RESUMO
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.
Assuntos
Inteligência Artificial , Tecnologia Farmacêutica , Preparações Farmacêuticas , Impressão TridimensionalRESUMO
Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.
Assuntos
Colo/efeitos dos fármacos , Colo/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Produtos Biológicos/administração & dosagem , Preparações de Ação Retardada , Microbioma Gastrointestinal/fisiologia , Trânsito Gastrointestinal/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Síndrome do Intestino Irritável/tratamento farmacológico , Prebióticos/administração & dosagem , Impressão Tridimensional , Probióticos/administração & dosagem , Fatores de Tempo , Vacinas/administração & dosagemRESUMO
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.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Mucosa Intestinal/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Animais , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos/métodos , Duodeno/metabolismo , Feminino , Humanos , Íleo/metabolismo , Absorção Intestinal , Jejuno/metabolismo , Masculino , Pessoa de Meia-Idade , Ratos , Fatores Sexuais , Especificidade da Espécie , Espectrometria de Massas em TandemRESUMO
Artificial intelligence (AI) has the potential to reshape pharmaceutical formulation development through its ability to analyze and continuously monitor large datasets. Fused deposition modeling (FDM) three-dimensional printing (3DP) has made significant advancements in the field of oral drug delivery with personalized drug-loaded formulations being designed, developed and dispensed for the needs of the patient. The FDM 3DP process begins with the production of drug-loaded filaments by hot melt extrusion (HME), followed by the printing of a drug product using a FDM 3D printer. However, the optimization of the fabrication parameters is a time-consuming, empirical trial approach, requiring expert knowledge. Here, M3DISEEN, a web-based pharmaceutical software, was developed to accelerate FDM 3D printing using AI machine learning techniques (MLTs). In total, 614 drug-loaded formulations were designed from a comprehensive list of 145 different pharmaceutical excipients, 3D printed and assessed in-house. To build the predictive tool, a dataset was constructed and models were trained and tested at a ratio of 75:25. Significantly, the AI models predicted key fabrication parameters with accuracies of 76% and 67% for the printability and the filament characteristics, respectively. Furthermore, the AI models predicted the HME and FDM processing temperatures with a mean absolute error of 8.9 °C and 8.3 °C, respectively. Strikingly, the AI models achieved high levels of accuracy by solely inputting the pharmaceutical excipient trade names. Therefore, AI provides an effective holistic modeling technology and software to streamline and advance 3DP as a significant technology within drug development. M3DISEEN is available at (http://m3diseen.com/predictions/).
Assuntos
Inteligência Artificial , Tecnologia Farmacêutica , Liberação Controlada de Fármacos , Excipientes , Humanos , Aprendizado de Máquina , Impressão TridimensionalRESUMO
Maple syrup urine disease (MSUD) is a rare metabolic disorder with a worldwide prevalence of 1 in every 185,000 live births. However, certain populations display a significant overexpression of the disorder where incidence is reported to be 1 in every 52,541 new-borns. The first-line therapy for MSUD involves a strict dietary leucine restriction and oral supplementation of isoleucine and valine. The dose administered to patients requires strict tailoring according to age, weight and blood levels. In current clinical practice, however, practitioners still have to prepare extemporaneous formulations due to the lack of suitable oral treatments for MSUD. Herein, we evaluate the first time use of 3D printing in a hospital setting for the preparation of personalised therapies with the aim of improving safety and acceptability to isoleucine supplementation in paediatric patients suffering from MSUD. This investigation was a single-centre, prospective crossover experimental study. Four paediatric patients with MSUD (aged 3-16â¯years) were treated at the Clinic University Hospital in Santiago de Compostela, Spain which is a MSUD reference hospital in Europe. The primary objective was to evaluate isoleucine blood levels after six months of treatment with two types of formulations; conventional capsules prepared by manual compounding and personalised chewable formulations prepared by automated 3D printing. A secondary investigation was to evaluate patient acceptability of 3D printed formulations prepared with different flavours and colours. Isoleucine blood levels in patients were well controlled using both types of formulations, however, the 3D printed therapy showed mean levels closer to the target value and with less variability (200-400⯵M). The 3D printed formulations were well accepted by patients regarding flavour and colour. The study demonstrates for the first time that 3D printing offers a feasible, rapid and automated approach to prepare oral tailored-dose therapies in a hospital setting. 3D printing has shown to be an effective manufacturing technology in producing chewable isoleucine printlets as a treatment of MSUD with good acceptability.
Assuntos
Isoleucina/administração & dosagem , Doença da Urina de Xarope de Bordo/tratamento farmacológico , Impressão Tridimensional , Adolescente , Criança , Pré-Escolar , Corantes/administração & dosagem , Estudos Cross-Over , Formas de Dosagem , Feminino , Aromatizantes/administração & dosagem , Humanos , Masculino , Projetos Piloto , PaladarRESUMO
Iron supplements are widely consumed; however most of the iron is not absorbed and enters the colon where potentially pathogenic bacteria can utilise it for growth. This study investigated the effect of iron availability on human gut microbial composition and function using an in vitro colonic fermentation model inoculated with faecal microbiota from healthy adult donors, as well as examining the effect of iron on the growth of individual gut bacteria. Batch fermenters were seeded with fresh faecal material and supplemented with the iron chelator, bathophenanthroline disulphonic acid (BPDS). Samples were analysed at regular intervals to assess impact on the gut bacterial communities. The growth of Escherichia coli and Salmonella typhimurium was significantly impaired when cultured independently in iron-deficient media. In contrast, depletion of iron did not affect the growth of the beneficial species, Lactobacillus rhamnosus, when cultured independently. Analysis of the microbiome composition via 16S-based metataxonomics indicated that under conditions of iron chelation, the relative abundance decreased for several taxa, including a 10% decrease in Escherichia and a 15% decrease in Bifidobacterium. Metabolomics analysis using 1 H-NMR indicated that the production of SCFAs was reduced under iron-limited conditions. These results support previous studies demonstrating the essentiality of iron for microbial growth and metabolism, but, in addition, they indicate that iron chelation changes the gut microbiota profile and influences human gut microbial homeostasis through both compositional and functional changes.
Assuntos
Colo/microbiologia , Microbioma Gastrointestinal/fisiologia , Ferro/farmacocinética , Técnicas Bacteriológicas , Bifidobacterium/efeitos dos fármacos , Bifidobacterium/crescimento & desenvolvimento , Disponibilidade Biológica , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/patogenicidade , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Fermentação , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Microbiota , RNA Ribossômico 16S , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/crescimento & desenvolvimento , Salmonella typhimurium/patogenicidadeRESUMO
Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pigAssuntos
Líquidos Corporais/química
, Desenho de Fármacos
, Avaliação Pré-Clínica de Medicamentos
, Trato Gastrointestinal/anatomia & histologia
, Tecido Linfoide/anatomia & histologia
, Modelos Animais
, Animais
, Líquidos Corporais/fisiologia
, Avaliação Pré-Clínica de Medicamentos/métodos
, Avaliação Pré-Clínica de Medicamentos/normas
, Trato Gastrointestinal/fisiologia
, Cobaias
, Concentração de Íons de Hidrogênio
, Tecido Linfoide/fisiologia
, Masculino
, Coelhos
, Especificidade da Espécie
, Suínos
RESUMO
Bicarbonate media are reflective of the ionic composition and buffer capacity of small intestinal luminal fluids. Here we investigate methods to stabilise bicarbonate buffers which can be readily applied to USP-II dissolution apparatus. The in vitro drug release behaviour of three enteric coated mesalazine (mesalamine) products is investigated. Asacol 400 mg and Asacol 800 mg (Asacol HD) and the new generation, high dose (1200 mg) delayed and sustained release formulation, Mezavant (Lialda), are compared in pH 7.4 Krebs bicarbonate and phosphate buffers. Bicarbonate stabilisation was achieved by: continuous sparging of the medium with 5% CO(2)(g), application of a layer of liquid paraffin above the medium, or a specially designed in-house seal device that prevents CO(2)(g) loss. Each of the products displayed a delayed onset of drug release in physiological bicarbonate media compared to phosphate buffer. Moreover, Mezavant displayed a zero-order, sustained release profile in phosphate buffer; in bicarbonate media, however, this slow drug release was no longer apparent and a profile similar to that of Asacol 400 mg was observed. These similar release patterns of Asacol 400 mg and Mezavant displayed in bicarbonate media are in agreement with their pharmacokinetic profiles in humans. Bicarbonate media provide a better prediction of the in vivo behaviour of the mesalazine preparations investigated.