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The direct 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of para-quinone methides (p-QMs) with Me3SiRf (Rf = CF2H, CF3, CF2CF3, CF2COOEt, and CF2SPh) under mild conditions are described. Although Me3SiCF2H shows lower reactivity than Me3SiCF3, it can react with p-QMs promoted by CsF/18-Crown-6 to give structurally diverse difluoromethyl products in good yields. The products can then be further converted into fluoroalkylated para-quinone methides and α-fluoroalkylated diarylmethanes.
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Extracellular vesicles (EVs) play an important role in human and bovine milk composition. According to excellent published studies, it also exerts various functions in the gut, bone, or immune system. However, the effects of milk-derived EVs on skeletal muscle growth and performance have yet to be fully explored. Firstly, the current study examined the amino acids profile in human milk EVs (HME) and bovine milk EVs (BME) using targeted metabolomics. Secondly, HME and BME were injected in the quadriceps of mice for four weeks (1 time/3 days). Then, related muscle performance, muscle growth markers/pathways, and amino acids profile were detected or measured by grip strength analysis, rotarod performance testing, Jenner-Giemsa/H&E staining, Western blotting, and targeted metabolomics, respectively. Finally, HME and BME were co-cultured with C2C12 cells to detect the above-related indexes and further testify relative phenomena. Our findings mainly demonstrated that HME and BME significantly increase the diameter of C2C12 myotubes. HME treatment demonstrates higher exercise performance and muscle fiber densities than BME treatment. Besides, after KEGG and correlation analyses with biological function after HME and BME treatment, results showed L-Ornithine acts as a "notable marker" after HME treatment to affect mouse skeletal muscle growth or functions. Otherwise, L-Ornithine also significantly positively correlates with the activation of the AKT/mTOR pathway and myogenic regulatory factors (MRFs) and can also be observed in muscle and C2C12 cells after HME treatment. Overall, our study not only provides a novel result for the amino acid composition of HME and BME, but the current study also indicates the advantage of human milk on skeletal muscle growth and performance.
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Vesículas Extracelulares , Leite Humano , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas 70-kDa , Músculos , Serina-Treonina Quinases TOR , Desempenho Físico Funcional , Aminoácidos , Transdução de SinaisRESUMO
Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-sequencing had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.
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Córtex Cerebral/diagnóstico por imagem , Variação Genética/genética , Hemimegalencefalia/diagnóstico por imagem , Hemimegalencefalia/genética , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Córtex Cerebral/cirurgia , Hemimegalencefalia/cirurgia , Humanos , Lactente , MasculinoRESUMO
Hot melt extrusion (HME) has been used for the formulation of topical solid lipid nanoparticle (SLN) gel without using any other size reduction technique including high pressure homogenization or sonication. SLN formulation solely using HME has not been applied to other drugs except IBU. Therefore, the purpose of the present study was to formulate FLB SLN solely using HME technique and evaluate the SLN formulation in inflammation animal model. Stable 0.5% w/v FLB SLN gel with particle size < 250 nm, PI < 0.3 and EE of > 98% was prepared. Differential scanning calorimetry (DSC) thermogram showed that the drug was converted to amorphous form in the HME process. Additionally, rheological studies demonstrated that FLB SLN gel and marketed FLB gel showed shear thinning property. FLB SLN formulation showed significantly (p < 0.05) higher peak force required to spread the formulation as compared to marketed FLB formulation. Stability studies showed that FLB SLN gel was stable for a month at room temperature and 2-4°C. Moreover, in vitro permeation test (IVPT) and ex vivo skin deposition study results revealed that FLB SLN gel showed significant (p < 0.05) increase in drug deposition in dermal layer and drug permeation as compared to control marketed formulation. Further, in vivo anti-inflammatory study showed equivalent inhibition of rat paw edema using 0.5% w/v FLB SLN gel which has 10 times less strength compared to control formulation. Overall, FLB SLN formulation was successfully manufactured solely using HME technique which resulted in enhanced the skin permeation of FLB and superior anti-inflammatory activity.
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Flurbiprofeno , Tecnologia de Extrusão por Fusão a Quente , Animais , Anti-Inflamatórios , Portadores de Fármacos/química , Géis , Lipossomos , Nanopartículas , RatosRESUMO
This study aimed to formulate and optimize solid-dispersion of meloxicam (MX) employing response-surface-methodology (RSM). RSM allowed identification of the main effects and interactions between studied factors on MX dissolution and acceleration of the optimization process. 33 full factorial design with 27 different formulations was proposed. Effects of drug loading percentage (A), carriers' ratio (B), method of preparation (C), and their interactions on percent MX dissolved after 10 and 30 min (Q10min & Q30min) from fresh and stored samples were studied in distilled water. The considered levels were 2.5%, 5.0%, and 7.5% (factor A), three ratios of Soluplus®/Poloxamer-407 (factor B). Physical mixture (PM), fusion method (FM), and hot-melt-extrusion (HME) were considered factor (C). Stability studies were carried out for 3 months under stress conditions. The proposed optimization design was validated by 3-extra checkpoints formulations. The optimized formulation was selected via numerical optimization and investigated by DSC, XRD, PLM, and in vitro dissolution study. Results showed that HME technique gave the highest MX dissolution rate compared to other techniques (FM & PM). At constant level of factor (C), the amount of MX dissolved increased by decreasing MX loading and increasing Soluplus in carriers' ratio. Actual responses of the optimized formulation were in close consistency with predicted data. Amorphous form of MX in the optimized formulation was proved by DSC, XRD, and PLM. Selected factors and their levels of the optimization design were significantly valuable for demonstrating and adapting the expected formulation characteristics for rapid dissolution of MX (Q10min= 89.09%) from fresh and stored samples.
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Química Farmacêutica , Tecnologia de Extrusão por Fusão a Quente , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Temperatura Alta , Meloxicam , SolubilidadeRESUMO
Blind nasal intubation (BNI) has been around for over a century now. Many clinicians advocate it as an "old-is-gold" skill, which can be performed without any adjuncts in cases where visualization of larynx is a problem. Even today, BNI not only comes handy in resource-limited centers, it may also come to the rescue of airway managers in well-equipped centers. However, in the century since it was first described, there have been other major developments in the field of airway management and BNI as a skill has taken a backseat when it comes to a priority order. More so because it is limited by modalities to teach and train as most of the available manikins, which are otherwise phenomenal when it comes to imitating anatomy and overall attention to detail of a human airway, suffer terribly in one basic aspect needed to teach, train, and learn BNI-"they" cannot breathe! Attempts have been made to fabricate some manikins on these lines. But what if they can not only breathe but breathe out CO2 as well! We describe a simple method whereby we created a "CO2 breathing" manikin and tested it in an Airway Management Workshop with 105 participants, and then evaluated it under controlled conditions in 20 volunteers. We got very encouraging results and realized that our manikin makes the teaching and training of BNI very interesting and attractive by simulating the actual clinical scenario. We feel that it has the potential of reinventing the valuable skill of BNI.
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The emergence of new active pharmaceutical ingredient (API) polymorphs in pharmaceutical development presents significant risks. Even with thorough polymorph screening, new pathways toward alternate crystal phases can present themselves over the course of formulation development; thus, further improvements in phase screening methods are needed. Herein, a case study is presented of a thermodynamically stable crystalline phase of the HIV drug Islatravir (MK-8591, EFdA) that was not isolated from initial pharmaceutical polymorph screening. In total, five Islatravir phases are identified: one monohydrate and four anhydrate phases. The new phase, anhydrate form IV, was unexpectedly discovered during hot melt extrusion (HME) process development of polymeric implant drug product formulations while probing extreme manufacturing process conditions (elevated shear forces). X-ray diffraction (XRD), differential scanning calorimetry (DSC), and solid-state nuclear magnetic resonance (ssNMR) were utilized as principal tools to identify the new polymorph. The result suggests that HME introduces conditions that may allow a thermodynamically stable crystalline phase to form and these conditions are not necessarily captured by routine pharmaceutical polymorph screening. Subsequent investigations identified procedures to generate the new anhydrate phase without HME equipment by the use of special thermal procedures. It is found that for a crystalline hydrate phase the rate of water loss as well as water entrapment in a heating vessel play a crucial role in phase conversions into different anhydrate polymorphs. Further, the polymer involved in the HME manufacturing process also plays a critical role in the phase conversion, likely by coating the API microparticles and thereby altering the phase conversion kinetics. Strategies presented herein to mimic phase changes during formulation manufacture hold promise for the identification of thermodynamically stable anhydrate forms in earlier stages of pharmaceutical development.
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Desoxiadenosinas/química , Preparações Farmacêuticas/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Tecnologia de Extrusão por Fusão a Quente/métodos , Temperatura Alta , Polímeros/química , Solubilidade/efeitos dos fármacos , Termodinâmica , Difração de Raios X/métodosRESUMO
PURPOSE: An investigation of underlying mechanisms of API-polymer interaction patterns has the potential to provide valuable insights for selecting appropriate formulations with superior physical stability and processability. MATERIALS AND METHODS: In this study, copovidone was used as a polymeric carrier for several model compounds including clotrimazole, nifedipine, and posaconazole. The varied chemical structures conferred the ability for the model compounds to form distinct interactions with copovidone. Rheology and nuclear magnetic resonance (NMR) were combined to investigate the molecular pattern and relative strength of active pharmaceutical ingredient (API)-polymer interactions. In addition, the impact of the interactions on formulation processability via hot melt extrusion (HME) and physical stability were evaluated. RESULTS: The rheological response of an API-polymer system was found to be highly sensitive to API-polymer interaction, depending both on API chemistry and API-polymer miscibility. In the systems studied, dispersed API induced a stronger plasticizer effect on the polymer matrix compared to crystalline/aggregated API. Correspondingly, the processing torque via HME showed a proportional relationship with the maximum complex viscosity of the API-polymer system. In order to quantitatively evaluate the relative strength of the API-polymer interaction, homogeneously dispersed API-polymer amorphous samples were prepared by HME at an elevated temperature. DSC, XRD, and rheology were employed to confirm the amorphous integrity and homogeneity of the resultant extrudates. Subsequently, the homogeneously dispersed API-polymer amorphous dispersions were interrogated by rheology and NMR to provide a qualitative and quantitative assessment of the nature of the API-polymer interaction, both macroscopically and microscopically. Rheological master curves of frequency sweeps of the extrudates exhibited a strong dependence on the API chemistry and revealed a rank ordering of the relative strength of API-copovidone interactions, in the order of posaconazole > nifedipine > clotrimazole. NMR data provided the means to precisely map the API-polymer interaction pattern and identify the specific sites of interaction from a molecular perspective. Finally, the impact of API-polymer interactions on the physical stability of the resultant extrudates was studied. CONCLUSION: Qualitative and quantitative evaluation of the relative strength of the API-polymer interaction was successfully accomplished by utilizing combined rheology and NMR. Graphical Abstract.
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Clotrimazol/química , Portadores de Fármacos/química , Nifedipino/química , Pirrolidinas/química , Triazóis/química , Compostos de Vinila/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Elasticidade , Tecnologia de Extrusão por Fusão a Quente , Temperatura Alta , Espectroscopia de Ressonância Magnética , Conformação Molecular , Reologia , Relação Estrutura-Atividade , ViscosidadeRESUMO
AIM: This work is to investigate the application characteristics of a new hot melt extrusion (HME) polymer (HME-grade hydroxypropyl methylcellulose, namely HPMC HME 15LV) in solid dispersion by HME. METHODS: Carbamazepine (CBZ) was chosen as the model drug. And two types of solid dispersion system was prepared by HME, that is, single carrier system which was composed of PVP VA64(VA64) or Soluplus (SOL), and binary carrier which was composed of HPMC HME 15LV and SOL. Phase analysis of the extrudates were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution, moisture absorption and thermal stability CBZ solid dispersion (CBZ-SD) were also investigated. In addition, the mechanism that affects the capsule dissolution was evaluated by the viscosity test and infiltration capability test. RESULTS: CBZ-SD was prepared by HME. DSC and PXRD results indicated that CBZ was amorphous in all solid dispersions. Unlike CBZ-SD powder with high dissolution, CBZ-SD capsules showed the variable gelatinization phenomenon during dissolution and different dissolution behaviors, which can be interpreted by the viscosity test and infiltration capacity test. Furthermore, compared with single carrier system, CBZ-SD made by binary carrier exhibited lower moisture absorption and better thermal stability, which is benefit to the long-term stability of CBZ-SD. CONCLUSION: HPMC HME 15LV, as a new HME carrier, has certain advantages in producing well CBZ-SD preparation. Its low viscosity can prevent the gelatinization phenomenon during capsule dissolution, as well as suitable Tg and low hygroscopicity were also benefit to the stability of CBZ-SD.
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Carbamazepina/química , Tecnologia de Extrusão por Fusão a Quente , Polímeros , Varredura Diferencial de Calorimetria , Portadores de Fármacos , Derivados da HipromeloseRESUMO
We recently reported lowly hydrolyzed polyvinyl alcohol (L-PVA, 70-74% hydrolyzed, about 580 polymerized, JR-05) as a promising matrix for hot-melt extrusion (HME) due to its unique micelle formation ability compared to the most commonly used PVA (87-89% hydrolyzed, about 580 polymerized). In the present study, we focused on the effect of composition [indomethacin (IND), L-PVA, sorbitol] and process parameters (temperature and screw speed) on each response, i.e. processing torque, and physicochemical properties such as residual crystallinity, residual ratio, and area under the dissolution curve (AUDC) in supersaturated solution using a HME by applying the design of experiment (DoE) approach. To overcome the poor processability of L-PVA, given its semicrystalline nature, we applied sorbitol as a plasticizer and systematically and simultaneously evaluated its influence on the outputs based on the mixture design combined with process factors. Few studies have focused on comprehensive evaluation of the composition and HME process conditions because obtaining a design space requires numerous experiments. We found that incorporating sorbitol into the L-PVA greatly improved the processing torque. However, sorbitol negatively influenced the degree of residual crystallinity and the AUDC of IND. Lastly, we established a laboratory-scale design space that could achieve high supersaturation and ensure adequate miscibility between each component, using an acceptable processing torque for HME, by applying the minimum amount of sorbitol. These fundamental results suggest that sorbitol maximizes the potency of L-PVA as a carrier in HME.
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Indometacina/química , Álcool de Polivinil/química , Química Farmacêutica/métodos , Cristalização/métodos , Composição de Medicamentos/métodos , Hidrólise , Micelas , Plastificantes/química , Solubilidade/efeitos dos fármacos , Sorbitol/química , TemperaturaRESUMO
Polymeric films are safe and effective and can be used for vaginal administration of microbicide drug candidates. Dapivirine (DPV), an investigational and clinically advanced antiretroviral drug, was selected as a model compound for this study. We have previously developed and clinically tested a quick-dissolving DPV film using solvent cast (SC) manufacturing technique. As an alternative to current pharmaceutical film manufacturing techniques, we investigated hot melt extrusion (HME) process in this study because it has several benefits, including its capacity as a continuous manufacturing process, lack of solvents, smaller footprint, and ease of scalability. The goal of this work was to evaluate the feasibility of using HME for DPV vaginal film manufacturing and to develop a robust manufacturing process using HME by evaluating the effect of process parameters on film quality and performance. DPV was successfully incorporated into a vaginal film using HME and maintained acceptable characteristics. Three process parameters (zone temperature, screw speed, and feed rate) had an impact on film quality and performance. Of these, the zone temperature was found to most significantly affect weight, thickness, puncture strength, and dissolution of films. Additionally, film manufacturing using HME was highly reproducible. Finally, the DPV HME film was comparable to films manufactured using SC in terms of physicochemical, biological, and safety characteristics including in vitro drug release, mechanical strength, tissue permeability, compatibility with commensal vaginal Lactobacilli, and in vitro bioactivity. These results demonstrate that HME is an effective, robust, and viable manufacturing method to produce vaginal films.
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Preparações Farmacêuticas/química , Pirimidinas/química , Inibidores da Transcriptase Reversa/química , Tecnologia Farmacêutica/métodos , Administração Intravaginal , Liberação Controlada de Fármacos , Feminino , Congelamento , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Temperatura Alta , Humanos , Testes de Sensibilidade Microbiana , Polímeros/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10â»20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. Thus, it is critical to develop more targeted and efficacious therapies that also demonstrate less side effects. Selenium, an essential dietary supplement, is incorporated as selenocysteine (Sec) in vivo into human selenoproteins, some of which exist as anti-oxidant enzymes and are of importance to human health. Studies have also shown that selenium compounds hinder cancer cell growth and induce apoptosis in cancer cell culture models. The focus of this study was to investigate whether selenium-antibody conjugates could be effective against triple negative breast cancer cell lines using clinically relevant, antibody therapies targeted for high expressing breast cancers and whether selenium cytotoxicity was attenuated in normal breast epithelial cells. To that end, the humanized monoclonal IgG1 antibodies, Bevacizumab and Trastuzumab were conjugated with redox selenium to form Selenobevacizumab and Selenotrastuzumab and tested against the triple negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231 as well as a normal, immortalized, human mammary epithelial cell line, HME50-5E. VEGF and HER2 protein expression were assessed by Western. Although expression levels of HER2 were low or absent in all test cells, our results showed that Selenobevacizumab and Selenotrastuzumab produced superoxide (O2â¢-) anions in the presence of glutathione (GSH) and this was confirmed by a dihydroethidium (DHE) assay. Interestingly, superoxide was not elevated within HME50-5E cells assessed by DHE. The cytotoxicity of selenite and the selenium immunoconjugates towards triple negative cells compared to HME-50E cells was performed in a time and dose-dependent manner as measured by Trypan Blue exclusion, MTT assay and Annexin V assays. Selenobevacizumab and Selenotrastuzumab were shown to arrest the cancer cell growth but not the HME50-5E cells. These results suggest that selenium-induced toxicity may be effective in treating TNBC cells by exploiting different immunotherapeutic approaches potentially reducing the debilitating side effects associated with current TNBC anticancer drugs. Thus, clinically relevant, targeting antibody therapies may be repurposed for TNBC treatment by attachment of redox selenium.
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Antineoplásicos Imunológicos/farmacologia , Bevacizumab/farmacologia , Imunoconjugados/farmacologia , Compostos Organosselênicos/farmacologia , Trastuzumab/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos Imunológicos/química , Apoptose/efeitos dos fármacos , Bevacizumab/química , Linhagem Celular Tumoral , Humanos , Imunoconjugados/química , Compostos Organosselênicos/química , Receptor ErbB-2/análise , Superóxidos/análise , Trastuzumab/química , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Continuous manufacturing, a gaining interest paradigm in the pharmaceutical industry, requires in-process monitoring of critical process parameters to ensure product consistency. This study demonstrated the application of Fourier transform near-infrared (FT-NIR) spectroscopy in conjunction with chemometrics modeling for in-line hot melt extrusion process monitoring. The obtained results suggested that inline FT-NIR analysis, along with a tailored NIR reflector, is a viable process analytical tool to monitor active pharmaceutical ingredient concentration as well as processing parameters.
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Sistemas Computacionais , Análise de Fourier , Temperatura Alta , Tecnologia Farmacêutica/métodos , Indústria Farmacêutica/métodos , Congelamento , Espectroscopia de Luz Próxima ao Infravermelho/métodosRESUMO
Due to the high number of poorly soluble drugs in the development pipeline, novel processes for delivery of these challenging molecules are increasingly in demand. One such emerging method is KinetiSol, which utilizes high shear to produce amorphous solid dispersions. The process has been shown to be amenable to difficult to process active pharmaceutical ingredients with high melting points, poor organic solubility, or sensitivity to heat degradation. Additionally, the process enables classes of polymers not conventionally processable due to their high molecular weight and/or poor organic solubility. Beyond these advantages, the KinetiSol process shows promise with other applications, such as the production of amorphous mucoadhesive dispersions for delivery of compounds that would also benefit from permeability enhancement.
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Química Farmacêutica/métodos , Formas de Dosagem , Composição de Medicamentos/métodos , Animais , Disponibilidade Biológica , Dessecação , Portadores de Fármacos , Humanos , Preparações Farmacêuticas/químicaRESUMO
PURPOSE: Progesterone (PRG) was selected as a model drug to develop a long-acting injection system for poorly water-soluble drugs. METHODS: Microspheres with high density-low porosity were prepared by hot-melt extrusion (HME) combined with wet-milling as the representative formulation, and a microcrystal suspension was also studied as a comparison. The morphology, particle size and distribution, polymorphism, drug distribution, density and porosity were characterized by scanning electron microscopy, laser diffraction particle size analyzer, power X-ray diffraction and DSC respectively. The in vivo performance of the different formulations within 7 days after intramuscular injection was evaluated in male SD rats. RESULTS: The drug-loading rate of the microspheres could be as high as 40%. The average initial burst release of the microspheres (PLGA lactide:glycolide = 75:25) was only 6.7% much lower than that of the microsuspension (25.7%) and a sustained release was exhibited for at least 7 days. The release mechanism was speculated to be as follows. The microspheres are a drug depot with drug microcrystals in the PLGA matrix which is a layer by layer honeycomb structure. CONCLUSIONS: Microspheres prepared by HME combined with wet-milling could achieve a long-term sustained release effect as a novel long-acting formulation strategy.
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Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Ácido Láctico/química , Ácido Poliglicólico/química , Progesterona/farmacocinética , Animais , Química Farmacêutica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Humanos , Masculino , Microesferas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Porosidade , Progesterona/administração & dosagem , Progesterona/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Propriedades de SuperfícieRESUMO
PURPOSE: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. METHODS: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC. RESULTS: Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO. CONCLUSIONS: Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.
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Anti-Inflamatórios não Esteroides/química , Cimetidina/química , Composição de Medicamentos/métodos , Excipientes/química , Antagonistas dos Receptores H2 da Histamina/química , Indometacina/química , Polietilenoglicóis/química , Varredura Diferencial de Calorimetria , Cristalização , Combinação de Medicamentos , Armazenamento de Medicamentos , Reologia , ViscosidadeRESUMO
We describe five children with Hereditary Multiple Exostosis (HME) who also had syringomyelia. Of these, four had a tethered cord/fibrolipoma. No spinal osteochondromas were found in these patients. All had antecedent neurological signs or symptoms that prompted spinal imaging with MRI. Of all patients with HME seen in the Midwest Regional Bone Dysplasia Clinic from 1982 to present, 44% (17/39) of patients had signs or symptoms concerning for possible cord-related neurological findings. However, only 10 of 39 had spinal imaging. Assuming that all individuals with syringomyelia were identified, then 5/39 (13%) were in that way affected. This, of course, is a minimal estimate given that many were not imaged. The incidence of syringomyelia appears to be increased in this population, and seems to be unrelated to spinal osteochondromas. A low threshold for obtaining spinal MRI in patients with Hereditary Multiple Exostosis seems rational. © 2016 Wiley Periodicals, Inc.
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Exostose Múltipla Hereditária/complicações , Exostose Múltipla Hereditária/diagnóstico , Siringomielia/complicações , Siringomielia/diagnóstico , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Exostose Múltipla Hereditária/genética , Exostose Múltipla Hereditária/cirurgia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , N-Acetilglucosaminiltransferases/genética , Fenótipo , Estudos Retrospectivos , Siringomielia/genética , Siringomielia/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
The production of amorphous solid dispersions via hot melt extrusion (HME) relies on elevated temperature and prolonged residence time, which can result in potential degradation and decomposition of thermally sensitive components. Herein, the rheological properties of a physical mixture of polymer and an active pharmaceutical ingredient (API) were utilized to guide the selection of appropriate HME processing temperature. In the currently studied copovidone-nifedipine system, a critical temperature, which is substantially lower (â¼13 °C) than the melting point of crystalline API, was captured during a temperature ramp examination and regarded as the critical point at which the API could molecularly dissolve into the polymer. Based on the identification of this critical point, various solid dispersions were prepared by HME processing below, at, and above the critical temperature (both below and above the melting temperature (Tm) of crystalline API). In addition, the resultant extrudates along with two control solid dispersions prepared by physical mixing and cryogenic milling were assessed by X-ray diffraction, differential scanning calorimetry, hot stage microscopy, rheology, and solid-state NMR. Physicochemical properties of resultant solid dispersions indicated that the identified critical temperature is sufficient for the polymer-API system to reach a molecular-level mixing, manifested by the transparent and smooth appearance of extrudates, the absence of API crystalline diffraction and melting peaks, dramatically decreased rheological properties, and significantly improved polymer-API miscibility. Once the critical temperature has been achieved, further raising the processing temperature only results in limited improvement of API dispersion, reflected by slightly reduced storage modulus and complex viscosity and limited improvement in miscibility.
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Nifedipino/química , Pirrolidinas/química , Reologia/métodos , Compostos de Vinila/química , Varredura Diferencial de Calorimetria , Composição de Medicamentos/métodos , Espectroscopia de Ressonância Magnética , Polímeros/química , Temperatura , Difração de Raios XRESUMO
PURPOSE: The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing. METHODS: Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus. RESULTS: Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern. CONCLUSIONS: Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.