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1.
Mol Pharm ; 19(2): 532-546, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34958588

RESUMO

The present study systematically investigates the effect of annealing conditions and the Kolliphor P 407 content on the physicochemical and structural properties of Compritol (glyceryl behenate) and ternary systems prepared via melt cooling (Kolliphor P 407, Compritol, and a hydrophilic API) representing solid-lipid formulations. The physical properties of Compritol and the ternary systems with varying ratios of Compritol and Kolliphor P 407 were characterized using differential scanning calorimetry (DSC), small- and wide-angle X-ray scattering (SWAXS) and infrared (IR) spectroscopy, and hot-stage microscopy (HSM), before and after annealing. The change in the chemical profiles of different Compritol components as a function of annealing was evaluated using 1H NMR spectroscopy. While no change in the polymorphic form of API and Kolliphor P 407 occurred during annealing, a systematic conversion of the α- to ß-form was observed in the case of Compritol. Furthermore, the polymorphic transformation of Compritol was found to be dependent on the Kolliphor P 407 content. As per the Flory-Huggins mixing theory, higher miscibility was observed in the case of monobehenin-Kolliphor P 407, monobehenin-dibehenin, and dibehenin-tribehenin binary mixtures. The miscibility of Kolliphor P 407 with monobehenin and 1,2-dibehenin was confirmed by 1H NMR analysis. The observed higher miscibility of Kolliphor P 407 with monobehenin and 1,2-dibehenin is proposed as the trigger for the physical separation from the 1,3-diglyceride and triglycerides during melt solidification of the formulations. The phase separation is postulated as the mechanism underlying the formation of a stable ß-polymorphic form (a native form of 1,3-diglyceride) of Compritol upon annealing. This finding is expected to have an important implication for developing stable solid-lipid-surfactant-based drug formulations.


Assuntos
Excipientes , Tensoativos , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Excipientes/química , Transição de Fase , Solubilidade , Tensoativos/química
2.
Biomed Res Int ; 2022: 8929715, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35924267

RESUMO

Enzymes play a powerful role as catalysts with high specificity and activity under mild environmental conditions. Significant hurdles, such as reduced solubility, reduced shelf-life, aggregate formation, and toxicity, are still ongoing struggles that scientists come across when purifying recombinant proteins. Over the past three decades, PEGylation techniques have been utilized to significantly overcome low solubility; increased protein stability, shelf-life, and bioactivity; and prevented protein aggregate formation. This review seeks to highlight the impact of PEG-based formulations that are significantly utilized to obtain favourable protein physiochemical properties. The authors further discuss other techniques that can be employed such as coexpression studies and nanotechnology-based skills to obtaining favourable protein physiochemical properties.


Assuntos
Polietilenoglicóis , Composição de Medicamentos , Polietilenoglicóis/química , Estabilidade Proteica , Proteínas Recombinantes/química , Solubilidade
3.
AAPS PharmSciTech ; 23(6): 214, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35918468

RESUMO

The present study investigates the preparation of amorphous solid dispersions (ASD) for the ent-kaurane diterpenoid siderol (SDR). Initially, evaluation of the pure drug (isolated from Sideritis scardica) revealed that the API is a non-stable glass former, and hence the selection of a suitable ASD's matrix/carrier needs special attention. For this reason, four commonly used polymers and copolymers, namely poly(vinylpyrrolidone), copovidone, hydroxypropyl cellulose, and Soluplus® (SOL), were screened via film casting and crystal growth rate measurements. Amongst them, SOL showed the highest SDR's crystal growth rate reduction, and, since it was also miscible with the drug, it was selected for further testing. In this direction, SDR-SOL ASDs were successfully prepared via melt-quench cooling. These formulations showed full API amorphization, while good physical stability (i.e., a stable SDR amorphous dispersions) were obtained after storage for several months. Finally, evaluation of molecular interactions (with the aid of ATR-FTIR spectroscopy) showed strong H-bonds between SOL and SDR, while the use of molecular dynamics (MD) simulations unraveled the nature of these interactions. Therefore, based on the findings of the present work, SOL seems to be an appropriate matrix/carrier for the preparation of SDR ASDs, although further studies are needed in order to explore its full potentials.


Assuntos
Excipientes , Polímeros , Composição de Medicamentos/métodos , Polímeros/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
4.
Eur J Pharm Biopharm ; 177: 289-307, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35872180

RESUMO

Amorphous solid dispersions (ASDs) are a proven system for achieving a supersaturated state of drug, in which the concentration of drug is greater than its crystalline solubility. The usage of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) in the development of ASDs has grown significantly, as evidenced by the fact that majority of commercially approved ASD formulations are based on HPMCAS. HPMCAS has been widely utilized as a solubility enhancer and precipitation inhibitor or stabilizer to achieve supersaturation and inhibit crystallization of drugs in the gastrointestinal tract. The characteristics of HPMCAS ASDs such as less hygroscopic, strong drug-polymer hydrophobic interactions, high solubilization efficiency, greater potential to generate, maintain drug supersaturation and crystallization inhibition outperform other polymeric carriers in ASD development. Furthermore, combining HPMCAS with other polymers or surfactants as ternary ASDs could be a viable approach for enhancing oral absorption of poorly soluble drugs. This review discusses the concepts of supersaturation maintenance or precipitation inhibition of HPMCAS in the ASD formulations. In addition, the mechanisms underlying for improved dissolution performance, oral bioavailability and stability of HPMCAS ASDs are explored.


Assuntos
Metilcelulose , Polímeros , Composição de Medicamentos , Metilcelulose/análogos & derivados , Metilcelulose/química , Polímeros/química , Solubilidade
5.
Science ; 377(6604): eabm5551, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35862544

RESUMO

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of SLC46A3, which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.


Assuntos
Antineoplásicos , Biomarcadores Farmacológicos , Proteínas de Transporte de Cobre , Composição de Medicamentos , Sistemas de Liberação de Fármacos por Nanopartículas , Nanopartículas , Neoplasias , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proteínas de Transporte de Cobre/genética , Expressão Gênica , Genômica , Humanos , Lipossomos , Camundongos , Nanomedicina , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
6.
Cancer Chemother Pharmacol ; 90(1): 71-82, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35799067

RESUMO

PURPOSE: Orally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1). METHODS: Fifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling. RESULTS: A pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67-1.33) and 0.46 (95%CI: 0.34-0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122-724). CONCLUSION: The developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.


Assuntos
Paclitaxel , Ritonavir , Administração Oral , Disponibilidade Biológica , Composição de Medicamentos , Humanos , Ritonavir/farmacologia , Trombospondina 1
7.
Drug Deliv ; 29(1): 2283-2295, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35866254

RESUMO

The purpose of this study was to prepare GeXIVA[1,2] PLGA microspheres by W/O/W re-emulsification-solvent evaporation technology and to develop sustained-release formulations to meet the clinical treatment needs of chronic neuropathic pain. Through prescription optimization, the uniformity of particle size and the encapsulation efficiency is improved, so as to achieve the quality standard of the microspheres. The mechanism of trehalose improving the stability of GeXIVA[1,2] was studied and verified by molecular simulation. The results showed that when adding trehalose to W1, using the PLGA model of 75:25, PLGA concentration of 30%, PVA concentration of 1.5%, adding 1% NaCl to PVA and adding 1% NaCl to solidification water, the prepared microspheres are smooth, the particle size is about 25 µm, and the encapsulation rate reaches 90%. The results of in vitro release experiments showed that the microspheres could be released steadily for about 30 days. The microsphere samples were characterized and analyzed by molecular simulation and powder X-ray diffractometer, and the protective mechanism of trehalose on GeXIVA[1,2] was discussed. The results showed that the hydrogen bond formed between trehalose and GeXIVA[1,2] acted as a hydration film and played a certain protective role on GeXIVA[1,2]. In addition, high-viscosity trehalose can form a glass state and wrap around GeXIVA[1,2], reducing the free movement of molecules. In the microsphere system, trehalose can also avoid the influence of PLGA material on the secondary structure of GeXIVA[1,2]. In conclusion, this study is expected to provide a new therapeutic strategy for the treatment of chronic neuropathic pain.


Assuntos
Neuralgia , Ácido Poliglicólico , Composição de Medicamentos/métodos , Humanos , Ácido Láctico/química , Microesferas , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Cloreto de Sódio , Trealose
8.
Curr Protoc ; 2(7): e489, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35857882

RESUMO

Polysorbates (PSs), including PS20 and PS80, are non-ionic surfactants widely used in the pharmaceutical industry to enhance drug solubility and stability. Despite their wide application, PSs are prone to degradation by either hydrolysis or oxidation in drug formulations during storage; therefore, a PS characterization method assessing protein products is needed for stability testing and for understanding the degradation pathway. In this article, we detail our protocol for sample preparation for forced degradation study and our instrumentation setup for PS profiling and quantitation in protein samples. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Sample preparation for forced degradation of polysorbate in protein samples Basic Protocol 2: Two-dimensional liquid chromatography coupled with charged aerosol detector or mass spectrometry to analyze polysorbate degradation.


Assuntos
Polissorbatos , Tensoativos , Cromatografia Líquida de Alta Pressão/métodos , Composição de Medicamentos , Espectrometria de Massas/métodos , Polissorbatos/análise , Tensoativos/química
9.
Int J Pharm Compd ; 26(4): 293-296, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35820134

RESUMO

Medications on the market for the treatment of arthritis are more commonly appropriate for adult arthritic patients. However, for patients with juvenile arthritis, a compounding pharmacist can prepare specialized medications for those patients who are in need of a specific dosage, or for those patients who require a different dosage form. Additionally, more than one active ingredient can be combined in pharmacy compounding to meet a specific patient's needs. Compounded topical/transdermal preparations can provide customized medication options, which may not be commercially available, for pediatric patients with juvenile arthritis.


Assuntos
Artrite Juvenil , Composição de Medicamentos , Assistência Farmacêutica , Artrite Juvenil/tratamento farmacológico , Criança , Humanos
10.
Int J Mol Sci ; 23(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35897838

RESUMO

Formulations of therapeutic proteins are sensitive to photo-degradation by near UV and visible light. Mechanistically, especially the processes leading to protein modification under visible light exposure are not understood. Potentially, these processes may be triggered by a ligand to metal charge transfer in excipient-metal complexes. This article summarizes recent analytical and mechanistic work on such reactions under experimental conditions relevant to pharmaceutical formulations.


Assuntos
Peróxido de Hidrogênio , Poluentes Químicos da Água , Composição de Medicamentos , Peróxido de Hidrogênio/química , Ferro/química , Oxirredução , Peptídeos/metabolismo , Proteínas/metabolismo , Raios Ultravioleta , Poluentes Químicos da Água/química
11.
Molecules ; 27(14)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35889365

RESUMO

Coupled with an azo coupling reaction, a simple, rapid, sensitive, and effective surface-enhanced resonance Raman scattering (SERRS) detection method for benzocaine was developed. In our study, benzocaine which is used clinically as a local anesthetic was derived with p-aminothiophenol into a corresponding azo product within 5 min, resulting in a strong SERRS response with the simple addition of Ag NPs excited with a 532 nm laser. The linear correlation between SERRS intensity of dominant bands and logarithm of benzocaine concentration was investigated for quantitative determination. The method reached a limit of detection (LOD) down to 0.139 and 0.0788 µg/mL calculated with two peak intensity ratios (I1568/I2260 and I1331/I2260), which is comparable to most studies reported previously, and meanwhile had superiority in simplicity and rapidness. The quantitative measurements for pharmaceutical preparations with benzocaine were conducted without complex extraction and enrichment processes. It was indicated that the SERRS assay combined with azo derivatization reaction has implications for practical applications in more complicated systems involving biological samples, in which appropriate and simplified pretreatments were conducted to remove interfering components.


Assuntos
Benzocaína , Análise Espectral Raman , Composição de Medicamentos , Lasers , Limite de Detecção , Análise Espectral Raman/métodos
12.
Sci Rep ; 12(1): 12551, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869132

RESUMO

Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre-few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations.


Assuntos
Terapia a Laser , Nanopartículas , Composição de Medicamentos/métodos , Meloxicam , Nanopartículas/química , Tamanho da Partícula , Solubilidade , Água
13.
Mol Pharm ; 19(8): 2950-2961, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35797094

RESUMO

Using sulfamethoxazole (SMZ) and trimethoprim (TMP) as model drugs, we designed amorphous solid dispersions (ASDs) for the simultaneous solubility enhancement of two active pharmaceutical ingredients (APIs) by exploiting the drug-drug and drug-polymer interactions. In order to make this approach broadly applicable and over a wide dose range, a mixture of SMZ and TMP at weight ratios of 5:1 and 1:5 (w/w) were formulated into ternary ASDs. Depending on the dose ratio of the two drugs, the polymer used was either an aminoalkyl methacrylate copolymer (Eudragit, EDE) or polyacrylic acid. The drug-drug and drug-polymer interactions were characterized to be ionic by infrared and solid-state nuclear magnetic resonance spectroscopy. The interactions resulted in a substantial reduction in molecular mobility, evident from the increase in the structural relaxation time determined by dielectric spectroscopy. The drug-drug interaction resulted in ∼3 orders of magnitude reduction in molecular mobility. The addition of a polymer led to a further decrease in molecular mobility of up to 4 orders of magnitude. The strength of intermolecular interactions was also estimated from the glass transition temperatures of the ASDs obtained by differential scanning calorimetry. The strong intermolecular interactions yielded highly stable ASDs with no evidence of crystallization, both at elevated temperatures and under accelerated storage conditions (40 °C/75% relative humidity; 6 weeks). The dissolution performances of the ASDs were evaluated using the area under the curve (AUC) obtained from the concentration-time profiles under the non-sink condition. SMZ and TMP in their ternary ASDs, when compared with their crystalline counterparts, exhibited up to 6.4- and 4.6-fold increases in AUC, respectively. Importantly, the synchronized release of the two drugs was observed, a desirable attribute in synergistic formulations. A single-phase ternary ASD, stabilized by drug-drug and drug-polymer interactions, is likely responsible for the unique release profile.


Assuntos
Polímeros , Cristalização , Combinação de Medicamentos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Polímeros/química , Solubilidade
14.
Mol Pharm ; 19(8): 2765-2775, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35833828

RESUMO

A graphical analysis of both drug and coformer concentrations contributed by dissolving cocrystals is presented in the context of a simplified cocrystal phase diagram. The conceptual basis and analysis identify parameters that control cocrystal dissolution-drug supersaturation-precipitation (DSP) behavior. The important effects of coformer concentration, cocrystal dose, and cocrystal solubility on drug supersaturation levels are demonstrated and quantified by the DSPindex. While the studies presented rely on high and nonstoichiometric coformer concentrations contributed by the dissolving cocrystals, the concepts and findings can answer the question of whether and how much coformer should be added to cocrystal dissolution media or formulations.


Assuntos
Solubilidade , Cristalização , Composição de Medicamentos
15.
Int J Pharm Compd ; 26(4): 298-301, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35820135

RESUMO

Prior to the COVID-19 pandemic, hospitals were already experiencing shortages of key injectable drugs. Unprecedented demand due to large numbers of critically ill patients with COVID-19 contributed to these shortages, especially analgesics, sedatives, and paralytics. Advocacy efforts are successfully creating changes that may improve the current situation. The United States Drug Enforcement Administration tried to combat the shortage situation by increasing annual production quotas of controlled substances necessary for COVID-19 care. This situation was discussed by the United States Drug Enforcement Administration in a press-release dated April 7, 2020. In addition to this, the U.S. Food and Drug Administration has provided guidance to compounding pharmacies, allowing for increased flexibility in the compounding and distribution of drug products. The website for the new guidances can be found within the resources provided in this article.


Assuntos
COVID-19 , Farmácias , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Composição de Medicamentos , Humanos , Pandemias , Preparações Farmacêuticas , Farmacêuticos
16.
Int J Pharm Compd ; 26(4): 309-315, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35820137

RESUMO

Dispensing compounded sterile injectable drug preparations that contain particulates can have serious patient-safety implications. While there is a lack of controlled human studies to demonstrate the clinical concerns that particles can be carriers for microbiological contamination, they have been shown to potentially block blood vessels. Anecdotal studies found that foreign body emboli and granulomas are the most common result of particulate matter present in intravenous solutions. The compounding of absolutely particle-free injectable preparations is nearly impossible under real-life conditions. Hence, inspection of each filled and sealed compounded injectable drug before it is labeled and dispensed is mandatory. To avoid a noncompliance observation, this article aims to outline the regulatory expectations, visual inspector training and qualification program, and adequate visual-inspection procedures and equipment.


Assuntos
Contaminação de Medicamentos , Material Particulado , Composição de Medicamentos/métodos , Humanos , Injeções
17.
Int J Pharm Compd ; 26(4): 342-351, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35820140

RESUMO

Amitriptyline hydrochloride is indicated for the relief of symptoms of depression. A review of the therapeutic uses of amitriptyline hydrochloride reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of amitriptyline currently exists. Amitriptyline hydrochloride is commercially available only as 10-mg, 25-mg, 50-mg, 75-mg, 100-mg, and 150-mg tablets. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded amitriptyline hydrochloride suspensions in PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two amitriptyline hydrochloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability- indicating high-performance liquid chromatographic assay for the determination of the chemical stability of amitriptyline hydrochloride in PCCA SuspendIt was developed and validated. Suspensions of amitriptyline hydro- chloride were prepared in PCCA SuspendIt at 1-mg/mL and 5-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, 49, 63, 91, 119, and 185. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that amitriptyline hydrochloride concentrations did not go below 99.8% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. The pH values remained constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that amitriptyline hydrochloride is physically, chemically, and microbiologically stable in PCCA SuspendIt for 185 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for amitriptyline hydrochloride in a liquid dosage form, with an extended beyond-use date to meet patient needs.


Assuntos
Amitriptilina , Cromonas , Composição de Medicamentos , Estabilidade de Medicamentos , Excipientes , Humanos , Suspensões
18.
J Control Release ; 348: 537-552, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35690278

RESUMO

Targeting the release of drugs in specific sites of the upper GI tract would meet local therapeutic goals, improve the bioavailability of specific drugs and help overcoming compliance-related limitations, especially in chronic illnesses of great social/economic impact and involving polytherapies (e.g. Parkinson's and Alzeimer's disease, tubercolosis, malaria, HIV, HCV). It has been traditionally pursued using gastroretentive (GR) systems, i.e. low-density, high-density, magnetic, adhesive and expandable devices. More recently, the interest towards oral administration of biologics has prompted the development of novel drug delivery systems (DDSs) provided with needles and able to inject different formulations in the mucosa of the upper GI tract and particularly of esophagus, stomach or small intestine. Besides comprehensive literature analysis, DDSs identified as smart devices in view of their high degree of complexity in terms of design, working mechanism, materials employed and manufacturing steps were discussed making use of graphic tools.


Assuntos
Trato Gastrointestinal Superior , Administração Oral , Disponibilidade Biológica , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos
19.
Front Endocrinol (Lausanne) ; 13: 859487, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757415

RESUMO

Congenital hypothyroidism (CH) is a relatively frequent congenital endocrine disorder, caused by defective production of thyroid hormones (THs) at birth. Because THs are essential for the development of normal neuronal networks, CH is also a common preventable cause of irreversible intellectual disability (ID) in children. Prolonged hypothyroidism, particularly during the THs-dependent processes of brain development in the first years of life, due to delays in diagnosis, inadequate timing and dosing of levothyroxine (l-thyroxine or l-T4), the non-compliance of families, incorrect follow-up and the interference of foods, drugs and medications affecting the absorption of l-T4, may be responsible for more severe ID. In this review we evaluate the main factors influencing levels of THs and the absorption of l-T4 in order to provide a practical guide, based on the existing literature, to allow optimal follow-up for these patients.


Assuntos
Hipotireoidismo Congênito , Tiroxina , Criança , Hipotireoidismo Congênito/tratamento farmacológico , Composição de Medicamentos , Humanos , Recém-Nascido , Hormônios Tireóideos/uso terapêutico , Tiroxina/uso terapêutico
20.
Antimicrob Agents Chemother ; 66(6): e0221821, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35658489

RESUMO

Liver-stage Plasmodium in humans is an early stage of malarial infection. Decoquinate (DQ) has a potent multistage antimalarial activity. However, it is practically water insoluble. In this study, the hot-melt extrusion (HME) approach was employed to prepare solid dispersions of DQ to improve oral bioavailability. The DQ dispersions were homogeneous in an aqueous suspension that contained most DQ (>90%) in the aqueous phase. Soluplus, a solubilizer, was found compatible with DQ in forming nanoparticle formulations during the HME process. Another excipient HPMC AS-126 was also proven to be suitable for making DQ nanoparticles through HME. Particle size and antimalarial activity of HME DQ suspensions remained almost unchanged after storage at 4°C for over a year. HME DQ was highly effective at inhibiting Plasmodium infection in vitro at both the liver stage and blood stage. HME DQ at 3 mg/kg by oral administration effectively prevented Plasmodium infection in mice inoculated with Plasmodium berghei sporozoites. Orally administered HME DQ at 2,000 mg/kg to mice showed no obvious adverse effects. HME DQ at 20 mg/kg orally administered to rats displayed characteristic distributions of DQ in the blood with most DQ in the blood cells, revealing the permeability of HME DQ into the cells in relation to its antimalarial activity. The DQ dispersions may be further developed as an oral formulation targeting Plasmodium infection at the liver stage.


Assuntos
Antimaláricos , Decoquinato , Malária , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Decoquinato/farmacologia , Composição de Medicamentos , Temperatura Alta , Fígado , Malária/tratamento farmacológico , Camundongos , Plasmodium berghei , Ratos , Solubilidade
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