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1.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361705

RESUMO

In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specific tumor uptake. Compared with [99mTc]Tc-CN5FA, the tumor/muscle ratios of [99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two 99mTc complexes have potential as tumor imaging agents to target folate receptors.


Assuntos
Diagnóstico por Imagem/métodos , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Rim/diagnóstico por imagem , Nitrilas/química , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Ligação Competitiva , Estabilidade de Medicamentos , Receptores de Folato com Âncoras de GPI/genética , Ácido Fólico/farmacocinética , Expressão Gênica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células KB , Rim/metabolismo , Camundongos , Ligação Proteica , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/química , Distribuição Tecidual
2.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443508

RESUMO

INTRODUCTION: Chemotherapy with anti-cancer drugs is considered the most common approach for killing cancer cells in the human body. However, some barriers such as toxicity and side effects would limit its usage. In this regard, nano-based drug delivery systems have emerged as cost-effective and efficient for sustained and targeted drug delivery. Nanotubes such as carbon nanotubes (CNT) and boron nitride nanotubes (BNNT) are promising nanocarriers that provide the cargo with a large inner volume for encapsulation. However, understanding the insertion process of the anti-cancer drugs into the nanotubes and demonstrating drug-nanotube interactions starts with theoretical analysis. METHODS: First, interactions parameters of the atoms of 5-FU were quantified from the DREIDING force field. Second, the storage capacity of BNNT (8,8) was simulated to count the number of drugs 5-FU encapsulated inside the cavity of the nanotubes. In terms of the encapsulation process of the one drug 5-FU into nanotubes, it was clarified that the drug 5-FU was more rapidly adsorbed into the cavity of the BNNT compared with the CNT due to the higher van der Waals (vdW) interaction energy between the drug and the BNNT. RESULTS: The obtained values of free energy confirmed that the encapsulation process of the drug inside the CNT and BNNT occurred spontaneously with the free energies of -14 and -25 kcal·mol-1, respectively. DISCUSSION: However, the lower value of the free energy in the system containing the BNNT unraveled more stability of the encapsulated drug inside the cavity of the BNNT comparing the system having CNT. The encapsulation of Fluorouracil (5-FU) anti-cancer chemotherapy drug (commercial name: Adrucil®) into CNT (8,8) and BNNT (8,8) with the length of 20 Å in an aqueous solution was discussed herein applying molecular dynamics (MD) simulation.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/química , Composição de Medicamentos , Fluoruracila/farmacologia , Nanotubos de Carbono/química , Estabilidade de Medicamentos , Fluoruracila/química , Conformação Molecular , Simulação de Dinâmica Molecular , Termodinâmica
3.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443445

RESUMO

Saponin is a biopesticide used to suppress the growth of the golden apple snail population. This study aims to determine the stabilized conditions for saponin storage. The maceration process was used for saponin extraction, and for saponin concentration, progressive freeze concentration (PFC) was used. Afterwards, stability analysis was performed by storing the sample for 21 days in two conditions: Room temperature (26 °C) and cold room (10 °C). The samples kept in a cold room were sterilized samples that undergo thermal treatment by placing the sample in the water bath. The non-sterilized samples were kept in room temperature condition for 21 days. The results showed that saponin stored in the cold room (sterilized sample) has low degradation with higher concentration than those stored at room temperature in stability analysis with the highest saponin concentration (0.730 mg/mL) at a concentration temperature of -6 °C and concentration time of 15 min. The lowest saponin concentration obtained by saponin stored at room temperature (non-sterilized sample) is 0.025 mg/mL at a concentration temperature of -6 °C and concentration time of 10 min. Thus, the finding concluded that saponin is sensitive to temperature. Hence, the best storage condition to store saponin after thermal treatment is to keep it in a cold room at 10 °C.


Assuntos
Congelamento , Saponinas/química , Esterilização , Estabilidade de Medicamentos , Fatores de Tempo
4.
Int J Pharm ; 606: 120894, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34280485

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune joint disorder that affects about 1% of the world population and may lead to severe disability and comorbidity. Despite breakthroughs in past decades to understand its pathogenesis and the development of transforming disease-modifying antirheumatic drugs, the symptoms of many patients are not substantially improved. Sinomenine (SIN), a natural alkaloid with poor solubility, has been used to treat RA in China for years because of its unique immunoregulative activity. However, its commercial hydrochloride form has a short half-time, which may cause huge fluctuations of blood drug concentration leading to severe adverse reactions. In this study, co-amorphous systems of SIN with three nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin, naproxen, and sulindac, were prepared for the combination therapy, as well as the improvement of its aqueous solubility and controlled release. Each co-amorphous sample was characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), and Fourier transform infrared spectroscopy (FTIR). The CO2- and N+H stretching vibration in the three co-amorphous samples appears in FTIR spectra, suggesting the formation of salts between SIN and NSAIDs. SIN also exhibits sustained release rates in all three co-amorphous samples. These co-amorphous systems show excellent physicochemical stability because no recrystallization was observed at 25 °C and 75% relative humidity (RH) after four months. Our study suggests that SIN-NSAIDs co-amorphous systems represent an affordable and promising treatment against RA.


Assuntos
Anti-Inflamatórios não Esteroides , Artrite Reumatoide , Artrite Reumatoide/tratamento farmacológico , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Combinação de Medicamentos , Estabilidade de Medicamentos , Humanos , Morfinanos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
5.
J Pharm Biomed Anal ; 203: 114231, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34225039

RESUMO

Eltrombopag olamine is prescribed for chronic immune (idiopathic) thrombocytopenic purpura (ITP). This work aims to investigate the formation of potential degradants of the drug and determine their toxicity in silico. A stability-indicating high performance liquid chromatography (HPLC) method was developed to separate six oxidative degradation impurities and three thermal degradation impurities employing the quality by design (QBD) approach. The degradation impurities were resolved with minimum resolution of 1.5 using a phenyl column with 0.1 % trifluoroacetic acid (TFA) and acetonitrile as the mobile phase and quantified at 245 nm. The structure and degradation pathway for the degradants was proposed by employing liquid chromatography with tandem mass spectrometry (LC-MS/MS), among the identified degradation pathways demethylation and decarboxylation are common reactions observed during oxidation resulted in majority of degradation products. All the degradation products are characterized with help of the daughter ions and product ion obtained upon LC-MS/MS analysis. The HPLC method parameters such as column temperature, flow rate, TFA concentration and organic concentration are identified as critical method attributes (CMA), a design of experiments (DOE) mediated design space was established through use of design experts. The resolution between sets of adjacent peaks was identified as a critical quality attribute; among the investigated CMAs, column temperature and flow rate significantly affected the resolution. Furthermore, the toxicology of the degradation products was predicted with the help of in silico TOPKAT analysis, the carcinogenicity of the impurities was discussed.


Assuntos
Contaminação de Medicamentos , Espectrometria de Massas em Tandem , Benzoatos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Simulação por Computador , Estabilidade de Medicamentos , Hidrazinas , Pirazóis
6.
J Pharm Biomed Anal ; 203: 114232, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34246845

RESUMO

An extensive forced degradation study using hydrolytic degradation conditions was performed on G334089, the S-enantiomer of the free fatty acid receptor 2 (FFA2) antagonist GLPG0974, to identify the degradation product structures and discern degradation pathways. Not all degradation products generated ions in the MS spectra, while several others were isomers, so more rigorous degradation conditions were applied to increase the degradant yield. Esterification of the degradants facilitated isolation via preparative HPLC and subsequent NMR and MS characterisation. The determined structures, retention times and fragmentation patterns were used to identify the original degradation products and postulate a degradation pathway. In addition to the expected amide bond hydrolysis, a second degradation mechanism involving azetidine activation through formation of an azetidinium ion was demonstrated.


Assuntos
Azetidinas , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Hidrólise , Espectroscopia de Ressonância Magnética
7.
AAPS PharmSciTech ; 22(5): 199, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212274

RESUMO

An emulsion is a biphasic dosage form comprising of dispersed phase containing droplets that are uniformly distributed into a surrounding liquid which forms the continuous phase. An emulsifier is added at the interface of two immiscible liquids to stabilize the thermodynamically unstable emulsion. Various types of emulsions such as water-in-oil (w-o), oil-in-water (o-w), microemulsions, and multiple emulsions are used for delivering certain drugs in the body. Water (aqueous) phase is commonly used for encapsulating proteins and several other drugs in water-in-oil-in-water (w-o-w) emulsion technique. But this method has posed certain problems such as decreased stability, burst release, and low entrapment efficiency. Thus, a novel "solid-in-oil-in-water" (s-o-w) emulsion system was developed for formulating certain drugs, probiotics, proteins, antibodies, and tannins to overcome these issues. In this method, the active ingredient is encapsulated as a solid and added to an oil phase, which formed a solid-oil dispersion. This dispersion was then mixed with water to form a continuous phase for enhancing the drug absorption. This article focuses on the various studies done to investigate the effectiveness of formulations prepared as solid-oil-water emulsions in comparison to conventional water-oil-water emulsions. A summary of the results obtained in each study is presented in this article. The s-o-w emulsion technique may become beneficial in near future as it has shown to improve the stability and efficacy of the entrapped active ingredient.


Assuntos
Portadores de Fármacos/química , Emulsões/química , Óleos/química , Água/química , Diclofenaco/química , Diclofenaco/metabolismo , Estabilidade de Medicamentos , Microesferas , Nanoestruturas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas/química , Proteínas/metabolismo
8.
Int J Pharm ; 606: 120902, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34293468

RESUMO

Freeze drying is known to be able to produce an amorphous product, but this approach has been mostly used with water-based media. With APIs which are virtually water insoluble, a more appropriate freeze-drying medium would be an organic solvent. Little is known about this approach in terms of forming a stable freeze-dried amorphous product stabilized by small molecule excipient out of organic solvents. In the present study, freeze-drying of APIs from DMSO solutions was used to produce stable solid dispersions from binary mixtures of APIs containing at least one poorly water soluble or practically water-insoluble API. The developed freeze-drying method produced amorphous binary solid dispersions which remained amorphous for at least two days while the 13 best binary dispersions remained stable at room temperature for the entire study period of 127 days. Average residual DMSO levels in dried dispersions were 3.5% ± 1.6%. The developed method proved feasible in producing relatively stable amorphous solid dispersions from practically water insoluble drug compounds which could subsequently be used in further research purposes.


Assuntos
Dessecação , Dimetil Sulfóxido , Composição de Medicamentos , Estabilidade de Medicamentos , Liofilização , Solubilidade
9.
Int J Pharm ; 606: 120912, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34298099

RESUMO

Adeno-associated viruses (AAV) are among the most actively investigated vectors for gene therapy. Supply of early clinical studies with frozen drug product (DP) can accelerate timelines and minimize degradation risks. In the long-term, logistical challenges of frozen DP may limit patient access. In this work, we developed a lyophilized (freeze-dried) formulation of AAV. The mass concentration of AAV is typically low, and AAV also requires a minimum ionic strength to inhibit aggregation. These factors result in a low collapse temperature, which is limiting to lyophilization. Mannitol crystallization was found to cause extensive degradation and potency loss of AAV during the freezing step. With further development, we determined that AAV could be lyophilized in a sucrose and citrate formulation with a more desirable high glass transition temperature of the dried cake. An optimal residual moisture range (1-3%) was found to be critical to maintaining AAV8 stability. Glycerol was found to protect AAV8 from over-drying by preventing capsid damage and genome DNA release. A lyophilized formulation was identified that maintained potency for 24 months at 2-8 °C, indicating the feasibility of a dried formulation for AAV gene therapy.


Assuntos
Química Farmacêutica , Dependovirus , Cristalização , Dependovirus/genética , Estabilidade de Medicamentos , Liofilização , Terapia Genética , Humanos
10.
Int J Pharm ; 606: 120929, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34303819

RESUMO

Lyophilization formulation and process development for lipophilic nanoparticle (NPs) products is highly challenging as the NPs have a low colloidal stability. We compared two different NP types, pure paliperidone palmitate nanocrystals and trimyristin solid lipid nanoparticles regarding formulation, process, and storage stability aspects. Freeze-thaw studies were conducted to investigate the basic formulation aspects such as buffer type, pH, and ionic strength as well as different cryoprotectants. In freeze-drying conventional ramp freezing was performed and compared to freezing with an annealing step added or with controlled ice nucleation. Different formulations were lyophilized and tested for short-term storage stability up to 6 weeks. Samples were analyzed for particle size, subvisible particle number, specific surface area, residual moisture, crystallinity, and glass transition temperature. Sucrose significantly better stabilized both NP types against freeze-thaw stress compared to mannitol demonstrating the importance of a fully amorphous matrix. While the impact of buffer type and pH was negligible, the aggregation propensity of NPs was reduced in presence of NaCl. The freezing step also impacted NP aggregation but the effect was less important than the formulation design. Surfactants did not necessarily improve the colloidal stability but resulted in a lower glass transition temperature of the lyophilizates and may cause phase separation which limits storage stability. This hurdle can be overcome by using a hydroxypropyl-ß-cyclodextrin/ sucrose mixture as cryoprotectant. In general, we could show a similar freeze-drying behavior of the two NP types. Thus, we established a formulation and process approach to achieve stable lyophilizates of lipophilic NPs based on two different types of NPs. The general rules should be transferable to other NPs facilitating lyophilization development.


Assuntos
Nanopartículas , Palmitato de Paliperidona , Química Farmacêutica , Estabilidade de Medicamentos , Liofilização , Lipídeos
11.
Int J Pharm ; 606: 120932, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34310956

RESUMO

The use of inorganic nanoparticles (NPs) gains interest for pharmaceutical applications, e.g. as adjuvants or drug delivery vehicles. Colloidal stability of NPs in aqueous suspensions is a major development challenge. Both frozen and lyophilized liquids are alternative presentations to liquid dispersion. To improve the basic understanding, we investigated the freeze-thawing stability of model α-Al2O3 NPs. Freeze-thawing was conducted in three different buffer types at pH5 and 8 without and with additives to determine fundamental formulation principles. Before freeze-thawing, α-Al2O3 NPs could be stabilized in sodium citrate buffer at pH5 and 8, and in sodium or potassium phosphate at pH8. Particles revealed low zeta potential values in phosphate buffers at pH5 indicating insufficient electrostatic stabilization. After freeze-thawing, an increase in NP size was strongly reduced in potassium phosphate and sodium citrate buffers. Subsequent pH measurements upon freezing revealed a drastic acidic pH shift in sodium phosphate which was further demonstrated to destabilize NPs. The ionic stabilizers gelatin A/B, Na-CMC, and SDS, were suitable to improve colloidal stability in phosphate buffers at pH5 highlighting the importance of charge stabilization. Freeze-thawing stability was best in presence of gelatin A/B, followed by PVA, mannitol, or sucrose. Depletion and steric stabilization were insufficient using PEG and surfactants respectively. Thus, we could identify the fundamental formulation principles to preserve inorganic NPs upon freezing: i) sufficient charge stabilization, ii) a maintained pH during freezing, and iii) the addition of a suitable stabilizer, preferably gelatin, not necessarily surfactants. This forms the basis for future studies, e.g. on lyophilization.


Assuntos
Óxido de Alumínio , Nanopartículas , Estabilidade de Medicamentos , Excipientes , Liofilização , Congelamento
12.
J Photochem Photobiol B ; 221: 112246, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34243023

RESUMO

Photo-oxidative skin damage is mainly caused by the UV-A radiation of the sun. Synthetic sunscreens used to counter this acts mostly on the superficial skin layer and possess serious side effects. P-coumaric acid (PCA) is a UV-A protective plant phenolic having quick diffusion and distribution in superficial skin layers limiting its application as herbal sunscreen. The present study was designed to formulate an optimized phospholipid complex of PCA (PCAPC) through response surface methodology to enhance its skin permeation to deeper skin layers providing protection against photo-oxidative stress. PCAPC was characterized by FT-IR, DTA, PXRD, TEM, zeta potential etc. PCAPC was then incorporated into a gel formulation (PCAPC-GE) to facilitate its transdermal delivery. Physicochemical properties of the gel were assessed by pH, homogeneity, rheology, spreadability etc. In-vitro SPF and UVA-PF of the gel was evaluated and compared with conventional gel (PCA-GE). Ex-vivo skin permeation flux, permeability coefficient, skin deposition and dermatokinetic analysis were carried out to measure the rate and level of skin permeation. This was accompanied by in-vivo evaluation of PCAPC-GE and PCA-GE in the experimental rat model by measuring the various oxidative stress markers such as superoxide dismutase, catalase etc. PCAPC-GE provided high SPF and UVA-PF value compared to PCA-GE. The physicochemical parameters were suitable for transdermal application. PCAPC-GE enhanced the permeation rate of PCA by almost 6 fold compared to PCA-GE. Besides, a significant reduction of UV-A induced oxidative stress biomarkers were observed for PCAPC-GE. Thus, the PCAPC-GE may be an effective alternative of synthetic sunscreens due to its enhanced permeation and protection against UVA-induced oxidative stress.


Assuntos
Ácidos Cumáricos/química , Géis/química , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeos/química , Substâncias Protetoras/farmacologia , Raios Ultravioleta , Animais , Estabilidade de Medicamentos , Masculino , Estresse Oxidativo/efeitos da radiação , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Permeabilidade/efeitos da radiação , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Ratos , Ratos Wistar , Reologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Solubilidade , Fator de Proteção Solar , Temperatura de Transição
13.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279377

RESUMO

Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature (Tg) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight (Mw) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different Mw of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer Mw on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes-Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest Mw (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.


Assuntos
Anti-Inflamatórios não Esteroides/química , Celecoxib/química , Raios Infravermelhos , Nanopartículas/química , Povidona/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Celecoxib/administração & dosagem , Estabilidade de Medicamentos , Lasers , Viscosidade
14.
Int J Biol Macromol ; 185: 782-791, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216672

RESUMO

In this work, a novel DHA-loaded nanoparticle with PLGA and chitosan (PCSDNP) was successfully prepared. The structure of PCSDNP and DHA-loaded PLGA nanoparticles was measured by transmission electron microscope, scanning electron microscope, and differential scanning calorimeter. The interaction strength between DHA, PLGA, and chitosan was evaluated through Fourier transform infrared spectroscopy. The curves of controlled DHA release and stabilities for different environmental factors of two NPs were evaluated. Importantly, two NPs were almost regularly spherical and the interactions were hydrogen bonds and electrostatic interactions between PLGA and chitosan. These NPs had a good encapsulation rate (80.45%) and high-water solubility than the free DHA molecule. In simulated gastrointestinal fluid, two NPs showed a controlled-release pattern. Overall, PCSDNP had better stability and controlled-release effect with the synergy between CS and PLGA under the conditions of pH (2- 7), ionic strength (0- 500 mM), storage time (0- 42 d), and temperature (30- 80 °C).


Assuntos
Quitosana/química , Ácidos Docosa-Hexaenoicos/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Preparações de Ação Retardada , Ácidos Docosa-Hexaenoicos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Ligação de Hidrogênio , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanopartículas , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier
15.
Int J Biol Macromol ; 185: 935-948, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34237365

RESUMO

A protein precipitation technique was optimized to produce biophysically stable 'protein microbeads', applicable to highly concentrated protein formulation. Initially, production of BSA microbeads was performed using rapid dehydration by vortexing in organic solvents followed by cold ethanol treatment and a vacuum drying. Out of four solvents, n-octanol produced the most reversible microbeads upon reconstitution. A Shirasu porous glass (SPG) membrane emulsification technique was utilized to enhance the size distribution and manufacturing process of the protein microbeads with a marketized human IgG solution. Process variants such as dehydration time, temperature, excipients, drying conditions, and initial protein concentration were evaluated in terms of the quality of IgG microbeads and their reversibility. The hydrophobized SPG membrane produced a narrow size distribution of the microbeads, which were further enhanced by shorter dehydration time, low temperature, minimized the residual solvents, lower initial protein concentration, and addition of trehalose to the IgG solution. Final reversibility of the IgG microbeads with trehalose was over 99% at both low and high protein concentrations. Moreover, the formulation was highly stable under repeated mechanical shocks and at an elevated temperature compared to its liquid state. Its in vivo pharmacokinetic profiles in rats were consistent before and after the 'microbeadification'.


Assuntos
1-Octanol/química , Imunoglobulina G/administração & dosagem , Imunoglobulina G/química , Soroalbumina Bovina/farmacocinética , Animais , Precipitação Química , Dessecação , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Imunoglobulina G/farmacologia , Masculino , Microesferas , Tamanho da Partícula , Ratos , Soroalbumina Bovina/química , Tempo , Vácuo
16.
Int J Biol Macromol ; 185: 966-982, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34237367

RESUMO

Herein, our suggestion is to immobilize enzymes in-situ on absorbable shape-memory stents instead of injecting therapeutic enzymes into the blood. Chitosan (CHI)-based stents were tailored as novel support and the enzyme-immobilizing ability was elucidated using L-asparaginase (L-ASNase). For developing shape-memory stents, CHI-glycerol (GLY) solution was prepared and further blended with different ratios of polyethylene glycol (PEG), and polyvinyl alcohol (PVA). Afterward, the blends were modified by ionic crosslinking with sodium tripolyphosphate to obtain a shape-memory character. L-ASNase was included in the blends by using in-situ method before ionic crosslinking. The prepared stents, with or without L-ASNase, were comprehensively characterized by using several techniques. Collectively, immobilized L-ASNase exhibited much better performance in immobilization parameters than free one, thanks to its improved stability and reusability. For instance, CHI/GLY/PEG-3@L-ASNase retained about 70% of the initial activity after storage at 30 °C for 2 weeks, whereas the free form lost half of its initial activity. Besides, it retained 73.4% residual activity after 15 consecutive cycles. Most importantly, stent formulations exhibited ~60% activity in the bioreactor system after 4 weeks of incubation. Given the above results, shape-memory stents can be a promising candidate as a new platform for immobilization, especially in the blood circulation system.


Assuntos
Asparaginase/farmacologia , Quitosana/química , Polietilenoglicóis/química , Álcool de Polivinil/química , Asparaginase/química , Estabilidade de Medicamentos , Estabilidade Enzimática , Enzimas Imobilizadas/química , Enzimas Imobilizadas/farmacologia , Concentração de Íons de Hidrogênio , Cinética , Polietilenoglicóis/farmacologia , Stents , Temperatura , Molhabilidade
17.
Vaccine ; 39(35): 5025-5036, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34256969

RESUMO

Particle engineering via spray drying was used to develop a dry powder presentation of an adjuvanted tuberculosis vaccine candidate. This presentation utilizing a trileucine-trehalose excipient system was designed to be both thermostable and suitable for respiratory delivery. The stability of the spray-dried vaccine powder was assessed over one year at various storage temperatures (-20, 5, 25, 40, 50 °C) in terms of powder stability, adjuvant stability, and antigen stability. A formulation without trileucine was included as a control. The results showed that the interior particle structure and exterior particle morphology of the powder was maintained for one year at 40 °C, while the control case exhibited a small extent of particle fusing under the same storage conditions. Moisture content was maintained, and powder solid state remained amorphous for all storage temperatures. Aerosol performance was assessed with a commercial dry powder inhaler in combination with a human mouth-throat model. The emitted dose and lung dose were maintained for all samples after one year at temperatures up to 40 °C. Nanoemulsion size and oil content of the adjuvant system were maintained after one year at temperatures up to 40 °C, and the agonist content was maintained after one year at temperatures up to 25 °C. The antigen was completely degraded in the control formulation at seven months of storage at 40 °C; by contrast, 45% of the antigen was still present in the trehalose-trileucine formulation after one year of storage at 50 °C. Comparatively, the antigen was completely degraded in a liquid sample of the vaccine candidate after only one month of storage at 37 °C. The spray-dried trehalose-trileucine vaccine powder clearly maintained its inhalable properties after one year's storage at high temperatures and improved overall thermostability of the vaccine.


Assuntos
Inaladores de Pó Seco , Vacinas contra a Tuberculose , Administração por Inalação , Aerossóis , Estabilidade de Medicamentos , Humanos , Tamanho da Partícula , Pós
18.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206357

RESUMO

In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, v/v/v. The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r2) = 0.9976. However, with acceptable r2, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.


Assuntos
Amidas/análise , Amidas/sangue , Antivirais/análise , Antivirais/sangue , Bioensaio/métodos , COVID-19/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Pirazinas/análise , Pirazinas/sangue , Aciclovir/análise , Aciclovir/sangue , COVID-19/sangue , Calibragem , Estabilidade de Medicamentos , Congelamento , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Solventes/química
19.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208193

RESUMO

Metronidazole is a drug widely used in the prevention and treatment of bacterial infections. Due to its possibility of the formation of stable metal complexes, it was decided to broaden its activity spectrum by introducing the silver(I) coordination compounds i.e., [Ag(MTZ)2NO3] and [(Ag(MTZ)2)2]SO4, which have significant antibacterial properties. The paper presents a description of a new qualitative and quantitative analysis of metronidazole in bulk and possible pharmaceutical preparations by thin-layer chromatography with densitometric detection. Optimal separation conditions were selected, and the analytical procedure was validated according to the ICH guidelines. The obtained data indicate that the method is sufficiently sensitive, precise, and accurate. The stability of the metronidazole solutions obtained from tablets, pure metronidazole, and its silver(I) complexes was tested. The research was carried out in various environments, at different temperatures, in H2O2 solution, and during exposure to radiation (UV, sunlight). The greatest degradation was found in the alkaline environment and at higher temperatures. The silver(I) complexes exhibited relatively high stability under analyzed conditions that are higher than standard metronidazole solutions and tablets. The observations were confirmed by the kinetic and thermodynamic analysis. The described studies of new metronidazole silver(I) complexes increase the potential for their application in infections both in humans and animals.


Assuntos
Antibacterianos/química , Complexos de Coordenação/química , Peróxido de Hidrogênio/química , Metronidazol/química , Compostos de Prata/química , Animais , Cromatografia em Camada Delgada/métodos , Densitometria/métodos , Estabilidade de Medicamentos , Humanos , Cinética , Comprimidos
20.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208408

RESUMO

Essential oils have been widely used as an active ingredient in mosquito repellent products. However, essential oils are highly unstable and prone to degradation when exposed to the environment during storage. Microencapsulation techniques help to maintain the stability of molecules in essential oils that are sensitive to environmental stress, and therefore improve shelf life. In this study, the physical stability and efficacy of a repellent formulation consisting of encapsulated Citrus grandis essential oil (CGEO) were evaluated under different storage conditions over a 12-month period by comparing the formulation with a non-encapsulated formulation. The formulations were both stored under two different storage conditions, i.e., 25 ± 2 °C/60% ± 5% relative humidity (RH) and 40 ± 2 °C/75% RH ± 5%, for 12 months. Droplet size, zeta potential, and pH value were measured after 1, 6, and 12 months of storage to determine their stability. For the study of efficacy, each formulation was tested against Aedes aegypti under laboratory conditions. We found that the microencapsulated formulation's physical characteristics showed insignificant changes as compared with the non-encapsulated formulation during storage. The microencapsulated formulation demonstrated better repellent effects, sustaining high protection (>80%) for 4 more hours of exposure after 12 months of storage as compared with the non-encapsulated formulation that demonstrated high protection for only an hour post application. Microencapsulation helped to preserve the stability of the formulation, which resulted in high protection being maintained for over 12 months of storage.


Assuntos
Aedes/efeitos dos fármacos , Citrus/química , Repelentes de Insetos/química , Óleos Voláteis/química , Aedes/fisiologia , Animais , Composição de Medicamentos , Avaliação de Medicamentos , Estabilidade de Medicamentos
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