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1.
Pharmaceutics ; 13(2)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546383

RESUMO

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation.

2.
Eur J Pharm Biopharm ; 157: 191-199, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33022391

RESUMO

RNA interference (RNAi) enables highly specific silencing of potential target genes for treatment of pulmonary pathologies. The intracellular RNAi pathway can be activated by cytosolic delivery of small interfering RNA (siRNA), inducing sequence-specific gene knockdown on the post-transcriptional level. Although siRNA drugs hold many advantages over currently applied therapies, their clinical translation is hampered by inefficient delivery across cellular membranes. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel core (nanogel) coated with Curosurf®, a clinically used pulmonary surfactant (PS). The latter enhances both particle stability as well as intracellular siRNA delivery, which was shown to be governed by the PS-associated surfactant protein B (SP-B). Despite having a proven in vitro and in vivo siRNA delivery potential when prepared ex novo, clinical translation of this liquid nanoparticle suspension requires the identification of a long-term preservation strategy that maintains nanoparticle stability and potency. In addition, to achieve optimal pulmonary deposition of the nanocomposite, its compatibility with state-of-the-art pulmonary administration techniques should be evaluated. Here, we demonstrate that PS-coated nanogels can be lyophilized, reconstituted and subsequently nebulized via a vibrating mesh nebulizer. The particles retain their physicochemical integrity and their ability to deliver siRNA in a human lung epithelial cell line. The latter result suggests that the functional integrity of SP-B in the PS coat towards siRNA delivery might be preserved as well. Of note, successful lyophilization was achieved without the need for stabilizing lyo- or cryoprotectants. Our results demonstrate that PS-coated siRNA-loaded nanogels can be lyophilized, which offers the prospect of long-term storage. In addition, the formulation was demonstrated to be suitable for local administration with a state-of-the-art nebulizer for human use upon reconstitution. Hence, the data presented in this study represent an important step towards clinical application of such nanocomposites for treatment of pulmonary disease.

3.
J Pharm Sci ; 109(12): 3636-3644, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32949563

RESUMO

The aim of this study was to evaluate the processability of poly(vinyl alcohol) (PVA)-based filaments containing paracetamol (PAR) prepared by hot-melt extrusion for fused deposition modelling (FDM) 3D printing, as function of drug content (0-50%w/w) and storage conditions (temperature: 20-40 °C and humidity: 11-75%). Thermal (DSC), crystallographic (XRPD), spectroscopic (FTIR), moisture content and mechanical tests were used to characterize the filaments, whereas their ability to produce tablets was confirmed by printing. XRPD revealed the absence of crystalline PAR in the extruded filaments with <30% PAR and FTIR confirmed interactions between PAR and PVA. Mechanical tests have shown a higher brittleness of the filaments with increasing PAR, making them non-printable. Throughout storage, temperature and moisture increased the plasticity of the filaments, which was reflected by changes on their thermal and mechanical properties improving the feeding performance on the printer. Filaments stored at low moisture remained unsuitable for printing with amorphous PAR being preserved. Dissolution tests have shown that the release of PAR from printed tablets was independent of the storage time of the filaments. The study highlights the need for optimized storage conditions of filaments for FDM and the dependency on the drug's content in such filaments.

4.
Int J Pharm ; 588: 119756, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32783981

RESUMO

In recent years, significant progress has been made in the field of continuous twin screw granulation. However, only limited knowledge is currently available on the impact of active pharmaceutical ingredient (API) properties on granule quality and processability. In this study, the response behavior of four formulations containing APIs (5-10% drug load) with diverse characteristics was compared to the behavior of the corresponding placebo formulation consisting of lactose, microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC). API selection was based on extensive material characterization, combining conventional testing with in silico descriptors. For each formulation, a design of experiments was set up, evaluating the impact of liquid to solid (L/S) ratio and screw speed. Response ranges, response behavior and processability of each of the four formulations proved very similar to the placebo formulation when an appropriate center point L/S ratio was chosen. Hence, this robust placebo formulation could prove useful by decreasing drug product development time and consequently providing patients with a faster access to innovative medicine. Additionally, APIs with similar properties exhibited highly comparable response behavior at similar L/S ratios, indicating the potential use of surrogate APIs in novel drug product development.

5.
J Biol Inorg Chem ; 25(6): 875-885, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32719971

RESUMO

L-ascorbic acid 2-phosphate magnesium (APMg) salt is a vitamin C derivative frequently used as a raw material in cell and tissue therapy. APMg is not only used as a replacement of the unstable ascorbate, but also shows additional cell-biological functionalities. However, its unknown structural characteristics hamper the mechanistic elucidation of its biological role. Therefore, different techniques were applied for APMg structure characterization. Firstly, the stoichiometric composition was characterized by its solvent, ligand and magnesium content. No crystals of APMg could be obtained; however, a single crystal of APNa, the sodium salt of l-ascorbic acid 2-phosphate, was successfully obtained and its crystal structure was elucidated. FT-IR was applied to further clarify the structure of solid APMg. Finally, the structure of APMg in aqueous solution was explored by potentiometric titration as well as FT-IR.

6.
Int J Pharm ; 587: 119675, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32721562

RESUMO

The internal blending of magnesium stearate is often associated with decreasing tensile strengths and longer disintegration and dissolution times. Therefore, external lubrication has gained interest in the pharmaceutical industry as these negative effects could be minimized using this method. In this study, an external lubrication system implemented in a compaction simulator was investigated. The influence of 2 process parameters related to the external lubrication system, spraying time and atomizing pressure, on the responses was studied using 4 common fillers and 2 model drugs. While the parameters of the external lubrication system had a significant impact on the ejection forces, no negative effect was observed on the tensile strength and disintegration time as similar values were obtained compared to non-lubricated experiments. Moreover, equal or lower ejection forces were obtained for external lubrication using a lower concentration of magnesium stearate compared to internal lubrication, where a decrease in tensile strength and prolonged disintegration was noticed for most formulations. The observed results could be correlated to the wall friction angle, compaction properties and tablet brittleness index of the raw materials and blends. This study showed the potential of external lubrication as an alternative lubrication method for lubricant-sensitive formulations.

7.
Materials (Basel) ; 13(13)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32630310

RESUMO

Spin-freeze-drying is a promising technique to enable long-term storage of pharmaceutical unit doses of aqueous drug solutions. To investigate the sublimation of the ice during the primary phase of freeze-drying, X-ray imaging can yield crucial temporally resolved information on the local dynamics. In this paper, we describe a methodology to investigate the sublimation front during single unit-dose freeze-drying using 4D in-situ X-ray imaging. Three spin-frozen samples of different solutions were imaged using this methodology and the process characteristics were analysed and reduced to two-dimensional feature maps.

8.
Pharmaceutics ; 12(6)2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32517052

RESUMO

Fused filament fabrication (FFF) 3D printing technology is widely used in many fields. For almost a decade, medical researchers have been exploring the potential use of this technology for improving the healthcare sector. Advances in personalized medicine have been more achievable due to the applicability of producing drug delivery devices, which are explicitly designed based on patients' needs. For the production of these devices, a filament-which is the feedstock for the FFF 3D printer-consists of a carrier polymer (or polymers) and a loaded active pharmaceutical ingredient (API). This systematic review of the literature investigates the most widely used approaches for producing drug-loaded filaments. It also focusses on several factors, such as the polymeric carrier and the drug, loading capacity and homogeneity, processing conditions, and the intended applications. This review concludes that the filament preparation method has a significant effect on both the drug homogeneity within the polymeric carrier and drug loading efficiency.

9.
Vet J ; 259-260: 105459, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32553240

RESUMO

The purpose of the present study was to investigate if rectal administration of imepitoin in healthy dogs leads to plasma concentrations comparable to those after oral administration. Significantly lower systemic exposure and maximal plasma concentration (Cmax) of imepitoin was achieved after rectal compared to oral administration (P≤0.001). Therefore, this study does not support the rectal administration of imepitoin in dogs.


Assuntos
Anticonvulsivantes/farmacocinética , Cães/metabolismo , Imidazóis/farmacocinética , Administração Oral , Administração Retal , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Doenças do Cão/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/veterinária , Imidazóis/administração & dosagem , Imidazóis/sangue
10.
Pharmaceutics ; 12(5)2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32392705

RESUMO

Maintaining chemical and physical stability of the product during freeze-drying is important but challenging. In addition, freeze-drying is typically associated with long process times. Therefore, mechanistic models have been developed to maximize drying efficiency without altering the chemical or physical stability of the product. Dried product mass transfer resistance ( R p ) is a critical input for these mechanistic models. Currently available techniques to determine R p only provide an estimation of the mean R p and do not allow measuring and determining essential local (i.e., intra-vial) R p differences. In this study, we present an analytical method, based on four-dimensional micro-computed tomography (4D- µ CT), which enables the possibility to determine intra-vial R p differences. Subsequently, these obtained R p values are used in a mechanistic model to predict the drying time distribution of a spin-frozen vial. Finally, this predicted primary drying time distribution is experimentally verified via thermal imaging during drying. It was further found during this study that 4D- µ CT uniquely allows measuring and determining other essential freeze-drying process parameters such as the moving direction(s) of the sublimation front and frozen product layer thickness, which allows gaining accurate process knowledge. To conclude, the study reveals that the variation in the end of primary drying time of a single vial could be predicted accurately using 4D- µ CT as similar results were found during the verification using thermal imaging.

11.
Int J Pharm ; 577: 119068, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981703

RESUMO

Despite the recent commercialization of several drug products manufactured through continuous manufacturing techniques, knowledge on the formulation aspect of these techniques, such as twin screw wet granulation, is still rather limited. Previous research identified lactose/MCC/HPMC as a robust platform formulation for several model formulations, although granulation of the high-dosed, poorly soluble API mebendazole proved challenging. Therefore, current research evaluated the binder addition method (wet or dry) as well as surfactant (SLS) addition when using PVP, instead of HPMC. Compared to the previous formulation, using HPMC as binder, all four formulations with PVP yielded significantly stronger granules at similar to significantly lower liquid to solid (L/S) ratios. Through the combination of four replicate center composite circumscribed designs, each evaluating the impact of screw speed and L/S ratio on granule quality attributes, the effect of the formulation variables was assessed. Overall, L/S ratio had the most significant impact on granule characteristics whereas the effect of screw speed was negligible. Similar granule quality attributes were obtained for each formulation, although the addition of SLS and wet binder addition significantly reduced the required L/S ratio to achieve the desired characteristics. This significant reduction could prove useful for processing other formulations requiring high amounts of moisture, which could otherwise not be dried at a high throughput due to the limited drying capacity of the dryer unit of the Consigma system.


Assuntos
Excipientes/química , Mebendazol/administração & dosagem , Tensoativos/química , Tecnologia Farmacêutica , Derivados da Hipromelose/química , Mebendazol/química , Povidona/química , Solubilidade
12.
Int J Pharm ; 576: 118981, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31935472

RESUMO

In recent years, continuous manufacturing techniques, such as twin screw wet granulation, have gained significant momentum. Due to the large diversity of the (model) formulations and equipment, it is often difficult to generalize conclusions about the importance of process settings. As only limited knowledge is available on the importance of formulation variables, this study focused on the systematic quantification of both process as formulation effects on critical quality attributes of granules from several model formulations. Apart from conventional process and formulation variables, also non-conventional process factors such as nozzle diameter, nozzle orientation and inclusion of a new type of size control elements were evaluated using a Plackett-Burman screening design. Although effects were often formulation-dependent, liquid-to-solid ratio proved the most influential variable for all formulations. Furthermore, binder concentration had a clear effect on granule characteristics, whereas barrel fill level and barrel temperature were less influential. The novel type of size control elements improved granule size distribution and density. The impact of nozzle diameter and wet binder addition proved negligible towards granule properties. Overall it was apparent that lactose/MCC-based formulations correlated better than lactose-based formulations, indicating the possible process robustness of the first filler combination to accommodate API and excipient variability and to handle APIs with different characteristics.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Parafusos Ósseos , Excipientes/química , Lactose/química , Tamanho da Partícula , Solubilidade , Comprimidos/química , Temperatura , Resistência à Tração
13.
Int J Pharm ; 576: 119004, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31935475

RESUMO

Due to the numerous advantages over batch manufacturing, continuous manufacturing techniques such as twin screw wet granulation are rapidly gaining importance in pharmaceutical production. Since a large knowledge gap on the importance of formulation variables exists, this study systematically assessed the impact of different screw configurations and process settings on eight model formulations, varying in filler type, active pharmaceutical ingredient (API) characteristics and drug load. Although liquid to solid (L/S) ratio was the most influential variable for all formulations, also a large effect of the kneading element thickness was observed. Narrow kneading elements with a length to diameter ratio (L/D) of 1/6 had a significant detrimental effect on granule size, flow and strength compared to 1/4 L/D elements. The effects of kneading element distribution and barrel fill level were less pronounced. At low drug load, both filler types could be used to obtain granules with acceptable critical quality attributes (CQAs) for both APIs. Granulation at high drug load of the poorly soluble, poorly wettable API mebendazole proved challenging as it could not be processed using lactose as filler, in contrast to lactose/MCC. As formulations containing lactose/MCC as filler were less influenced by different screw configurations, process settings and API characteristics than formulations without MCC, lactose/MCC/HPMC was considered a promising platform formulation.


Assuntos
Mebendazol/química , Metformina/química , Tecnologia Farmacêutica/métodos , Celulose/química , Composição de Medicamentos , Excipientes/química , Lactose/química , Tamanho da Partícula , Solubilidade , Molhabilidade
14.
Sci Rep ; 9(1): 14881, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619730

RESUMO

Patients with advanced ovarian cancer develop recurrence despite initial treatment response to standard treatment of surgery and intravenous/intraperitoneal (IP) chemotherapy, partly due to a limited peritoneal exposure time of chemotherapeutics. Paclitaxel-loaded genipin-crosslinked gelatin microspheres (PTX-GP-MS) are evaluated for the treatment of microscopic peritoneal carcinomatosis and prevention of recurrent disease. The highest drug load (39.2 µg PTX/mg MS) was obtained by immersion of GP-MS in aqueous PTX nanosuspension (PTXnano-GP-MS) instead of ethanolic PTX solution (PTXEtOH-GP-MS). PTX release from PTX-GP-MS was prolonged. PTXnano-GP-MS displayed a more controlled release compared to a biphasic release from PTXEtOH-GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTXEtOH-GP-MS, D = 7.5 mg PTX/kg; PTXnano-GP-MS D = 7.5 and 35 mg PTX/kg), IP nanoparticular albumin-bound PTX (D = 35 mg PTX/kg) and controls (0.9% NaCl, blank GP-MS) was evaluated in a microscopic peritoneal carcinomatosis xenograft mouse model. PTXnano-GP-MS showed superior anticancer efficacy with significant increased survival time, decreased peritoneal carcinomatosis index score and ascites incidence. However, prolonged PTX release over 14 days from PTXnano-GP-MS caused drug-related toxicity in 27% of high-dosed PTXnano-GP-MS-treated mice. Dose simulations for PTXnano-GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5-15 mg PTX/kg. Low-dosed PTXnano-GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Epitelial do Ovário/terapia , Portadores de Fármacos , Gelatina/química , Ovário/efeitos dos fármacos , Paclitaxel/farmacologia , Neoplasias Peritoneais/prevenção & controle , Abdome/patologia , Animais , Antineoplásicos Fitogênicos/farmacocinética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos , Camundongos Nus , Microesferas , Ovário/patologia , Paclitaxel/farmacocinética , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Pharm ; 571: 118760, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31622742

RESUMO

The use of native starch as in situ binder in a continuous twin screw wet granulation process was studied. Gelatinization of pea starch occurred in the barrel of the granulator using a poorly soluble excipient (anhydrous dicalcium phosphate), but the degree of gelatinization depended on the liquid-to-solid ratio, the granule heating and the screw configuration. Furthermore, the degree of starch gelatinization was correlated with the granule quality: higher binder efficiency was observed in runs where starch was more gelatinized. SEM and PLOM images showed experimental runs which resulted in completely gelatinized starch. Other starch types (maize, potato and wheat starch) could also be gelatinized when processed above a critical barrel temperature for gelatinization. This barrel temperature was different for all starches. In situ starch gelatinization was also investigated in combination with a highly soluble excipient (mannitol). The lower granule friability observed using pure mannitol compared to a mannitol/starch mixture indicated that starch did not contribute to the binding, hence starch did not gelatinize during processing. The study showed that native starch can be considered as a promising in situ binder for continuous twin screw wet granulation of a poorly soluble formulation.


Assuntos
Veículos Farmacêuticos/química , Amido/química , Química Farmacêutica , Composição de Medicamentos/instrumentação , Gelatina/química , Manitol/química , Tamanho da Partícula , Ervilhas/química , Solanum tuberosum/química , Solubilidade , Comprimidos , Temperatura , Triticum/química , Zea mays/química
16.
Int J Pharm ; 569: 118587, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31377409

RESUMO

In this research, the volumetric scale-up law was assessed for its applicability to scale-up from a laboratory-scale extruder (11 mm diameter) to a pilot-scale extruder (16 mm diameter) with geometric similarity using low feed rates (0.1-0.26 kg/h at lab-scale). A sustained release formulation was extruded on both scales using scaled feed rates according to the volumetric scale-up law. The specific mechanical energies, drug solid-state, drug dissolution and the residence time distribution responses (i.e. axial mixing degree, mean residence time, width of distribution) were compared between both scales. The results showed that the difference in mean residence time between both scale extruders reduced with higher throughput and thus fill level. Overall, the specific mechanical energies (SME) were comparable between scales when using the volumetric scale-up law (i.e. applying scaling factor q = 3) and were exactly matching with a scaling factor of q = 2.6. Furthermore, plug flow conditions at lab-scale should be avoided before scaling up to obtain similar SMEs. The same degree of axial mixing (represented by the Peclet number) was demonstrated at a scaling factor of q = 2. If drug solid-state is a critical quality attribute (CQA), focus should be on the screw speed and cooling capacity of the larger scale extruder. The drug dissolution showed similarity between scales and was independent of drug solid-state for this formulation, indicating that successful scale-up was possible.


Assuntos
Preparações de Ação Retardada/química , Tecnologia Farmacêutica/métodos , Liberação Controlada de Fármacos , Metoprolol/química , Ácidos Polimetacrílicos/química
17.
Int J Pharm ; 570: 118631, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31442499

RESUMO

The applicability of DCCs in a continuous freeze-drying concept based on spin freezing and infrared heating was evaluated. Maximum applicable filling volume was evaluated. Secondly the mechanistic model for the determination of the optimal dynamic infrared heater temperature during primary drying of regular vials during continuous freeze-drying was adapted and validated for DCCs. Finally, since spin frozen DCCs may be more prone to choked flow due to the small neck opening and the large product surface area, it was evaluated if the choked flow constraints in the model could be increased to improve the efficiency of the drying process. The experiments revealed that the maximum allowable filling volume for spin freezing at the current experimental setup was 0.8 ml which is 80% of the maximum filling volume. Applying the mechanistic model for the determination of the optimal dynamic infrared heater temperature during primary drying of the studied DCCs and experimentally verifying this determined infrared heater temperature trajectory resulted in an elegant freeze-dried product without visual signs of collapse. The experimentally determined primary drying time agreed with the one calculated based on the mechanistic model. Choked flow did not occur during the continuous freeze-drying of DCCs containing 3% sucrose or 3% mannitol.


Assuntos
Preparações Farmacêuticas/química , Composição de Medicamentos/métodos , Liofilização/métodos , Congelamento , Manitol/química , Sacarose/química , Temperatura
18.
Nutrients ; 11(7)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330811

RESUMO

Despite the presumption of the beneficial effects of magnesium supplementation, little is known about the pharmacokinetics of different magnesium formulations. We aimed to investigate the value of two in vitro approaches to predict bioavailability of magnesium and to validate this in subsequent in vivo testing. In vitro assessment of 15 commercially available magnesium formulations was performed by means of a Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) and by dissolution tests. Two magnesium formulations with contrasting bioavailability prediction from both in vitro tests (best vs. worst) were selected for in vivo testing in 30 subjects. In vivo bioavailability was compared following one acute ingestion by monitoring blood magnesium concentrations up to 6 h following intake. The in vitro tests showed a very wide variation in absorption and dissolution of the 15 magnesium products. In the in vivo testing, a significant different serum magnesium absorption profile was found up to 4 h following supplement ingestion for the two supplements with opposing in vitro test results. Moreover, maximal serum magnesium increase and total area under the curve were significantly different for both supplements (+6.2% vs. +4.6% and 6.87 vs. 0.31 mM.min, respectively). Collectively, poor bioaccessibility and bioavailability in the SHIME model clearly translated into poor dissolution and poor bioavailability in vivo. This provides a valid methodology for the prediction of in vivo bioavailability and effectiveness of micronutrients by specific in vitro approaches.


Assuntos
Magnésio/farmacocinética , Adolescente , Adulto , Disponibilidade Biológica , Suplementos Nutricionais , Formas de Dosagem , Liberação Controlada de Fármacos , Feminino , Humanos , Magnésio/sangue , Magnésio/química , Magnésio/urina , Masculino , Adulto Jovem
19.
Pharm Res ; 36(9): 127, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236836

RESUMO

PURPOSE: Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. METHODS: PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. RESULTS: A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. CONCLUSIONS: The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.


Assuntos
Paclitaxel Ligado a Albumina/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Peritoneais/tratamento farmacológico , Paclitaxel Ligado a Albumina/química , Paclitaxel Ligado a Albumina/farmacocinética , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Reagentes para Ligações Cruzadas/química , Portadores de Fármacos , Gelatina/química , Humanos , Iridoides/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Microesferas , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Pharm Biopharm ; 141: 172-179, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150810

RESUMO

Mangiferin, a poorly water soluble compound, was processed via a dry amorphisation technique (ball milling) in combination with mesoporous silica to enhance the solubility of mangiferin. The amorphous samples were prepared by mixing 1:1 (w/w) Syloid® XDP 3050 silica-mangiferin mixtures using a planetary mono mill at different milling speeds and milling times according to a 32 full factorial experimental design. The prepared samples were characterized for dissolution profile, particle size distribution using laser diffraction particle size analyzer, thermal characteristics using DSC, crystalline characteristics using XRD and molecular interactions using FTIR and ss-NMR. The samples were tested for stability at stress conditions (40 °C/75%RH) for up to 6 months in open and closed containers. To improve stability of the samples, mixtures of 1:1:2 mangiferin-polymer (Soluplus or HPMC)-silica samples were also prepared and analyzed. Amorphisation of mangiferin is possible using dry amorphisation by ball milling with mesoporous silica in a short amount of time. The amorphisation rate of the samples improved with the energy input of the milling process. The samples prepared with high energy input resulted in amorphous samples and showed a better stability at the stress conditions for up to 3 months. Solubility of these samples increased from 0.32 to 0.50 mg/ml and the particle size decreased from 35.5 µm to around 7 µm. The spectral analysis suggest presence of interactions between the silica material and the compound. The amorphous stability was improved with addition of polymer, even though the solubility of the samples was lower.


Assuntos
Dióxido de Silício/química , Solubilidade/efeitos dos fármacos , Água/química , Xantonas/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Tamanho da Partícula , Polietilenoglicóis/química , Polímeros/química , Polivinil/química
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