Do probiotic interventions improve female unexplained infertility? A critical commentary.

Disruption of women's gut and cervicovaginal microbiota has been associated with multiple gynaecological diseases such as endometriosis, polycystic ovary syndrome, non-cyclic pelvic pain and infertility. Female infertility affects 12.6% of women worldwide; its aetiology is complex and multifactorial and can be underpinned by uterine pathologies, systemic diseases and age. In addition, a new perspective has emerged on the role of the gut and vaginal microbiomes in reproductive health. Research shows that the administration of precisely selected probiotics, often in combination with prior antibiotic treatment, may facilitate the restoration of symbiotic microbiota to increase successful conception and assisted reproductive technology outcomes. However, clarity on this issue from fuller research is currently hampered by a lack of consistency and harmonization in clinical studies: various lactobacilli and bifidobacteria species have been delivered through both the oral and vaginal routes, in different dosages, for different treatment durations. This commentary explores the intricate relationship between the microbiota in the cervicovaginal area and gut of women, exploring their potential contribution to infertility. It highlights ongoing research on the use of probiotic formulations in improving pregnancy outcomes, critically examining the divergent findings in these studies, which complicate a conclusive assessment of the efficacy of these interventions.

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter.

Intestinal efflux transporters affect the gastrointestinal processing of many drugs but further data on their intestinal expression levels are required. Relative mRNA expression and relative and absolute protein expression data of transporters are commonly measured by real-time polymerase chain reaction (RT-PCR), Western blot and mass spectrometry-based targeted proteomics techniques. All of these methods, however, have their own strengths and limitations, and therefore, validation for optimized quantification methods is needed. As such, the identification of the most appropriate technique is necessary to effectively translate preclinical findings to first-in-human trials. In this study, the mRNA expression and protein levels of the efflux transporter P-glycoprotein (P-gp) in jejunal and ileal epithelia of 30 male and female human subjects, and the duodenal, jejunal, ileal and colonic tissues in 48 Wistar rats were quantified using RT-PCR, Western blot and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A similar sex difference was observed in the expression of small intestinal P-gp in humans and Wistar rats where P-gp was higher in males than females with an increasing trend from the proximal to the distal parts in both species. A strong positive linear correlation was determined between the Western blot data and LC-MS/MS data in the small intestine of humans (R2 = 0.85). Conflicting results, however, were shown in rat small intestinal and colonic P-gp expression between the techniques (R2 = 0.29 and 0.05, respectively). In RT-PCR and Western blot, an internal reference protein is experimentally required; here, beta-actin was used which is innately variable along the intestinal tract. Quantification via LC-MS/MS can provide data on P-gp expression without the need for an internal reference protein and consequently, can give higher confidence on the expression levels of P-gp along the intestinal tract. Overall, these findings highlight similar trends between the species and suggest that the Wistar rat is an appropriate preclinical animal model to predict the oral drug absorption of P-gp substrates in the human small intestine.

A Proof of Concept for 3D Printing of Solid Lipid-Based Formulations of Poorly Water-Soluble Drugs to Control Formulation Dispersion Kinetics.

PURPOSE: The use of three-dimensional printing (3DP) in the development of pharmaceutical dosage forms is growing rapidly. However, the research is almost exclusively focussed on polymer-based systems with very little reported on 3D printing of lipid-based formulations. Thus, the aim of the work was to explore the feasibility of 3DP technology to prepare solid lipid-based formulations. Here, 3DP was applied for the preparation of solid self-microemulsifying drug delivery systems (S-SMEDDS) with defined surface area to volume (SA/V) ratios. METHODS: The S-SMEDDS formulations, comprised of Gelucire® 44/14, Gelucire® 48/16 and Kolliphor® P 188 were loaded with fenofibrate or cinnarizine as model drugs. The formulations were printed into four geometrical shapes - cylindrical, prism, cube and torus, and compared to a control cube manually prepared from bulk formulation. RESULTS: The printing process was not significantly affected by the presence of the model drugs. The as-printed S-SMEDDS formulations were characterised using differential scanning calorimetry and wide-angle X-ray scattering. The kinetics of dispersion depended on the SA/V ratio values. The digestion process was affected by the initial geometry of the dosage form by virtue of the kinetics of dispersion of the dosage forms into the digestion medium. CONCLUSIONS: This proof of concept study has demonstrated the potential of 3DP for the development of customised S-SMEDDS formulations without the need for an additional carrier or additive and with optimisation could elaborate a new class of dosage forms based on 3D printed lipids. Graphical abstract Lipid based formulations were 3D printed in various shapes to control the surface are to volume ratio and consequently the kinetics of dispersion.

Correction to: Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Low Dose.

The original version of the article unfortunately contained an error in article title. The corrected title is 'Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Low Dose'.

Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose.

BACKGROUND: Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium. difficile infection (rCDI). FMT capsules have emerged, and it is unknown if delivery location and dose impact efficacy. METHODS: We compared two cohorts of patients receiving two capsule formulations: gastric release (FMTgr) and targeted colonic release (FMTcr) at two different sites. Cohort A received FMTgr at (1) high dose: 60 capsules and low dose: 30 capsules. Patients in Cohort B received FMTcr at (1) high dose: 30 capsules (2) low dose: 10 capsules. Clinical cure rates and adverse events were monitored through week 8. Paired t-tests were used to compare diversity pre- and post-FMT. RESULTS: 51 rCDI patients were enrolled. Cohort A contained n = 20 and Cohort B contained n = 31. Overall cure at week 8 for FMTgr was 75% (15/20) compared to 80.6% for FMTcr, (25/31), p = 0.63. Both formulations were safe with no serious adverse events. FMTcr was superior at increasing gut microbial diversity. DISCUSSION: To our knowledge, this is the first study to compare targeted delivery of FMT capsules. While both capsules were safe and efficacious, microbial engraftment patterns were superior in FMTcr.

An Overview of 3D Printing Technologies for Soft Materials and Potential Opportunities for Lipid-based Drug Delivery Systems.

PURPOSE: Three-dimensional printing (3DP) is a rapidly growing additive manufacturing process and it is predicted that the technology will transform the production of goods across numerous fields. In the pharmaceutical sector, 3DP has been used to develop complex dosage forms of different sizes and structures, dose variations, dose combinations and release characteristics, not possible to produce using traditional manufacturing methods. However, the technology has mainly been focused on polymer-based systems and currently, limited information is available about the potential opportunities for the 3DP of soft materials such as lipids. METHODS: This review paper emphasises the most commonly used 3DP technologies for soft materials such as inkjet printing, binder jetting, selective laser sintering (SLS), stereolithography (SLA), fused deposition modeling (FDM) and semi-solid extrusion, with the current status of these technologies for soft materials in biological, food and pharmaceutical applications. RESULT: The advantages of 3DP, particularly in the pharmaceutical field, are highlighted and an insight is provided about the current studies for lipid-based drug delivery systems evaluating the potential of 3DP to fabricate innovative products. Additionally, the challenges of the 3DP technologies associated with technical processing, regulatory and material issues of lipids are discussed in detail. CONCLUSION: The future utility of 3DP for printing soft materials, particularly for lipid-based drug delivery systems, offers great advantages and the technology will potentially support patient compliance and drug effectiveness via a personalised medicine approach.

Influence of Geometry on the Drug Release Profiles of Stereolithographic (SLA) 3D-Printed Tablets.

Additive manufacturing (3D printing) permits the fabrication of tablets in shapes unattainable by powder compaction, and so the effects of geometry on drug release behavior is easily assessed. Here, tablets (printlets) comprising of paracetamol dispersed in polyethylene glycol were printed using stereolithographic 3D printing. A number of geometric shapes were produced (cube, disc, pyramid, sphere and torus) with either constant surface area (SA) or constant surface area/volume ratio (SA/V). Dissolution testing showed that printlets with constant SA/V ratio released drug at the same rate, while those with constant SA released drug at different rates. A series of tori with increasing SA/V ratio (from 0.5 to 2.4) were printed, and it was found that dissolution rate increased as the SA/V ratio increased. The data show that printlets can be fabricated in multiple shapes and that dissolution performance can be maintained if the SA/V ratio is constant or that dissolution performance of printlets can be fine-tuned by varying SA/V ratio. The results suggest that 3D printing is therefore a suitable manufacturing method for personalized dosage forms.

Toward oral delivery of biopharmaceuticals: an assessment of the gastrointestinal stability of 17 peptide drugs.

A major barrier to successful oral delivery of peptide and protein molecules is their inherent instability in the lumen of the gastrointestinal tract. The aim of this study was to determine the stability of 17 disparate peptide drugs (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, [Arg(8)]-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [d-Ser](4)-gonadorelin, deslorelin, and goserelin) in gastric and small intestinal fluids from both humans and pigs, and in simulated gastric and intestinal fluids. In human gastric fluid, the larger peptides including somatostatin, calcitonin, secretin, glucagon, and insulin were metabolized rapidly, while the smaller peptides showed good stability. In human small intestinal fluid, however, both small and large peptides degraded rapidly with the exception of the cyclic peptide ciclosporin and the disulfide-bridge containing peptides octreotide and desmopressin, which showed good stability. The stability of peptides in both simulated gastric fluid and pig gastric fluid correlated well with stability in human gastric fluid. However, it was not possible to establish such a correlation with the small intestinal fluids because of the rapid rate of peptide degradation. This work has identified the molecular features in the structure of a wide range of peptides that influence their stability in the environment of the gastrointestinal tract, which in turn will allow for better selection of peptide candidates for oral delivery.

3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics.

Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.

The role of artificial intelligence in generating original scientific research.

Artificial intelligence (AI) is a revolutionary technology that is finding wide application across numerous sectors. Large language models (LLMs) are an emerging subset technology of AI and have been developed to communicate using human languages. At their core, LLMs are trained with vast amounts of information extracted from the internet, including text and images. Their ability to create human-like, expert text in almost any subject means they are increasingly being used as an aid to presentation, particularly in scientific writing. However, we wondered whether LLMs could go further, generating original scientific research and preparing the results for publication. We taskedGPT-4, an LLM, to write an original pharmaceutics manuscript, on a topic that is itself novel. It was able to conceive a research hypothesis, define an experimental protocol, produce photo-realistic images of 3D printed tablets, generate believable analytical data from a range of instruments and write a convincing publication-ready manuscript with evidence of critical interpretation. The model achieved all this is less than 1 h. Moreover, the generated data were multi-modal in nature, including thermal analyses, vibrational spectroscopy and dissolution testing, demonstrating multi-disciplinary expertise in the LLM. One area in which the model failed, however, was in referencing to the literature. Since the generated experimental results appeared believable though, we suggest that LLMs could certainly play a role in scientific research but with human input, interpretation and data validation. We discuss the potential benefits and current bottlenecks for realising this ambition here.

Inkjet Printing of Pharmaceuticals.

Inkjet printing (IJP) is an additive manufacturing process that selectively deposits ink materials, layer-by-layer, to create 3D objects or 2D patterns with precise control over their structure and composition. This technology has emerged as an attractive and versatile approach to address the ever-evolving demands of personalized medicine in the healthcare industry. Although originally developed for nonhealthcare applications, IJP harnesses the potential of pharma-inks, which are meticulously formulated inks containing drugs and pharmaceutical excipients. Delving into the formulation and components of pharma-inks, the key to precise and adaptable material deposition enabled by IJP is unraveled. The review extends its focus to substrate materials, including paper, films, foams, lenses, and 3D-printed materials, showcasing their diverse advantages, while exploring a wide spectrum of therapeutic applications. Additionally, the potential benefits of hardware and software improvements, along with artificial intelligence integration, are discussed to enhance IJP's precision and efficiency. Embracing these advancements, IJP holds immense potential to reshape traditional medicine manufacturing processes, ushering in an era of medical precision. However, further exploration and optimization are needed to fully utilize IJP's healthcare capabilities. As researchers push the boundaries of IJP, the vision of patient-specific treatment is on the horizon of becoming a tangible reality.

3D printed dispersible efavirenz tablets: A strategy for nasogastric administration in children.

Enteral feeding tubes (EFTs) can be placed in children diagnosed with HIV which need nutritional support due to malnutrition. EFTs are the main route for medication administration in these patients, bringing up concerns about off label use of medicines, dose inaccuracy and tube clogging. Here we report for the first time the use of selective laser sintering (SLS) 3D printing to develop efavirenz (EFZ) dispersible printlets for patients with HIV that require EFT administration. Water soluble polymers Parteck® MXP and Kollidon® VA64 were used to obtain both 500 mg (P500 and K500) and 1000 mg printlets (P1000 and K1000) containing 200 mg of EFZ each. The use of SLS 3D printing obtained porous dosage forms with high drug content (20 % and 40 % w/w) and drug amorphization using both polymers. P500, K500 and K1000 printlets reached disintegration in under 230 s in 20 mL of water (25 ± 1 °C), whilst P1000 only partially disintegrated, possibly due to saturation of the polymer in the medium. As a result, the development of dispersible EFZ printlets using hydrophilic polymers can be explored as a potential strategy for drug delivery through EFTs in paediatrics with HIV, paving the way towards the exploration of more rapidly disintegrating polymers and excipients for SLS 3D printing.

Visualizing disintegration of 3D printed tablets in humans using MRI and comparison with in vitro data.

Three-dimensional (3D) printing is revolutionising the way that medicines are manufactured today, paving the way towards more personalised medicine. However, there is limited in vivo data on 3D printed dosage forms, and no studies to date have been performed investigating the intestinal behaviour of these drug products in humans, hindering the complete translation of 3D printed medications into clinical practice. Furthermore, it is unknown whether conventional in vitro release tests can accurately predict the in vivo performance of 3D printed formulations in humans. In this study, selective laser sintering (SLS) 3D printing technology has been used to produce two placebo torus-shaped tablets (printlets) using different laser scanning speeds. The printlets were administered to 6 human volunteers, and in vivo disintegration times were assessed using magnetic resonance imaging (MRI). In vitro disintegration tests were performed using a standard USP disintegration apparatus, as well as an alternative method based on the use of reduced media volume and minimal agitation. Printlets fabricated at a laser scanning speed of 90 mm/s exhibited an average in vitro disintegration time of 7.2 ± 1 min (measured using the USP apparatus) and 25.5 ± 4.1 min (measured using the alternative method). In contrast, printlets manufactured at a higher laser scanning speed of 130 mm/s had an in vitro disintegration time of 2.8 ± 0.8 min (USP apparatus) and 18.8 ± 1.9 min (alternative method). When tested in humans, printlets fabricated at a laser scanning speed of 90 mm/s showed an average disintegration time of 17.3 ± 7.2 min, while those manufactured at a laser scanning speed of 130 mm/s exhibited a shorter disintegration time of 12.7 ± 6.8 min. Although the disintegration times obtained using the alternative method more closely resembled those obtained in vivo, no clear correlation was observed between the in vitro and in vivo disintegration times, highlighting the need to develop better in vitro methodology for 3D printed drug products.

Electroactive Polymers for On-Demand Drug Release.

Conductive materials have played a significant role in advancing society into the digital era. Such materials are able to harness the power of electricity and are used to control many aspects of daily life. Conductive polymers (CPs) are an emerging group of polymers that possess metal-like conductivity yet retain desirable polymeric features, such as processability, mechanical properties, and biodegradability. Upon receiving an electrical stimulus, CPs can be tailored to achieve a number of responses, such as harvesting energy and stimulating tissue growth. The recent FDA approval of a CP-based material for a medical device has invigorated their research in healthcare. In drug delivery, CPs can act as electrical switches, drug release is achieved at a flick of a switch, thereby providing unprecedented control over drug release. In this review, recent developments in CP as electroactive polymers for voltage-stimuli responsive drug delivery systems are evaluated. The review demonstrates the distinct drug release profiles achieved by electroactive formulations, and both the precision and ease of stimuli response. This level of dynamism promises to yield "smart medicines" and warrants further research. The review concludes by providing an outlook on electroactive formulations in drug delivery and highlighting their integral roles in healthcare IoT.

Developing an innovative 3D printing platform for production of personalised medicines in a hospital for the OPERA clinical trial.

Breast cancer is the most frequently diagnosed cancer in women worldwide, and non-adherence to adjuvant hormonotherapy can negatively impact cancer recurrence and relapse. Non-adherence is associated with side effects of hormonotherapy. Pharmacological strategies to mitigate the side effects include coadministration of antidepressants, however patients remain non-adherent. The aim of this work was to develop medicines containing both hormonotherapy, tamoxifen (20 mg), along with anti-depressants, either venlafaxine (37.5 or 75 mg) or duloxetine (30 or 60 mg), to assess the acceptability and efficacy of this personalised approach for mitigating tamoxifen side effects in a clinical trial. A major criterion for the developed medicines was the production rate, specified at minimum 200 dosage units per hour to produce more than 40,000 units required for the clinical trial. A novel capsule filling approach enabled by the pharmaceutical 3D printer M3DIMAKER 2 was developed for this purpose. Firstly, semi-solid extrusion 3D printing enabled the filling of tamoxifen pharma-ink prepared according to French compounding regulation, followed by filling of commercial venlafaxine or duloxetine pellets enabled by the development of an innovative pellet dispensing printhead. The medicines were successfully developed and produced in the clinical pharmacy department of the cancer hospital Gustave Roussy, located in Paris, France. The developed medicines satisfied quality and production rate requirements and were stable for storage up to one year to cover the duration of the trial. This work demonstrates the feasibility of developing and producing combined tamoxifen medicines in a hospital setting through a pharmaceutical 3D printer to enable a clinical trial with a high medicines production rate requirement.

Can in vitro/in silico tools improve colonic concentration estimations for oral extended-release formulations? A case study with upadacitinib.

Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an in vitro-in vivo correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma Cmax and AUC were most accurate for USP IV compared to the other models (based on predicted versus observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific in vitro assays.

The colon targeting efficacies of mesalazine medications and their impacts on the gut microbiome.

Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.

Customizable orodispersible films: Inkjet printing and data matrix encoding for personalized hydrocortisone dosing.

The aim of this study was to exploit the versatility of inkjet printing to develop flexible doses of drug-loaded orodispersible films that encoded information in a data matrix pattern, and to introduce a specialised data matrix-generator software specifically focused on the healthcare sector. Pharma-inks (drug-loaded inks) containing hydrocortisone (HC) were developed and characterised based on their rheological properties and drug content. Different strategies were investigated to improve HC solubility: formation of ß-cyclodextrin complexes, Soluplus® based micelles, and the use of co-solvent systems. The software automatically adapted the data matrix size and identified the number of layers for printing. HC content deposited in each film layer was measured, and it was found that the proportion of co-solvent used directly affected the drug solubility and simultaneously played a role in the modification of the viscosity and surface tension of the inks. The formation of ß-cyclodextrin complexes improved the drug quantity deposited in each layer. On the contrary, micelle-based inks were not suitable for printing. Orodispersible films containing flexible and low doses of personalised HC were successfully prepared, and the development of a code generator software oriented to medical use provided an additional, innovative, and revolutionary advantage to personalised medicine safety and accessibility.

Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders.

Rare diseases are infrequent, but together they affect up to 6-10 % of the world's population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants' responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

Poly(D,l-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids.

The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs.