RESUMO
The adjuvant is essential for vaccines because it can enhance or directly induce a strong immune response associated with vaccine antigens. Ginsenoside Rh2 (Rh2) had immunomodulatory effects but was limited by poor solubility and hemolysis. In this study, Rh2 liposomes (Rh2-L) were prepared by ethanol injection methods. The Rh2-L effectively dispersed in a double emulsion adjuvant system to form a Water-in-Oil-in-Water (W/O/W) emulsion and had no hemolysis. The physicochemical properties of the adjuvants were tested, and the immune activity and auxiliary effects indicated by the Foot-and-Mouth disease (FMDV) antigen were evaluated. Compared with the mice vaccinated with the FMD vaccine prepared with the double emulsion adjuvant alone, those with the FMD vaccine prepared with the double emulsion adjuvant containing Rh2-L had significantly higher neutralizing antibody titer and splenocyte proliferation rates and showed higher cellular and humoral immune responses. The results demonstrated that Rh2-L could further enhance the immune effect of the double emulsion adjuvant against Foot-and-Mouth Disease.
Assuntos
Vírus da Febre Aftosa , Febre Aftosa , Vacinas Virais , Camundongos , Animais , Febre Aftosa/prevenção & controle , Lipossomos , Emulsões , Anticorpos Antivirais , Adjuvantes Imunológicos/farmacologia , Adjuvantes Farmacêuticos , ÁguaRESUMO
Biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) have been widely used as delivery vehicles for chemotherapy drugs. However, premature drug release in PLGA NPs can damage healthy tissue and cause serious adverse effects during systemic administration. Here, we report a tannic acid-Fe(III) (FeIII-TA) complex-modified PLGA nanoparticle platform (DOX-TPLGA NPs) for the tumor-targeted delivery of doxorubicin (DOX). A PEGylated-PLGA inner core and FeIII-TA complex outer shell were simultaneously introduced to reduce premature drug release in blood circulation and increase pH-triggered drug release in tumor tissue. Compared to the unmodified NPs, the initial burst rate of DOX-TPLGA NPs was significantly reduced by nearly 2-fold at pH 7.4. Moreover, the cumulative drug release rate at pH 5.0 was 40% greater than that at pH 7.4 due to the pH-response of the FeIII-TA complex. Cellular studies revealed that the TPLGA NPs had enhanced drug uptake and superior cytotoxicity of breast cancer cells in comparison to free DOX. Additionally, the DOX-TPLGA NPs efficiently accumulated in the tumor site of 4T1-bearing nude mice due to the enhanced permeability and retention (EPR) effect and reached a tumor inhibition rate of 85.53 ± 8.77% (1.31-fold versus DOX-PLGA NPs and 3.12-fold versus free DOX). Consequently, the novel TPLGA NPs represent a promising delivery platform to enhance the safety and efficacy of chemotherapy drugs.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacocinética , Sistemas de Liberação de Fármacos por Nanopartículas/química , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos Férricos/química , Compostos Férricos/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Sistemas de Liberação de Fármacos por Nanopartículas/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Taninos/química , Taninos/farmacologiaRESUMO
Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with poor prognosis. Therapeutic drugs for RCC can easily develop resistance or have unignorable toxicity or limited efficiency. Here, the thermosensitive mitochondrial metabolism-interfering anticancer drug lonidamine (LND) was combined with the photothermal material polydopamine (PDA) to treat RCC. To delivery drugs accurately to RCC site, LND and PDA were loaded in stellate mesoporous silica nanoparticles (MSNs) with a large surface area and cloaked with RCC membranes (MLP@M). The results showed that MLP@M exhibited excellent tumor targeting ability. The synergistic effects of LND and PDA in MLP@M were greatly enhanced when triggered by an 808â¯nm laser. Moreover, the antiproliferative and tumor suppressing abilities were enhanced with good biocompatibility after MLP@Mâ¯+â¯laser treatment. Additionally, 80% of RCC tumor-bearing mice treated with MLP@Mâ¯+â¯laser did not relapse. Our study provides a potential therapeutic approach for RCC treatment.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Indazóis/uso terapêutico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Terapia Fototérmica , Polímeros/uso terapêutico , Animais , Antineoplásicos/farmacologia , Carcinoma de Células Renais/metabolismo , Humanos , Indazóis/farmacologia , Indóis/farmacologia , Neoplasias Renais/metabolismo , Camundongos , Mitocôndrias/metabolismo , Polímeros/farmacologia , Dióxido de Silício/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this work, we have developed a reducible, self-assembling disulfide cross-linked and peptide-based micelle system for codelivery of miR-4638-5p and DTX to improve the efficacy of castration-resistant prostate cancer (CRPC) therapy. The result showed that DTX in micelles (DTX-VPs) inhibited cell growth and induced apoptosis more effectively than free DTX both in vitro and in vivo. In addition, the DTX and miR-4638-5p loaded micelles (Co-VPs) achieved the most pronounced anticancer effect of all groups. Immunohistochemical analysis indicated that miR-4638-5p in micelle system could effectively downregulate the expression of Kidins220 and further improve the anticancer effect by enhancing tumor cell apoptosis and suppressing tumor cell proliferation. Finally, the bioimaging analysis demonstrated that DIR in micelles (DIR-VPs) showed a higher concentration and a longer retention time in tumor tissue than did free DIR, which indicated an excellent tumor-targeting ability of the micelle system. All these results suggest that codelivery of miR-4638-5p and DTX via polypeptide micelle system has a potential for CRPC treatment.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Peptídeos/química , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Humanos , Masculino , Proteínas de Membrana/metabolismo , Micelas , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oxirredução/efeitos dos fármacosRESUMO
The solvent-shift method was used to identify appropriate polymers that inhibit the growth of felodipine crystals by monitoring particle size in supersaturated drug solutions in the presence of different polymers. We speculated that there would be an intermolecular interaction between the selected polymer (zein) and felodipine by extrapolating the inhibitory effect on crystal growth and then used the selected polymer as a carrier to prepare solid dispersions. The formulations were characterized by crystalline properties, thermodynamics of mixing, dissolution behavior, and physical stability. Powder x-ray diffraction and differential scanning calorimetry experiments indicated that amorphous solid dispersions were formed when the proportion of felodipine was < 30% (w/w). Stability tests showed that a solid dispersion with 20% felodipine remained in an amorphous state and was stable under accelerated storage conditions for 6 months. The dissolution rates of solid dispersions were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Analysis by Fourier-transform infrared spectroscopy and Raman microspectroscopy indicated the formation of intermolecular interactions between zein and felodipine. The study demonstrates the successful application of the chosen polymer as a carrier in solid dispersions and validates the concept of extrapolating the inhibitory effect on crystal growth to intermolecular interactions.
Assuntos
Felodipino/administração & dosagem , Felodipino/química , Cristalização , Composição de Medicamentos , Estabilidade de Medicamentos , Polímeros/química , Solubilidade , Solventes , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica , Difração de Raios X , Zeína/químicaRESUMO
The objective of this research was to develop a novel solvent system to prepare spherically agglomerated crystals (SAC) of ascorbic acid with improved flowability for direct compression. A spherical agglomeration method was developed by selecting the mixed solvents (n-butyl and ethyl acetate) as a poor solvent and the process was further optimized by using triangular phase diagram and particle vision measurement. Physiochemical properties of SAC were characterized and compared with original drug crystals. It showed that amount of poor solvent, ratio of solvent mixture, and drug concentration are critical for preparation of SAC with desirable properties. The solid state of SAC was same as original crystals according to DSC, XRD, and FT-IR results. There was no significant difference in solubility and dissolution rate of drug between SAC and original crystals. The flowability and packability of SAC as well as the tensile strength and elastic recovery of tablets made from SAC were all significantly improved when compared with original crystals and tablets from crystals. It is concluded that the present method was suitable to prepare SAC of ascorbic acid for direct compression.
Assuntos
Ácido Ascórbico , Cristalização , Tamanho da Partícula , Solubilidade , Solventes , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The objective of this study was to prepare ibuprofen (IBP) microparticles by pH-change method and enhance the dissolution rate in vitro. Tween80 and Cremophor RH40 were selected as stabilizers to change the microparticles morphology. The microparticles were evaluated by dissolution profiles and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), laser particle size analyzer, scanning electron microscope (SEM) and Fourier transform infrared spectroscopy (FTIR). IBP microparticle prepared with surfactants showed a significant increase in dissolution rate (more than three times within 10 min) and an obvious decrease in mean particle size. The morphology of microparticles was obviously changed. XRD and DSC results revealed that the crystalline state of the untreated IBP and the prepared IBP microparticles were similar. The crystallinity of microparticles produced might be lightly reduced by adding surfactants in preparation process. All results showed that it was useful to prepare high dispersion microparticle by adding surfactants in the preparation process for improving the dissolution.
Assuntos
Anti-Inflamatórios não Esteroides/química , Excipientes/química , Ibuprofeno/química , Varredura Diferencial de Calorimetria , Cristalização , Tamanho da Partícula , Polietilenoglicóis/química , Polissorbatos/química , Difração de Pó , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química , Difração de Raios XRESUMO
Micro-particles of 17ß-estradiol (ED) were prepared with polyvinylpyrrolidone (PVP) by in situ pH-dependent solubility technique. Products were characterized using multiple instruments, and molecular interactions between ED and PVP were explored. Powder X-ray diffraction and thermal analysis revealed crystalline ED in the micro-particles is hemihydrated. PVP was also present in the micro-particles. Laser particle size analysis and scanning electron microscopy revealed thin slice morphology, which might have resulted from the influence of PVP. Moreover, the results of contact angle, specific surface area, and dynamic vapor sorption showed that the surface properties of products were improved. These physicochemical properties of the micro-particles resulted in an obvious improvement in dissolution rate. Fourier transform infrared spectroscopy and 1H nuclear magnetic resonance revealed hydrogen bonding between ED and PVP. A method was established for the preparation of micro-particles through the addition of PVP during the reaction process.
Assuntos
Química Farmacêutica/métodos , Estradiol/síntese química , Excipientes Farmacêuticos/química , Povidona/química , Varredura Diferencial de Calorimetria/métodos , Fenômenos Químicos , Cristalização , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura/métodos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodosRESUMO
It is crucial to develop non-viral gene vectors that can efficiently and safely transfect plasmid DNA into cells. Low transfection efficiency and high cytotoxicity of cationic polymers hinder their application as gene carriers. Modification of cationic polymers has emerged as an attractive strategy for efficient and safe nucleic acids delivery. In this study, a simple and rapid method is developed to synthesize a series of multifunctional polymers by utilizing biodegradable polyaspartic acid as the backbone and modifying it with three modules. This one-component polymer possesses capabilities for nucleic acid condensation, cellular uptake, and endosomal escape. Polymers containing imidazole, triazole, or pyridine group exhibited promising transfection activity. Substituted with dodecylamine or 2-hexyldecan-1-amine enhance cellular uptake and subsequent transfection. Furthermore, the influence of ionizable amine side chains on gene delivery is investigated. Two optimal polymers, combined with the avian encephalomyelitis virus (AEV) plasmid vaccine, induced robust specific antibody responses and cellular immune responses in mice and chickens. Through module-combination design and screening of polyaspartamide polymers, this study presents a paradigm for the development of gene delivery vectors.
Assuntos
DNA , Técnicas de Transferência de Genes , Peptídeos , Plasmídeos , Polímeros , Transfecção , Animais , Peptídeos/química , Polímeros/química , Camundongos , Humanos , DNA/administração & dosagem , Transfecção/métodos , Galinhas , Feminino , Camundongos Endogâmicos BALB C , Vacinas de DNA/administração & dosagem , Vetores Genéticos/administração & dosagemRESUMO
The objective of the study is to prepare a new self-nanoemulsifying drug delivery system (SNEDDS) with amphiphilic diblock copolymers methoxy poly (ethylene glycol)-block-poly (ε-caprolactone) (MPEG-b-PCL) and to investigate the effect of MPEG-b-PCL on the characteristics of SNEDDS. MPEG-b-PCL was synthesized and characterized by (1)H-NMR, IR and GPC. Various ratios of MPEG-b-PCL copolymers and Tween 80 were used as emulsifier to prepare the new SNEDDS. SNEDDS with high oil and low surfactant content forms a semi-solid gel at room temperature, which could be effectively sealed in soft or hard capsules. The mean droplet size of SNEDDS-generated nanoemulsions significantly decreased after the addition of diblock polymer and increased with increase of PCL chain in MPEG-b-PCL. The drug Coenzyme Q10 (CoQ10) was chosen as the model compound in this study due to its insolubility in water. CoQ10 from SNEDDS was rapidly dissolved regardless of the fluid condition.
Assuntos
Caproatos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/síntese química , Lactonas/química , Nanosferas/química , Poliésteres/síntese química , Polietilenoglicóis/síntese química , Caproatos/administração & dosagem , Emulsificantes/administração & dosagem , Lactonas/administração & dosagem , Nanosferas/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polissorbatos/administração & dosagem , Polissorbatos/químicaRESUMO
Cholesterol (CHOL) is essential for developing lipid nanoparticles (LNPs) for gene delivery because it enhances membrane fusion and improves the delivery efficiency of gene cargos. An attractive pDNA carrier, corosolic acid (CA)-modified lipid nanoparticles (CLNPs), was developed by replacing CHOL in LNPs to deliver pDNA at various ratios of nitrogen groups to phosphate groups (N/P). The resultant CLNPs with a higher CHOL/CA ratio exhibited similar mean particle size, zeta potential, and encapsulation efficiency to those of LNPs. In comparison with LNPs, CLNPs (CHOL:CA ratio = 2:1) achieved increased cellular uptake and enhanced transfection efficacy while maintaining low cytotoxicity. In vivo results from chicken experiments demonstrated that CLNPs encapsulating DNA vaccines against avian influenza at a N/P ratio of 3 could elicit similar-level humoral and cellular immune responses compared with those of LNPs at a higher N/P ratio, thereby suggesting the induction of desirable immune effects using less ionizable lipids. Our study provides a reference for further research on the application of CA in LNPs for gene delivery, and the development of novel delivery systems for DNA vaccines against avian influenza.
Assuntos
Influenza Aviária , Nanopartículas , Vacinas de DNA , Animais , Influenza Aviária/prevenção & controle , LipídeosRESUMO
BACKGROUND: Subcutaneous injection of biopharmaceutical agents or microparticles is challenging due to issues with low injection efficiency and high residual amounts. OBJECTIVE: This study aimed to determine the important factors affecting the injectability of microparticle delivery systems, establish a suitable injection system with lower injection force and higher discharge rate, and eventually develop a reliable injectability evaluation system for injectable microparticle delivery systems in vitro and in vivo. METHODS: The effects of various parameters, including particle size, injection speed, concentration of microspheres suspension, vehicle viscosity, needle length and gauge were evaluated by measuring the injection force and discharge rate. The characteristics of microparticles and rheological measurement of the suspension systems were studied. A design of experiment approach was utilized to evaluate the interaction between the microsphere suspension, vehicle viscosity and needle gauges. Both in vitro sieve tests and in vivo tests in rats were conducted to evaluate injectability. RESULTS: The in vitro test results showed that the vehicle viscosity and injection speed have varying effects on discharge rate and injection force, respectively. Particle size and needle gauge have substantial influence on injectability, larger particle size and smaller needle gauges resulting in poor injectability, while the needle gauge was found to have the greatest influence on injectability. Levonorgestrel (LNG) microsphere and glass bead were relatively uniform spherical, the glass bead had extremely smooth surface; while mesoporous silica had irregular shape. The settling rate of glass bead was the fastest, which was about 18 times faster than the LNG microsphere. The CMC-Na had a poor interaction with the LNG microspheres, glass bead and mesoporous silica and showed basically Newtonian behavior in the shear rate range of 0.1 s-1-100 s-1. When shear rate increased to more than 100 s-1, no obvious shear thinning behavior was observed. CMC-Na formed a nodule structure with whether LNG microspheres or the glass beads, which were much lower than that with the mesoporous silica in static state, among which the glass beads were the weakest. The viscosity of the suspension increased with the rising of the volume fraction of particles. Fundamentals of hydrodynamics in capillaries were referenced, such as Navier-Stokes Law equation, Krieger-Dougherty (K-D) equation, Hagen-Poiseuille equation. The best results achieved was using a suspension concentration of 120-240 mg /mL and a viscosity of 60 cP at 20 °C with 23-gauge needles. The optimized conditions were verified in vivo tests. It was proven that the LNG microsphere suspension had a good injectability when injected into subcutaneous tissue of rats. CONCLUSION: The injection system of injectable microparticle delivery system with lower injection force and higher discharge rate was established and the evaluation method was suitable for the injectability evaluation both in vivo and in vitro. Improved injectability would promote the clinical translation of microparticle delivery systems.
Assuntos
Fenômenos Mecânicos , Alta do Paciente , Humanos , Animais , Ratos , Injeções Subcutâneas , Suspensões , Microesferas , ViscosidadeRESUMO
Microparticles (MPs) and amorphous solid dispersions (SDs) are effective methods to improve the dissolution of insoluble drugs. However, stability is a concern for these two high-energy systems, resulting from high surface area and amorphous polymorph, respectively. As an amphiphilic polymer, Soluplus (SOL) is usually used as a carrier in SDs. In this study, erlotinib microparticles (ERL MPs) and erlotinib solid dispersions (ERL SDs) were prepared with SOL by bottom-up technology and solvent evaporation. The solid-state properties of ERL MPs and ERL SDs were characterized by Differential Scanning Calorimetry (DSC), Powder X-Ray Diffraction (PXRD) and Scanning Electron Microscopy (SEM). The ERL MPs existed in a metastable crystal form A while the ERL SDs existed in an amorphous state. Fourier transform infrared spectroscopy (FT-IR) showed that there was a hydrogen bond interaction between the N-H group of ERL and the carbonyl group of SOL in ERL MPs and SDs. The dissolution profiles of ERL SDs and ERL MPs were improved significantly. ERL MPs showed better stability than ERL SDs in accelerated stability test. The discrepant stabilizing effects of polymer SOL in two systems may provide effective ideas for solubilization of insoluble drugs and the stability of drugs after recrystallization.
RESUMO
Cannabidiol (CBD), a primary bioactive phytocannabinoid extracted from hemp, is reported to possess potent anti-tumorigenic activity in multiple cancers. However, the effects of CBD on bladder cancer (BC) and the underlying molecular mechanisms are rarely reported. Here, several experiments proved that CBD promoted BC cells (T24, 5637, and UM-UC-3) death. For example, T24 cells were treated with 12 µM CBD for 48 h, flow cytometry analysis demonstrated that early and late apoptotic cells were accounted for by 49.91%, indicating CBD enhanced cell apoptosis ability. To deeper explore molecular mechanisms, the CBD-treated T24 cell transcriptome libraries were established. KEGG analysis implied that the significantly changed genes were enriched in the PI3K/Akt pathway. qRT-PCR and Western blot assays verified that CBD regulated BC cells growth and migration and induced apoptosis by inactivating the PI3K/Akt pathway. Meanwhile, the developed chitosan to wrap CBD-loaded PLGA nanoparticles can significantly enhance the adhesion of the material to the mouse bladder wall, and the binding efficiency of mucin to chitosan-PLGA nanoparticles reached 97.04% ± 1.90%. In summary, this work demonstrates that CBD may become a novel reliable anticancer drug and the developed intravesical adhesion system is expected to turn into a potential means of BC chemotherapy drug delivery.
RESUMO
AIM: This study aims to investigate the suitability of thermosensitive triblock polymer poly-(DL-lactic acid-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA as a matrix material for ocular delivery of dexamethasone acetate (DXA). METHODS: The copolymer was synthesized and evaluated for its thermosensitive and gelation properties. DXA in situ gel-forming solution based on PLGA-PEG-PLGA copolymer of 20% (w/w) was prepared and evaluated for ocular pharmacokinetics in rabbit according to the microdialysis method, which was compared to the normal eye drop. RESULT: The copolymer with 20% (w/w) had a low critical solution temperature of 32 degrees C, which is close to the surface temperature of the eye. The C(max) of DXA in the anterior chamber for the PLGA-PEG-PLGA solution was 125.2 microg/mL, which is sevenfold higher than that of the eye drop, along with greater area under the concentration-time curves (AUC). CONCLUSION: These results suggest that the PLGA-PEG-PLGA copolymer is potential thermosensitive in situ gel-forming material for ocular drug delivery, and it may improve the bioavailability, efficacy of some eye drugs.
Assuntos
Anti-Inflamatórios/administração & dosagem , Dexametasona/análogos & derivados , Excipientes , Soluções Oftálmicas/administração & dosagem , Polietilenoglicóis , Poliglactina 910 , Administração Tópica , Animais , Câmara Anterior/efeitos dos fármacos , Câmara Anterior/metabolismo , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacocinética , Disponibilidade Biológica , Dexametasona/administração & dosagem , Dexametasona/análise , Dexametasona/farmacocinética , Sistemas de Liberação de Medicamentos , Excipientes/síntese química , Excipientes/química , Excipientes/farmacologia , Oftalmopatias/tratamento farmacológico , Hidrogéis , Soluções Oftálmicas/análise , Soluções Oftálmicas/farmacocinética , Transição de Fase , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Poliglactina 910/síntese química , Poliglactina 910/química , Poliglactina 910/farmacologia , Coelhos , Temperatura , ViscosidadeRESUMO
PURPOSE: Nimodipine (NIMO) is used clinically to treat ischemic damage resulting from subarachnoid hemorrhage. However, clinical application of NIMO is limited by poor aqueous solubility and low safety. To overcome these limitations, a novel two-vial NIMO-loaded nanoemulsion (NIMO-TNE) was designed in this study. METHODS: NIMO-TNE was prepared by mixing a nimodipine-polyethylene glycol 400 (NIMO-PEG400) solution and a commercially available 20% injectable blank nanoemulsion (BNE). Drug distribution in NIMO-TNE, physical stability, and dilution stability were evaluated in vitro, and pharmacokinetics and pharmacodynamics were evaluated in vivo. Safety was assessed using the hemolysis test and the intravenous irritation test, and acute toxicity of NIMO-TNE was compared with that of commercial Nimotop injection. RESULTS: Drug loading (DL) in NIMO-TNE was enhanced 5-fold compared with that in Nimotop injection. The mean particle size of NIMO-TNE was 241.53 ± 1.48 nm. NIMO-TNE and NIMO-TNE diluted in 5% glucose injection and 0.9% sodium chloride was stable for a sufficient duration to allow for clinical use. In addition, NIMO-TNE exhibited a similar pharmacokinetic profile and similar brain ischemia reduction in a rat middle cerebral artery occlusion (MCAO) model compared to Nimotop injection. Furthermore, NIMO-TNE did not induce hemolysis at 37°C, and NIMO-TNE induced less intravenous irritation than Nimotop injection. Moreover, NIMO-TNE could be injected at a 23-fold higher dose than the LD50 of Nimotop injection with no obvious toxicity or side effects. CONCLUSION: NIMO-TNE is a promising formulation suitable for intravenous injection, is easy to prepare, and exhibits excellent safety.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Nimodipina/administração & dosagem , Animais , Portadores de Fármacos/administração & dosagem , Estabilidade de Medicamentos , Emulsões/química , Feminino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Camundongos Endogâmicos ICR , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Nimodipina/farmacocinética , Tamanho da Partícula , Polietilenoglicóis , Coelhos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual , Testes de Toxicidade AgudaRESUMO
Amorphous solid dispersion (SD) is an effective solubilization technique for water-insoluble drugs. However, physical stability issue of solid dispersions still heavily hindered the development of this technique. Traditional stability experiments need to be tested at least three to six months, which is time-consuming and unpredictable. In this research, a novel prediction model for physical stability of solid dispersion formulations was developed by machine learning techniques. 646 stability data points were collected and described by over 20 molecular descriptors. All data was classified into the training set (60%), validation set (20%), and testing set (20%) by the improved maximum dissimilarity algorithm (MD-FIS). Eight machine learning approaches were compared and random forest (RF) model achieved the best prediction accuracy (82.5%). Moreover, the RF models revealed the contribution of each input parameter, which provided us the theoretical guidance for solid dispersion formulations. Furthermore, the prediction model was confirmed by physical stability experiments of 17ß-estradiol (ED)-PVP solid dispersions and the molecular mechanism was investigated by molecular modeling technique. In conclusion, an intelligent model was developed for the prediction of physical stability of solid dispersions, which benefit the rational formulation design of this technique. The integrated experimental, theoretical, modeling and data-driven AI methodology is also able to be used for future formulation development of other dosage forms.
Assuntos
Estabilidade de Medicamentos , Modelos Moleculares , Estradiol/química , Aprendizado de Máquina , Povidona/químicaRESUMO
Molecular interactions between drug and polymeric carriers are believed to be the key for high drug loading and better physical stability of micro-particles. However, molecular interactions between drug and polymer are still difficult to investigate using only experimental tools. In this study, high-loaded glipizide (GLP)/hydroxypropyl methylcellulose acetate succinate (HPMCAS) (1/1 w/w) micro-particles were prepared using an in situ pH-dependent solubility method. Molecular interactions within the micro-particles were investigated by integrated experimental and modeling techniques. The dissolution rate of GLP/HPMCAS micro-particles was significantly better than those of solid dispersions and physical mixtures. Scanning electron microscopy images showed that the polymer inhibited GLP recrystallization. Experimental (FTIR spectroscopy, differential scanning calorimetry, powder X-ray diffraction and nuclear magnetic resonance spectroscopy) and molecular dynamics simulation revealed that hydrogen-bonding was the key to the properties of the micro-particles. Our research developed high drug-loading GLP/HPMCAS micro-particles and investigated the interactions between drug and polymer at the molecular level. This integrated approach could be practical methodology for future formulation design.
Assuntos
Glipizida/química , Hipoglicemiantes/química , Metilcelulose/análogos & derivados , Cristalização , Liberação Controlada de Fármacos , Ligação de Hidrogênio , Metilcelulose/química , Simulação de Dinâmica Molecular , SolubilidadeRESUMO
To improve the dissolution of felodipine, felodipine-zein complexes were prepared using a dual shift technique, with zein as both stabilizer and carrier. The complexes were characterized by particle size, zeta potential, morphology, crystalline properties, and release behavior. The complexes could be prepared in high yield and showed good redispersibility. The mean diameters of the felodipine particles in complexes were 150-300 nm, with negative zeta potentials of -30 to -25 mV after rehydration, and the particle sizes of the complexes were in the range 10-80 µm. The size of the felodipine nanoparticles incorporated into zein increased gradually with increasing drug content. Powder X-ray diffraction and differential scanning calorimetry indicated that felodipine in the complexes was markedly less crystalline than the pure drug. Both the rate and extent of dissolution of the complexes were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Spectroscopic analyses indicated that intermolecular interactions, especially hydrophobic interactions, are the major driving forces for the formation of the felodipine nanoparticles and contribute to the stabilization effect. This study provides a promising strategy for enhancing the dissolution rate of drugs using simplified preparation processes and showcases the design of zein-based oral delivery systems for bioactive components.