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1.
AAPS PharmSciTech ; 16(5): 1091-100, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25690735

RESUMO

The development of drug dispersions using solid lipids is a novel formulation strategy that can help address the challenges of poor drug solubility and systemic exposure after oral administration. The highly lipophilic and poorly water-soluble drug torcetrapib could be effectively formulated into solid lipid microparticles (SLMs) using an anti-solvent precipitation strategy. Acoustic milling was subsequently used to obtain solid lipid nanoparticles (SLNs). Torcetrapib was successfully incorporated into the lipid matrix in an amorphous state. Spherical SLMs with mean particle size of approximately 15-18 µm were produced with high drug encapsulation efficiency (>96%) while SLNs were produced with a mean particle size of 155 nm and excellent colloidal stability. The in vitro drug release and the in vivo absorption of the solid lipid micro- and nanoparticles after oral dosing in rats were evaluated against conventional crystalline drug powders as well as a spray dried amorphous polymer dispersion formulation. Interestingly, the in vitro drug release rate from the lipid particles could be tuned for immediate or extended release by controlling either the particle size or the precipitation temperature used when forming the drug-lipid particles. This change in the rate of drug release was manifested in vivo with changes in Tmax as well. In addition, in vivo pharmacokinetic studies revealed a significant increase (∼6 to 11-fold) in oral bioavailability in rats dosed with the SLMs and SLNs compared to conventional drug powders. Importantly, this formulation approach can be performed rapidly on a small scale, making it ideal as a formulation technology for use early in the drug discovery timeframe.


Assuntos
Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/farmacocinética , Portadores de Fármacos , Lipídeos/química , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Administração Oral , Animais , Anticolesterolemiantes/sangue , Anticolesterolemiantes/química , Disponibilidade Biológica , Preparações de Ação Retardada , Composição de Medicamentos , Masculino , Modelos Biológicos , Nanopartículas , Tamanho da Partícula , Quinolinas/sangue , Quinolinas/química , Ratos Wistar , Solubilidade , Temperatura
2.
J Med Chem ; 65(7): 5593-5605, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35298158

RESUMO

We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Receptor de Insulina , Suínos , Porco Miniatura , Índice Terapêutico
3.
J Med Chem ; 65(1): 485-496, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34931831

RESUMO

Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/farmacologia , Venenos de Aranha/síntese química , Animais , Degranulação Celular/efeitos dos fármacos , Cistina/química , Desenho de Fármacos , Temperatura Alta , Mastócitos/efeitos dos fármacos , Modelos Moleculares , Medição da Dor/efeitos dos fármacos , Ratos , Venenos de Aranha/farmacologia
4.
Int J Pharm ; 592: 120026, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33137448

RESUMO

A diverse set of drug and polymer combinations have been effectively evaluated utilizing a newly developed method called acoustic fusion to form amorphous solid dispersions (ASD) on the mg-scale, indicating that this approach is a general procedure that can be applied for ASD drug formulations. We have demonstrated the effectiveness of this acoustic fusion process by generating amorphous solid dispersions of various BCS class 2 and 4 drug candidates, including torcetrapib, itraconazole, and lopinavir, with a variety of polymer systems, including HPMCAS (L, M, and H), copovidone, Soluplus®, PEG1500, Vitamin-E TPGS, Kolliphor EL, and Eudragit, etc. Formulations of these ASD drug products demonstrated significantly elevated solubility of the drug substance compared to the solubility of the crystalline form of the drug. Acoustic fusion products using the model drug torcetrapib in either HPMCAS-LF, copovidone + Vitamin-E TPGS, or Soluplus®, exhibited enhanced supersaturation solubility in aqueous buffer in vitro compared to the drug in crystalline form, indicating that the acoustic fusion process resulted in an amorphous solid dispersion state similar to those formed in spray drying (SD) or hot melt extrusion (HME) processes. In vivo dosing of formulations of the acoustic fusion products in a rat pharmacokinetic study at a dose level of 10 mg/kg resulted in an improvement in exposures of approximately 8-fold by AUC(0-24) in comparison to a conventional suspension formulation of the drug material in crystalline form, thus validating the efficiency of this novel acoustic fusion approach for elevating the bioperformance in preclinical studies.


Assuntos
Tecnologia de Extrusão por Fusão a Quente , Itraconazol , Acústica , Animais , Composição de Medicamentos , Ratos , Solubilidade
5.
Vaccines (Basel) ; 9(11)2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34835271

RESUMO

Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in the disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria from Lachnospiraceae, Ruminococcaceae, and Clostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.

6.
Chem Res Toxicol ; 23(12): 1871-3, 2010 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-21121646

RESUMO

A simple, reliable, and accurate method was developed for quantitative assessment of metabolite coverage in preclinical safety species by mixing equal volumes of human plasma with blank plasma of animal species and vice versa followed by an analysis using high-resolution full-scan accurate mass spectrometry. This approach provided comparable results (within (±15%) to those obtained from regulated bioanalysis and did not require synthetic standards or radiolabeled compounds. In addition, both qualitative and quantitative data were obtained from a single LC-MS analysis on all metabolites and, therefore, the coverage of any metabolite of interest can be obtained.


Assuntos
Cromatografia Líquida de Alta Pressão , Preparações Farmacêuticas/metabolismo , Espectrometria de Massas em Tandem , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/normas , Humanos , Marcação por Isótopo , Nitrilas/sangue , Nitrilas/metabolismo , Nitrilas/normas , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/normas , Piperazinas/sangue , Piperazinas/metabolismo , Piperazinas/normas , Coelhos , Padrões de Referência , Espectrometria de Massas em Tandem/normas , Testes de Toxicidade , Ureia/análogos & derivados , Ureia/sangue , Ureia/metabolismo , Ureia/normas
7.
J Am Soc Mass Spectrom ; 30(9): 1779-1789, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250320

RESUMO

Peptides represent a promising modality for the design of novel therapeutics that can potentially modulate traditionally non-druggable targets. Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) are two large families that are being explored extensively as drug delivery vehicles, imaging reagents, or therapeutic treatments for various diseases. Many CPPs and AMPs are cationic among which a significant portion is extremely basic and hydrophilic (e.g., nona-arginine). Despite their attractive therapeutic potential, it remains challenging to directly analyze and quantify these super cationic peptides from biological matrices due to their poor chromatographic behavior and MS response. Herein, we describe a generic method that combines solid phase extraction and LC-MS/MS for analysis of these peptides. As demonstrated, using a dozen strongly basic peptides, low µM concentration of perfluoropentanoic acid (PFPeA) in the mobile phase enabled excellent compound chromatographic retention, thus avoiding co-elution with solvent front ion suppressants. PFPeA also had a charge reduction effect that allowed the selection of parent/ion fragment pairs in the higher m/z region to further reduce potential low molecular weight interferences. When the method was coupled to the optimized sample extraction process, we routinely achieved low digit ng/ml sensitivity for peptides in plasma/tissue. The method allowed an efficient evaluation of plasma stability of CPPs/AMPs without fluorescence derivatization or other tagging methods. Importantly, using the widely studied HIV-TAT CPP as an example, the method enabled us to directly assess its pharmacokinetics and tissue distribution in preclinical animal models.


Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Ácidos Pentanoicos/química , Peptídeos/análise , Peptídeos/farmacocinética , Animais , Peptídeos Catiônicos Antimicrobianos/análise , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Penetradores de Células/análise , Precipitação Química , Estabilidade de Medicamentos , Fluorocarbonos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Peptídeos/química , Ratos Wistar , Extração em Fase Sólida , Distribuição Tecidual , Ácido Tricloroacético/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/análise , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacocinética
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