

Design and development of imediate and modified release pharmaceutical formulations with the aid of Solid Dispersions

The aim of the present thesis was to investigate per os immediate and controlled release tablet formulations based on solid dispersions. Melt mixing was selected as the preparation technique, while polyethylene glycol (PEG) was used as melting agent. Nimodipine (NIM, 2nd generation calcium antagonist) was selected as a model drug in all formulations. In the first part of the work, an isocratic reversed-phase high performance liquid chromatography was developed for the determination of nimodipine and impurities (A, B and C) using statistical experimental design. Initially, a full factorial design (Full-FD) was selected in order to screen five independent factors: type and concentration of the organic modifier (methanol or aceto¬nitrile), column temperature, mobile phase flow rate and pH. Except pH, the rest examined factors were identified as significant. The optimum conditions of separation, determined with the aid of central composite design (CCD), were: 1) mobile phase: acetonitrile/water (67.5/32.5 (v/v)), 2) column temperature: 40 oC and 3) mobile phase flow rate: 0.9 ml/min. The proposed method showed good prediction performance. The analysis was found to be linear, specific, precise, sensitive and accurate. The method was also studied for robustness and intermediate precision using experimental design methodology. Five commercially available nimodipine tablets showed good % recovery and % RSD, while only traces of impurities (amounts below LOQ) were found in all products. In the next stage of the study a physicochemical characterization of NIM/PEG solid dispersions was conducted. Powder XRD, SEM analysis and contact angle measurements revealed NIM’s crystal size reduction and system’s increased wettability. Phase diagrams of NIM and PEG were constructed using DSC and statistical thermodynamics. Depending on the assumption made for the Flory-Huggins coefficient, χ, eutectic (for χ = 0 and χ = α) and monotectic (for χ = f(φ) and χ = f(φ,Τ)) systems were identified. The system’s monotectic nature was verified by hot stage polarized light microscopy. Isothermal crystallization of NIM in the melts with PEG (25oC and 0% RH) showed increased rate of crystallization compared to the pure drug. FT-IR analysis conducted for the physical mixtures and solid dispersions showed absence of hydrogen bonding between drug and polymer, while experiments evaluating the influence of PEG and solid dispersion’s preparation temperature on NIM’s crystallization process showed that temperatures above NIM’s liquidus favor mod II crystal growth, while PEG-rich samples favor mod I crystals. In the final stage of the study, the in vitro behavior of immediate (I) and sustained (II) release solid dispersion tablets was investigated: Ι) Immediate release tablets Increased dissolution rates were observed for immediate release solid dispersion tablets compared to physical mixtures, while PEG-rich dispersions led to increasing release rates due to NIM’s size reduction and system’s increased wettability. ΙI) Sustained release tablets -Matrix type tablets: In the matrix type sustained release solid dispersions, the preparation of a nimodipine zero-order release tablet formulation was investigated. The amounts of PEG 4000 (used as melting agent), PVP K30 and HPMC (K100 and E50LV) were selected as independent variables following a statistical experimental design combined with multi-linear regression (MLR), artificial neural networks (ANN) and genetic programming (GP). NIM release was controlled by simultaneous matrix swelling and erosion. GP showed increased prediction performance (tested on an external validation test set) for all responses, compared to the ANN and MLR models. The optimum formulation (weighted 184 mg) consisted of 63 mg PEG, 11 mg PVP, 40 mg HPMC K100M, 40 mg HPMC E50LV and 30 mg NIM. -Effervescent floating tablets: In the development of sustained release effervescent floating tablet formulations, mixture-proportions of PEG 4000, PVP K30, HPMC K100M, effervescent agents (EFF, 1:1 w/w ratio of sodium bicarbonate and citric acid) and NIM were investigated following a 25-run D-optimal mixture design. NIM release was controlled by simultaneous matrix swelling and erosion. Solid dispersions reduced the extent of burst effect compared to physical mixtures. The root mean squared error of prediction (RMSEp) on an external validation (test) set was used to compare the prediction performance of ANN, GP, and conventional MLR fitted to the data obtained according to the statistical experimental design. The global optimum formulation, evaluated by minimizing the standardized Euclidian distance between the predicted value of each response (based on the equations generated by GP) and the desirable ones (limited burst effect, good floating characteristics and prolonged release) had the following concentration proportions: PEG= 9%, PVP= 30%, HPMC= 36%, EFF= 11%, NIM = 14% (30 mg per tablet).Στην παρούσα διδακτορική διατριβή μελετήθηκε η ανάπτυξη per os χορηγούμενων φαρμακευτικών δισκίων άμεσης και ελεγχόμενης αποδέσμευσης από συστήματα στερεής διασποράς. Για την παρασκευή των συστημάτων επιλέχθηκε η τεχνική της τήξης (melt mixing) του φαρμάκου μαζί με πολυμερικό φορέα (πολυαιθυλενογλυκόλη, PEG). Ως πρότυπη φαρμακευτική ουσία (model drug) χρησιμοποιήθηκε η Νιμοδιπίνη (ΝΙΜ, αναστολέας ασβεστίου 2ης γενιάς). Στο πρώτο στάδιο της διατριβής μετά την παρασκευή των συστημάτων και πριν το φυσικοχημικό χαρακτηρισμό τους, αναπτύχθηκε και βελτιστοποιήθηκε μια νέα μέθοδος ανάλυσης για τον ποσοτικό προσδιορισμό και τον έλεγχο καθαρότητας της ΝΙΜ στις διασπορές. Συγκεκριμένα, μελετήθηκε ο ποσοτικός προσδιορισμός τόσο της δραστικής ουσίας όσο και των προσμίξεών της (Α, Β και C) με τη χρήση υγρής χρωματογραφίας υψηλής απόδοσης (HPLC) αντίστροφης φάσης (RP) και τη βοήθεια στατιστικού πειραματικού σχεδιασμού. Ο πειραματικός σχεδιασμός (πλήρης παραγοντικός σχεδιασμός) περιελάμβανε πέντε ανεξάρτητους παράγοντες: είδος και αναλογία των συστατικών της κινητής φάσης, θερμοκρασία στήλης, ρυθμός ροής και pH της κινητής φάσης. Η ανάλυση των αποτελεσμάτων έδειξε ότι όλοι οι παράγοντες που εξετάστηκαν εκτός του pH είχαν σημαντική επίδραση στην ποιότητα του διαχωρισμού (εκφρασμένη από τη διαχωριστική ικανότητα της ΝΙΜ με την πρόσμιξη Α (Rs), το χρόνο που απαιτείται για την έκλουση του πρώτου και του τελευταίου συστατικού και την τιμή της συνάρτησης βελτιστοποίησης χρωματογραφήματος). Οι βέλτιστες συνθήκες διαχωρισμού, οι οποίες προσδιορίσθηκαν με τη βοήθεια ενός νέου πειραματικού σχεδιασμού (κεντρικός σύνθετος σχεδιασμός), ήταν: κινητή φάση ακετονιτρίλιο-νερό (67,5-32,5 ο/ο), θερμοκρασία στήλης 40 oC και ρυθμός ροής κινητής φάσης 0,9 ml•min-1. Η μέθοδος αξιολογήθηκε ως προς την εξειδίκευση, τη γραμμικότητα, την ακρίβεια, την επαναληψιμότητα, την ενδιάμεση επαναληπτικότητα, ενώ η αξιολόγηση της ευρωστίας και της ανθεκτικότητα έγιναν με τη βοήθεια στατιστικού πειραματικού σχεδιασμού. Η μέθοδος αξιολογήθηκε περαιτέρω σε πέντε εμπορικά δισκία Νιμοδιπίνης. Στο επόμενο στάδιο της διατριβής έγινε ο φυσικοχημικός χαρακτηρισμός των στερεών διασπορών ΝΙΜ-PEG (2000, 4000 και 6000). Αρχικά, με τη βοήθεια περίθλασης ακτίνων Χ σε κονιοποιημένα δείγματα και ηλεκτρονικής μικροσκοπίας σάρωσης (SEM) σε τομές υμενίων έδειξε πως η ουσία παραμένει κρυσταλλική, ενώ η μέτρηση της γωνίας συνεπαφής έδειξε αύξηση της διαβρεκτικότητας των συστημάτων με την αύ¬ξηση της περιεκτικότητας του πολυμερικού φορέα (PEG). Εν συνεχεία, κατασκευάστηκαν τα διαγράμματα φάσεως με τη βοήθεια DSC και στατιστικής θερμοδυναμικής. Ανάλογα με την τιμή του συντελεστή χ της εξίσωσης Flory-Huggins, προσδιορίστηκε ο σχηματισμός ευτηκτικού (για χ=0 και χ=α) και μονοτηκτικού (για χ=f(φ) και χ=f(φ,Τ)) συστήματος. Ο σχηματισμός μονοτηκτικών συστημάτων επιβεβαιώθηκε με τη χρήση οπτικής μικροσκοπίας πολωμένου φωτός με θερμαινόμενη τράπεζα. Ακολούθως, η μελέτη ισόθερμης κρυστάλλωσης της ΝΙΜ από τήγματα με PEG στους 25oC και σε περιβάλλον μηδενικής υγρασίας έδειξε αύξηση του ρυθμού κρυστάλλωσης της ουσίας (η αύξηση ήταν εντονότερη για τήγματα με PEG χαμηλού ΜΒ), σε αντίθεση με τήγματα καθαρής ΝΙΜ όπου η ουσία παρέμενε άμορφη ακόμη και τρεις μήνες μετά την αποθήκευσή της. Στη συνέχεια, η ανάλυση με φασματοσκοπία FT-IR έδειξε απουσία σημαντικών αλληλεπιδράσεων μεταξύ της δραστικής ουσίας και των πολυμερικών φορέων (απουσία δεσμών υδρογόνου). Τέλος, διαπιστώθηκε ότι κατά την παρασκευή των συστημάτων, θερμοκρασίες τήξης που βρίσκονται πάνω από τη liquidus της ΝΙΜ οδηγούν σε κρυστάλλους μορφής ΙΙ, ενώ η παρουσία του PEG οδηγεί στην σταθεροποίηση κρυστάλλων μορφής Ι. Στο τελευταίο στάδιο της διατριβής μελετήθηκε η in vitro αποδέσμευση από κυλινδρικά συσσωματώματα (δισκία) κονιοποιημένης στερεής διασποράς καθώς και αντίστοιχων φυσικών μειγμάτων με δυνατότητα άμεσης (Ι) και ελεγχόμενης (ΙΙ) αποδέσμευσης: Ι) Δισκία άμεσης αποδέσμευσης Παρατηρήθηκε αύξηση του ρυθμού αποδέσμευσης της ΝΙΜ στις στερεές διασπορές σε σχέση με τα φυσικά μείγματα. Η αύξηση αυτή ήταν μεγαλύτερη καθώς αυξάνονταν η περιεκτικότητα σε φορέα (PEG 2000, 4000 και 6000) και αποδόθηκε στην αύξηση της διαβρεκτικότητας του συστήματος και στη μείωση του μεγέθους των σωματιδίων της φαρμακευτικής ουσίας και κατά συνέπεια στην αύξηση της ειδικής επιφάνειά της. ΙΙ) Δισκία ελεγχόμενης αποδέσμευσης -Δισκία μήτρας: Εκτός από την πολυαιθυλενογλυκόλη (PEG 4000) για την παρασκευή δισκίων χρησιμοποιήθηκαν PVP K30 και HPMC (K100M και Ε50LV) και μελετήθηκε η ικανότητα ελέγχου της αποδέσμευσης και η επίτευξη μηδενοταξικής κινητικής, κάνοντας χρήση πειραματικού σχεδιασμού (πλήρης παραγοντικός και κεντρικός σύνθετος σχεδιασμός) με 1) πολλαπλή γραμμική παλινδρόμηση (MLR), 2) τεχνητά νευρωνικά δίκτυα (ANN) και 3) γενετικό προγραμματισμό (GP). Βρέθηκε ότι η αποδέσμευση της ουσία ελέγχονταν από την ταυτόχρονη διόγκωση και διάβρωση της μήτρας, ενώ ο GP έδειξε αυξημένη ικανότητα πρόβλεψης σε σχέση με τις υπόλοιπες τεχνικές. Η βέλτιστη σύνθεση δισκίων βάσει του GP ήταν: βάρος δισκίων 184 mg, με σύσταση: 63 mg PEG, 11 mg PVP, 40 mg HPMC K100M, 40 mg HPMC E50LV, 30 mg NIM η οποία έδειχνε μηδενοταξική κινητική αποδέσμευσης. Η μελέτη σταθερότητας των δισκίων για έξι μήνες έδειξε ότι η δραστική ουσία παραμένει σταθερή και το προφίλ αποδέσμευσης αμετάβλητο. - Αναβράζοντα επιπλέοντα δισκία: Η ανάπτυξη και βελτιστοποίηση επιπλεόντων δισκίων ελεγχόμενης αποδέσμευσης με ικανότητα επίτευξης πολλαπλών στόχων (παρατεταμένη αποδέσμευση, επιθυμητά χαρακτηριστικά επίπλευσης και ελαχιστοποίηση της ποσότητας της ουσίας που απελευθερώνεται άμεσα στα πρώτα στάδια της αποδέσμευσης, burst effect) έγινε με τη χρήση πειραματικού σχεδιασμού (D-optimal σχεδιασμός μείγματος) σε συνδυασμό με MLR, ANN και GP. Εκτός από τα PEG 4000, PVP K30 και HPMC K100M για την παρασκευή των δισκίων χρησιμοποιήθηκαν διττανθρακικό νάτριο (SB) και κιτρικό οξύ (CA) σε αναλογία 1:1 (β/β) ως αναβράζοντες παράγοντες. Πειραματική μελέτη του μηχανισμού αποδέσμευσης της ουσίας έδειξε ταυτόχρονη διόγκωση και διάβρωση της μήτρας. Καθοριστικό ρόλο στο μηχανισμό αποδέσμευσης είχε η παραγωγή του CO2 και η ισχύς της σχηματιζόμενης στοιβάδας γέλης. Η χρήση των στερεών διασπορών είχε ως αποτέλεσμα τη μείωση της ποσότητας της ουσίας που απελευθερώνεται ανεξέλεγκτα από το σκεύασμα κατά τα αρχικά στάδια της αποδέσμευσης σε σχέση με τα φυσικά μείγματα. Ο GP και τα ANN έδειξαν αυξημένη ικανότητα πρόβλεψης σε σχέση με την MLR. Το βέλτιστο δισκίο, βάσει GP, είχε βάρος 214 mg (με σύσταση: 9% PEG, 30% PVP, 36% HPMC, 11% EFF και 14% NIM) και ικανοποιούσε όλους τους στόχους αποδέσμευσης και επίπλευσης που τέθηκαν

Preparation and Evaluation of Amorphous Solid Dispersions for Enhancing Luteolin’s Solubility in Simulated Saliva

Luteolin (LUT), a bioactive flavonoid, possesses various pharmacological properties, including antioxidant, antimicrobial, anti-allergic, cardio-protective, and anti-cancer activity. Among them, LUT’s administration for the treatment of periodontal disease is very promising. However, its low water solubility magnifies the challenge of formulating LUT into an effective dosage form. In this vein, the aim of the present study examines the preparation of amorphous solid dispersions (ASD) for the solubility improvement of LUT in saliva. At first, the physicochemical properties of the active pharmaceutical ingredient (API) were studied before the selection of the most suitable ASD matrix/carrier. For this reason, six commonly used polymeric ASD matrix/carriers (namely, povidone, PVP; copovidone, coPVP; hydroxypropyl cellulose, HPC-SL; hydroxypropyl methyl cellulose acetate succinate, HPMC-AS; Eudragit® RS, Eud-RS; and Soluplus®, SOL) were screened via the film casting method, as to whether they could suspend the drug’s recrystallization. The most promising matrix/carriers were then evaluated, based on their ability to inhibit LUT’s precipitation after its solubilization, via the solvent shift method. Based on both screening methods, it was determined that PVP was the most promising matrix/carrier for the preparation of LUT’s ASDs. Hence, in a further step, after the successful testing of components’ miscibility, LUT-PVP ASDs were prepared via the solvent evaporation method. These systems (examined via powder X-ray diffractometry, pXRD) showed full API amorphization immediately after preparation and excellent physical stability (since they were stable after 3 months of storage). The study of LUT-PVP ASD’s ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) spectra demonstrated strong H-bonds between the molecules of the drug and the matrix/carrier, while molecular dynamics (MD) simulations were able to shed light on these drug–matrix/carrier interactions, at a molecular level. Finally, in vitro dissolution studies in simulated saliva proved that the prepared ASDs were able to significantly enhance LUT’s dissolution profile. Hence, according to findings of the present work, the preparation of LUT-ASDs utilizing PVP as the polymeric matrix/carrier is regarded as a highly promising technique for the improvement of API’s solubility in the oral cavity

A Review on the Role of Pilocarpine on the Management of Xerostomia and the Importance of the Topical Administration Systems Development

Xerostomia is linked to an increased risk of dental caries, oral fungal infections, and speaking/swallowing difficulties, factors that may significantly degrade patients’ life, socially- or emotionally-wise. Consequently, there is an increasing interest in developing management approaches for confronting this oral condition, at which pilocarpine, a parasympathomimetic agent, plays a vital role. Although the therapeutic effects of orally administrated pilocarpine on the salivary gland flow and the symptoms of xerostomia have been proved by numerous studies, the systemic administration of this drug is affiliated with various adverse effects. Some of the typical adverse effects include sweating, nausea, vomiting, diarrhea, rhinitis, dizziness and increased urinary frequency. In this vein, new strategies to develop novel and effective dosage forms for topical (i.e., in the oral cavity) pilocarpine administration, in order for the salivary flow to be enhanced with minimal systemic manifestations, have emerged. Therefore, the purpose of the current review is to survey the literature concerning the performance of topical pilocarpine delivery systems. According to the findings, the topical delivery of pilocarpine can be regarded as the equivalent to systemic delivery of the drug, efficacy-wise, but with improved patient tolerance and less adverse effects

Clinical Effectiveness of Herbal Oral Care Products in Periodontitis Patients: A Systematic Review

Background: The use of herbal products in oral cavity has shown an increased popularity and potential benefits due to their additional anti-inflammatory and antioxidant properties as well as the lack of side effects related to their use. Objective: To assess the clinical effectiveness of herbal dental products (mouthwash, dentifrice, gel) when compared to conventional products or placebo in periodontitis patients. Material and methods: A systematic review with 22 studies was carried out using MEDLINE/Pubmed, EMBASE and Web of Science databases in addition to hand searches. Randomized and non-randomized clinical trials that evaluated the effect of any herbal dental product and compared it with conventional products or placebo in periodontitis patients and published up to March 2022, were screened. Results: Herbal products used as adjuncts to scaling and root planing (SRP) or supragingival debridement (SPD) led to superior clinical outcomes than placebo or no adjuncts (8 studies). In conjunction with SRP, these products showed comparable outcomes with chlorhexidine (6 studies) or better (4 studies). When used as adjuncts to SPD, herbal oral care products demonstrated comparable outcomes with chlorhexidine and conventional products (4 studies). Conclusions: Within the limitations of this systematic review, herbal oral care products may play a key role in the management of periodontal disease. Further well-designed studies are needed to establish their efficacy

Multidimensional 3D-Printed Scaffolds and Regeneration of Intrabony Periodontal Defects: A Systematic Review

Background: The utilization of regenerative techniques in periodontology involves tailoring tissue engineering principles to suit the oral cavity’s unique environment. Advancements in computer-assisted technology, specifically utilizing cone beam computed tomography (CBCT), enabled the fabrication of 3D-printed scaffolds. The current review aims to explore whether 3D-printed scaffolds are effective in promoting osteogenesis in patients with periodontal defects. Methods: A thorough exploration was undertaken across seven electronic databases (PubMed, Scopus, ScienceDirect, Google Scholar, Cochrane, Web of Science, Ovid) to detect pertinent research in accordance with specified eligibility criteria, aligning with the PRISMA guidelines. Two independent reviewers undertook the screening and selection of manuscripts, executed data extraction, and evaluated the bias risk using the Newcastle–Ottawa Scale for non-randomized clinical trials and SYRCLE’s risk of bias tool for animal studies. Results: Initially, 799 articles were identified, refined by removing duplicates. After evaluating 471 articles based on title and abstract, 18 studies remained for full-text assessment. Eventually, merely two manuscripts fulfilled all the eligibility criteria concerning human trials. Both studies were prospective non-randomized clinical trials. Moreover, 11 animal studies were also included. Conclusions: The use of multidimensional, 3D-printed, customized scaffolds appears to stimulate periodontal regeneration. While the reported results are encouraging, additional studies are required to identify the ideal characteristics of the 3D scaffold to be used in the regeneration of periodontal tissue

Leflunomide Loaded Chitosan Nanoparticles for the Preparation of Aliphatic Polyester Based Skin Patches

In the present study, the preparation of controlled-released leflunomide (LFD)-loaded skin patches was evaluated, utilizing the combination of chitosan (CS) nanoparticles (NPs) incorporated into suitable poly(l-lactic acid) (PLLA) or poly(lactic-co-glycolic acid) (PLGA) polyester matrices. Initially, LFD-loaded CS NPs of ~600 nm and a smooth surface were prepared, while strong inter-molecular interactions between the drug and the CS were unraveled. In the following step, the prepared LFD-loaded CS NPs were incorporated into PLLA or PLGA, and thin-film patches were prepared via spin-coating. Analysis of the prepared films showed that the incorporation of the drug-loaded CS NPs resulted in a significant increase in the drug’s release rate and extent as compared to neat LFD-loaded polyester patches (i.e., prepared without the use of CS NPs). In-depth analysis of the prepared formulations showed that the amorphization of the drug within the matrix and the increased wetting properties of the prepared CS NPs were responsible for the improved thin-film patch characteristics

Preparation and Investigation of the SPF and Antioxidant Properties of O/W and W/O Emulsions Containing Vitamins A, C and E for Cosmetic Applications

In the current work, Oil in Water (O/W) and Water in Oil (W/O) emulsions containing Vitamins A, C and E in 0.5, 1 and 2% wt concentrations were prepared. The pH and viscosity stability over storage, as well as the sunscreen and antioxidant properties of the obtained emulsions, were investigated. The results obtained showed that vitamins slightly increased the pH of the blank emulsions; however, their pH values were within the acceptable values (pH = 4–6). Nevertheless, all emulsions presented excellent pH stability during storage for up to 90 days. Similar results were observed by rheological measurements as the prepared emulsions did not exhibit viscosity instabilities deriving during storage. Moreover, emulsions containing Vitamin A exhibited higher UV protection than the other emulsions, as the W/O emulsion containing 2% wt Vitamin A presented the highest SPF value at 22.6