Evaluation of the printability of agar and hydroxypropyl methylcellulose gels as gummy formulations: Insights from rheological properties.

The trial-and-error method currently used to create formulations with excellent printability demands considerable time and resources, primarily due to the increasing number of variables involved. Rheology serves as a relatively rapid and highly beneficial method for assessing materials and evaluating their effectiveness as 3D constructs. However, the data obtained can be overwhelming, especially for users lacking experience in this field. This study examined the rheological properties of formulations of agar, hydroxypropyl methylcellulose, and the model drug caffeine, alongside exploring their printability as gummy formulations. The gels' rheological properties were characterized using oscillatory and rotational experiments. The correlation between these gels' rheological properties and their printability was established, and three clusters were formed based on the rheological properties and printability of the samples using principal component analysis. Furthermore, the printability was predicted using the sample's rheological property that correlated most with printability, the phase angle δ, and the regression models resulted in an accuracy of over 80%. Although these relationships merit confirmation in later studies, this study suggests a quantitative definition of the relationship between printability and one rheological property and can be used for the development of formulations destined for extrusion 3D printing.

Potentially Harmful Excipients: State of the Art for Oral Liquid Forms Used in Neonatology and Pediatrics Units.

The pediatric population exhibits an important age-dependent heterogeneity in pharmacokinetics and pharmacodynamics parameters, resulting in differences in drug efficacy and toxicity compared to the adult population, particularly for neonates. Toxicity and efficacy divergences have been studied for active molecules, but the impact on the pharmacological parameters of excipients remains less well known. To fill this lack of knowledge, several initiatives have been started to gather information on the specific toxicity of excipients, such as the KIDS list or the STEP database. In order to contribute to this much-needed action, in this work, a compilation of the 219 formulations of oral liquid forms prescribed in pediatrics and neonatology units was established based on the summary of product characteristics. Then, for excipients found in more than 10% of the analyzed formulations, a review of their toxicity data was carried out using the STEP database. Finally, for a selection of 10 frequently used liquid forms, the amounts of excipients administered daily were calculated based on the recommended posology in the Summary of Product Characteristics (SPC) and compared with the recommended daily limits proposed by the European Medicine Agency. Pediatrics-adapted formulations are still rare, and it is not always possible to find safe alternatives to drugs containing excipients of interest.

Fused Deposition Modelling 3D printing and solubility improvement of BCS II and IV active ingredients - A narrative review.

In the field of pharmaceutical research and development, Fused Deposition Modelling (FDM) 3D printing (3DP) has aroused growing interest within the last ten years. The use of thermoplastic polymers, combined with the melting process of the raw materials, offers the possibility of manufacturing amorphous solid dispersions (ASDs). In the pharmaceutical industry, the formulation of an ASD is a widely used strategy to improve the solubility of poorly soluble drugs (classified by the Biopharmaceutical Classification System (BCS) as class II and IV). In this review, an analysis of studies that have developed a FDM printed form containing a BCS class II or IV active substance was performed. The focus has been placed on the evaluation of the solid state of the active molecules (crystalline or amorphous) and on the study of their dissolution profile. Thus, the aim of this work is to highlight the interest of FDM 3DP to induce the amorphisation phenomenon of Class II and IV active substances by forming an ASD, and as result improving their solubility.

Preliminary Study on the Development of Caffeine Oral Solid Form 3D Printed by Semi-Solid Extrusion for Application in Neonates.

Apnea of prematurity can be treated with a body-weight-adjusted dosage of caffeine. Semi-solid extrusion (SSE) 3D printing represents an interesting approach to finely tailor personalized doses of active ingredients. To improve compliance and ensure the right dose in infants, drug delivery systems such as oral solid forms (orodispersible film, dispersive form, and mucoadhesive form) can be considered. The aim of this work was to obtain a flexible-dose system of caffeine by SSE 3D printing by testing different excipients and printing parameters. Gelling agents (sodium alginate (SA) and hydroxypropylmethyl cellulose (HPMC)) were used to obtain a drug-loaded hydrogel matrix. Disintegrants (sodium croscarmellose (SC) and crospovidone (CP)) were tested for get rapid release of caffeine. The 3D models were patterned by computer-aided design with variable thickness, diameter, infill densities, and infill patterns. The oral forms produced from the formulation containing 35% caffeine, 8.2% SA, 4.8% HPMC, and 52% SC (w/w) were found to have good printability, achieving doses approaching to those used in neonatology (between 3 and 10 mg of caffeine for infants weighing approximately between 1 and 4 kg). However, disintegrants, especially SC, acted more as binder/filler, showing interesting properties to maintain the shape after extrusion and enhance printability without a significant effect on caffeine release.

Decellularized Spinach Biomaterials Support Physiologically Relevant Mechanical Cyclic Strain and Prompt a Stretch-Induced Cellular Response.

Recently, decellularized plant biomaterials have been explored for their use as tissue engineered substitutes. Herein, we expanded upon the investigation of the mechanical properties of these materials to explore their elasticity as many anatomical areas of the body require biomechanical dynamism. We first constructed a device to secure the scaffold and induce a strain within the physiological range of the normal human adult lung during breathing (12-20 movements/min; 10-20% elongation). Results showed that decellularized spinach leaves can support cyclic strain for 24 h and displayed heterogeneous local strain values (7.76-15.88%) as well as a Poisson's ratio (0.12) similar to that of mammalian lungs (10.67-19.67%; 0.01), as opposed to an incompressible homogeneous standard polymer (such as PDMS (10.85-12.71%; 0.4)). Imaging and mechanical testing showed that the vegetal scaffold exhibited strain hardening but maintained its structural architecture and water retention capacity, suggesting an unaltered porosity. Interestingly, we also showed that cells seeded on the scaffold can also sense the mechanical strain as demonstrated by a nuclear reorientation perpendicular to strain direction (63.3° compared to 41.2° for nonstretched cells), a nuclear location of YAP and increased expression of YAP target genes, a high cytoplasmic calcium level, and an elevated expression level of collagen genes (COL1A1, COL3A1, COL4A1, and COL6A) with an increased collagen secretion at the protein level. Taken together, these data demonstrated that decellularized plant leaf tissues have an inherent elastic property similar to that found in the mammalian system to which cells can sense and respond.

Alginate ester: New moisture-scavenging excipients for direct compressible pharmaceutical tableting.

The objective of this work is to evaluate methyl ester alginates and alginic acid (AA) as moisture-scavenging excipients for the formulation of aspirin tablets obtained by direct compression. The tablets were stored at accelerated conditions (40 °C/75 % RH) and assessed for changes in tensile strength, mass, thickness and disintegration time. While moisture caused a reduction in the hardness of MCC and AA tablets, hardness of the tablets made from methylated materials was virtually unaffected. The physical stability of alginate ester tablets was found to be related to their increased plastic deformation leading to extended interparticle contact with less impact on tablet porosity. Finally, the combination of higher moisture affinity and lower water dissociation exhibited by alginates esters resulted in tablets with the lowest aspirin degradation. These findings suggest that excipients with high water retention can act as moisture-scavengers without losing their functional properties and reducing the degradation of moisture-sensitive drugs.

Feasibility of Neovessel Embolization in a Large Animal Model of Tendinopathy: Safety and Efficacy of Various Embolization Agents.

Targeting neovessels in chronic tendinopathies has emerged as a new therapeutic approach and several embolization agents have been reported. The aim of this study was to investigate the feasibility of embolization with different agents in a porcine model of patellar tendinopathy and evaluate their safety and efficacy. Eight 3-month-old male piglets underwent percutaneous injection of collagenase type I to induce patellar tendinopathies (n = 16 tendons). They were divided into four groups (2 piglets, 4 tendons/group): the control group, 50-100 µm microspheres group, 100-300 µm microspheres group, and the Imipenem/Cilastatin (IMP/CS) group. Angiography and embolization were performed for each patellar tendon on day 7 (D7). The neovessels were evaluated visually with an angiography on day 14. The pathological analysis assessed the efficacy (Bonar score, number of neovessels/mm2) and safety (off-target persistent cutaneous ischemic modifications and presence of off-target embolization agents). The technical success was 92%, with a failed embolization for one tendon due to an arterial dissection. Neoangiogenesis was significantly less important in the embolized groups compared to the control group angiographies (p = 0.04) but not with respect to histology (Bonar score p = 0.15, neovessels p = 0.07). Off-target cutaneous embolization was more frequently depicted in the histology of the 50-100 µm microspheres group (p = 0.02). Embolization of this animal model with induced patellar tendinopathy was technically feasible with different agents and allowed assessing the safety and efficacy of neovessel destruction. Particles smaller than 100 µm seemed to be associated with more complications.

A QbD Approach for Evaluating the Effect of Selective Laser Sintering Parameters on Printability and Properties of Solid Oral Forms.

The aim of this work was to investigate the effect of process parameters on the printability of a formulation containing copovidone and paracetamol, and on the properties of solid oral forms 3D-printed through selective laser sintering. Firstly, the influence of the heating temperature was evaluated individually, and it was revealed that this parameter was critical for printability, as a sufficiently high temperature (100 °C) is necessary to avoid curling. Secondly, the effects of laser power, scan speed, and layer thickness were determined using a Box-Behnken design. The measured responses, printing yield, height, weight, hardness, disintegration time, and percentage of drug release at 10 min showed the following ranges of values: 55.6-100%, 2.92-3.96 mm, 98.2-187.2 mg, 9.2-83.4 N, 9.7-997.7 s, and 25.8-99.9%, respectively. Analysis of variance (ANOVA) proved that the generated quadratic models and the effect of the three-process parameters were significant (p < 0.05). Yield improved at high laser power, low scan speed, and increased layer thickness. Height was proportional to laser power, and inversely proportional to scan speed and layer thickness. Variations in the other responses were related to the porosity of the SOFs, which were dependent on the value of energy density. Low laser power, fast scan speed, and high layer thickness values favored a lower energy density, resulting in low weight and hardness, rapid disintegration, and a high percentage of drug release at 10 min. Finally, an optimization was performed, and an additional experiment validated the model. In conclusion, by applying a Quality by Design approach, this study demonstrates that process parameters are critical for printability, but also offer a way to personalize the properties of the SOFs.

Investigating the Potential Plasticizing Effect of Di-Carboxylic Acids for the Manufacturing of Solid Oral Forms with Copovidone and Ibuprofen by Selective Laser Sintering.

In selective laser sintering (SLS), the heating temperature is a critical parameter for printability but can also be deleterious for the stability of active ingredients. This work aims to explore the plasticizing effect of di-carboxylic acids on reducing the optimal heating temperature (OHT) of polymer powder during SLS. First, mixtures of copovidone and di-carboxylic acids (succinic, fumaric, maleic, malic and tartaric acids) as well as formulations with two forms of ibuprofen (acid and sodium salt) were prepared to sinter solid oral forms (SOFs), and their respective OHT was determined. Plasticization was further studied by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). Following this, the printed SOFs were characterized (solid state, weight, hardness, disintegration time, drug content and release). It was found that all acids (except tartaric acid) reduced the OHT, with succinic acid being the most efficient. In the case of ibuprofen, only the acid form demonstrated a plasticizing effect. DSC and FTIR corroborated these observations showing a decrease in the glass transition temperature and the presence of interactions, respectively. Furthermore, the properties of the sintered SOFs were not affected by plasticization and the API was not degraded in all formulations. In conclusion, this study is a proof-of-concept that processability in SLS can improve with the use of di-carboxylic acids.

Sodium alginate and alginic acid as pharmaceutical excipients for tablet formulation: Structure-function relationship.

Alginic acid and its sodium salt are well-accepted pharmaceutical excipients fulfilling several roles in the development of solid oral dosage forms. Although they have attractive advantages as safety, abundance, relatively low cost and biodegradability, these natural polysaccharides possess a high variability that may limit their use as excipients for tablet formulation. Thus, to obtain robust formulations and high-quality drug products with consistent performance a complete understanding of the structure-property relationship becomes necessary as the structure of alginates affects both, technological and biopharmaceutical properties. This review compiles the compaction studies carried out that relate the structure of alginates to their mechanical and dissolution performances. The different analytical methods used to determine the chemical composition, primary structure and molecular weight distribution, major factors affecting the behavior of alginates in direct compression, are also exposed. Finally, different strategies reported to improve the properties of alginic acid as direct compression excipient are discussed.

Selective Laser Sintering (SLS), a New Chapter in the Production of Solid Oral Forms (SOFs) by 3D Printing.

3D printing is a new emerging technology in the pharmaceutical manufacturing landscape. Its potential advantages for personalized medicine have been widely explored and commented on in the literature over recent years. More recently, the selective laser sintering (SLS) technique has been investigated for oral drug-delivery applications. Thus, this article reviews the work that has been conducted on SLS 3D printing for the preparation of solid oral forms (SOFs) from 2017 to 2020 and discusses the opportunities and challenges for this state-of-the-art technology in precision medicine. Overall, the 14 research articles reviewed report the use of SLS printers equipped with a blue diode laser (445-450 nm). The review highlights that the printability of pharmaceutical materials, although an important aspect for understanding the sintering process has only been properly explored in one article. The modulation of the porosity of printed materials appears to be the most interesting outcome of this technology for pharmaceutical applications. Generally, SLS shows great potential to improve compliance within fragile populations. The inclusion of "Quality by Design" tools in studies could facilitate the deployment of SLS in clinical practice, particularly where Good Manufacturing Practices (GMPs) for 3D-printing processes do not currently exist. Nevertheless, drug stability and powder recycling remain particularly challenging in SLS. These hurdles could be overcome by collaboration between pharmaceutical industries and compounding pharmacies.

D-Sorbitol Physical Properties Effects on Filaments Used by 3D Printing Process for Personalized Medicine.

Fused filament fabrication (FFF) is a process used to manufacture oral forms adapted to the needs of patients. Polyethylene oxide (PEO) filaments were produced by hot melt extrusion (HME) to obtain a filament suitable for the production of amiodarone hydrochloride oral forms by FFF 3D printing. In order to produce personalized oral forms adapted to the patient characteristics, filaments used by FFF must be controlled in terms of mass homogeneity along filament. This work highlights the relation between filament mass homogeneity and its diameter. This is why the impact of filler excipients physical properties was studied. It has been showed that the particle's size distribution of the filler can modify the filament diameter variability which has had an impact on the mass of oral forms produced by FFF. Through this work it was shown that D-Sorbitol from Carlo Erba allows to obtain a diameter variability of less than 2% due to its unique particle's size distribution. Using the filament produced by HME and an innovating calibration method based on the filament length, it has been possible to carry out three dosages of 125 mg, 750 mg and 1000 mg by 3D printing with acceptable mass uniformity.

Performance Evaluation of a Novel Biosourced Co-Processed Excipient in Direct Compression and Drug Release.

This study exposes the potential usefulness of a new co-processed excipient, composed of alginic acid and microcrystalline cellulose (Cop AA-MCC), for the preparation of immediate drug release tablets by direct compression. Evaluation of the physical and mechanical properties as well as the disintegration behavior of Cop AA-MCC in comparison to commercial co-processed excipients (Cellactose®, Ludipress®, Prosolv® SMCC HD90 and Prosolv® ODT) and to the physical mixture of the native excipients (MCC and AA), was carried out. The obtained results illustrate the good performance of Cop AA-MCC in terms of powder flowability, tablet tensile strength, compressibility, and disintegration time. Although, this new co-processed excipient showed a slightly high lubricant sensitivity, which was explained by its more plastic than fragmentary deformation behavior, it presented a low lubricant requirement due to the remarkably low ejection force observed during compression. Compression speed and dwell time seemed not to affect significantly the tabletability of Cop AA-MCC. The study exposed evenly the performance of Cop AA-MCC compared to Prosolv® ODT, in terms of tabletability and dissolution rate of Melatonin. Cop AA-MCC presented comparable hardness, lower dilution potential, higher lubricant sensitivity, lower ejection force, and faster Melatonin's release time than Prosolv® ODT. In summary, Cop AA-MCC exhibited interesting physical, mechanical, and biopharmaceutical properties, which demonstrate its concurrence to commercially available co-processed excipients. Furthermore, the simplicity of its composition and the scalability of its elaboration makes this multifunctional excipient highly recommended for direct compression.

Production of Reproducible Filament Batches for the Fabrication of 3D Printed Oral Forms.

Patients need medications at a dosage suited to their physiological characteristics. Three-dimensional printing (3DP) technology by fused-filament fabrication (FFF) is a solution for manufacturing medication on demand. The aim of this work was to identify important parameters for the production of reproducible filament batches used by 3DP for oral formulations. Amiodarone hydrochloride, an antiarrhythmic and insoluble drug, was chosen as a model drug because of dosage adaptation need in children. Polyethylene oxide (PEO) filaments containing amiodarone hydrochloride were produced by hot-melt extrusion (HME). Different formulation storage conditions were investigated. For all formulations, the physical form of the drug following HME and fused-deposition modeling (FDM) 3D-printing processes were assessed using thermal analysis and X-ray powder diffraction (XRPD). Filament mechanical properties, linear mass density and surface roughness, were investigated by, respectively, 3-point bending, weighing, and scanning electron microscopy (SEM). Analysis results showed that the formulation storage condition before HME-modified filament linear mass density and, therefore, the oral forms masses from a batch to another. To obtain constant filament apparent density, it has been shown that a constant and reproducible drying condition is required to produce oral forms with constant mass.

Selective Laser Sintering of Solid Oral Dosage Forms with Copovidone and Paracetamol Using a CO2 Laser.

Material suitability needs to be considered for the 3D printing of solid oral dosage forms (SODFs). This work aims to assess the suitability of a CO2 laser (λ = 10.6 µm) for selective laser sintering of SODFs containing copovidone and paracetamol. First, physicochemical characterization of powders (two grades of copovidone, two grades of paracetamol and their mixtures at various proportions) was conducted: particle size distribution, morphology, infrared absorbance, flowability, and compactness. Then, printing was launched, and printability of the powders was linked to their physicochemical characteristics. The properties of the sintered SODFs were evaluated (solid state, general aspect, porosity, hardness, drug content and release). Hence, it was found that as copovidone absorbs at the laser's wavelength, sintering was feasible without using an absorbance enhancer. Also, flowability, which mainly depends on the particle size, represents the first control line for "sinterability" as a fair flow is at least required. Low compactness of copovidone and mixtures reduces the mechanical properties of the SODFs but also increases porosity, which can modulate drug release. Moreover, the drug did not undergo degradation and demonstrated a plasticizer effect by lowering the heating temperature. In conclusion, this work proves the applicability of CO2 laser SLS printer to produce SODFs.

Collagenase-Induced Patellar Tendinopathy with Neovascularization: First Results towards a Piglet Model of Musculoskeletal Embolization.

BACKGROUND: Therapeutic strategies targeting neovessels responsible for musculoskeletal chronic pain have emerged, including neovessels embolization. Our study aimed to develop a large animal model of patellar tendinopathy with neovascularization. METHODS: Nine 3-month-old male piglets (18 patellar tendons) received percutaneous injections of increasing doses of collagenase (0 to 50 mg) at day 0 (D0). Tendinopathy was evaluated by ultrasound (D7 and D14). Neovascularization was evaluated visually and on angiographies. Bonar score was used for histological analysis (D14). Correlations were evaluated using Spearman's rank (Rs) test. RESULTS: Research protocol was well tolerated. All tendons were enlarged with a median increase of 31.58% [25-40.28] at D7 (p = 0.244) at D7 and 57.52% [48.41-91.45] at D14 (p = 0.065). Tendons with collagenase injection had more hypoechoic changes, with one tendon rupture (p = 0.012). Neovascularization was reported above 5 mg collagenase (p < 0.01) at D7 and D14 with dose-related neovessels induction (Rs = 0.8, p < 0.001). The Bonar score increased above 5 mg collagenase, correlated with the dose (Rs = 0.666, p = 0.003). CONCLUSIONS: The study shows the feasibility, safety and reproducibility of this new large animal model of patellar tendinopathy with neovascularization after collagenase injection. It will allow studying new treatments on direct embolization of neovessels by endovascular approach.

Fused Deposition Modeling (FDM), the new asset for the production of tailored medicines.

Over the last few years, conventional medicine has been increasingly moving towards precision medicine. Today, the production of oral pharmaceutical forms tailored to patients is not achievable by traditional industrial means. A promising solution to customize oral drug delivery has been found in the utilization of 3D Printing and in particular Fused Deposition Modeling (FDM). Thus, the aim of this systematic literature review is to provide a synthesis on the production of pharmaceutical solid oral forms using FDM technology. In total, 72 relevant articles have been identified via two well-known scientific databases (PubMed and ScienceDirect). Overall, three different FDM methods have been reported: "Impregnation-FDM", "Hot Melt Extrusion coupled with FDM" and "Print-fill", which yielded to the formulation of thermoplastic polymers used as main component, five families of other excipients playing different functional roles and 47 active ingredients. Solutions are underway to overcome the high printing temperatures, which was the initial brake on to use thermosensitive ingredients with this technology. Also, the moisture sensitivity shown by a large number of prints in preliminary storage studies is highlighted. FDM seems to be especially fitted for the treatment of rare diseases, and particular populations requiring tailored doses or release kinetics. For future use of FDM in clinical trials, an implication of health regulatory agencies would be necessary. Hence, further efforts would likely be oriented to the use of a quality approach such as "Quality by Design" which could facilitate its approval by the authorities, and also be an aid to the development of this technology for manufacturers.

Development of alginate esters as novel multifunctional excipients for direct compression.

Methyl ester derivatives of alginic acid have been evaluated as potential multifunctional excipients for pharmaceutical direct compression. The use of alginic acid as an excipient in tablet formulation is limited because of certain drawbacks such as low tablet hardness and poor compressibility. The objective of this work is to improve these properties through esterification of alginic acid, chemical modification commonly used for enhancing the functionality of tableting excipients. It has been observed that the degree of methylation (DM) has a profitable impact in the physico-chemical and mechanical properties of the obtained materials. In general, an increase in the degree of methylation yielded tablets with higher tensile strength and better compressibility. Furthermore, modified alginates exhibited extended disintegration times compared to native alginic acid due to the introduced hydrophobicity. Finally, the functional versatility of the modified alginates as disintegrating and filling/binding agents was tested by formulating them with microcrystalline cellulose and lactose.

Assessment of anti-infective medication adherence in pediatric outpatients.

The objective of this pilot study was to assess the overall adherence rate of the pediatric population to anti-infective drugs prescribed for acute infection at hospital discharge and to identify risk factors for non-adherence behavior. Pediatric patients discharged from a French university hospital with at least one oral drug prescription for acute infection were included for 3 months. Medication adherence and antibiotic knowledge were assessed through data collected by calling the parents. Overall adherence was assessed according to seven items: medication order filling, administered dose, time of intake, frequency of doses, medication omission, dose modification, and length of treatment. Seventy-five patients were included, and 63 interviews were exploited. The median age was 1.4 years, IQR = [0.7; 3.3]. Overall adherence to anti-infective agents concerned 34.9% of patients. The most frequently prescribed antibiotics were amoxicillin (29.3%), amoxicillin associated with clavulanic acid (25.3%), cotrimoxazole (18.7%), and cefixime (12.0%). A lack of parents' anti-infective knowledge was associated with non-adherence to anti-infective drugs.Conclusion: Two-thirds of outpatients were non-adherent to anti-infectives in acute infectious diseases. The misunderstanding of anti-infective treatment could be a risk factor for non-adherence. Implementation of preventive actions such as therapeutic education or pharmaceutical counseling at hospital discharge could improve adherence to anti-infective agents. What Is Known: • Non-adherence to anti-infective drugs involves the emergence and spread of antibiotic resistance. • Very few studies have assessed medication adherence in acute infectious diseases in pediatrics after hospital discharge. What Is New: • Only 35% of children were overall adherent to anti-infective drugs in acute infectious disease after hospital discharge. • Most patients (89%) had a good primary adherence but very few (40%) had good secondary adherence mainly due to dose omission and dose modification.