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1.
Food Chem ; 398: 133953, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35998486

RESUMO

The aim of this study was to evaluate the influence of l-ascorbyl palmitate (LAP) as an additive to liposome formulations by self-assembling with soy lecithin to form hybrid liposomes, in order to enhance the physical stability and bioactivator-loaded retention ratio of the LAP incorporated liposomes (LAP-LP). The addition of LAP significantly increased its surface negative charge and strong hydrophobic interactions occurred between the hydrophobic tails of LAP and phospholipids resulting in more compactly ordered, rigid and hydrophobic phospholipid bilayers as indicated by surface tension, fluorescence probes and DSC. These changes enhanced the stability of hydrophobic polyphenol loaded LAP-LP during storage. Particularly, after four weeks storage at 37 °C for naringenin loaded liposomes, the retention ratio of pure liposome decreased dramatically to 12.5 %, while the LAP-LP remained above 74.5 %. This study opens up the potential for the LAP-LP to be developed as a food-grade multifunctional formulation for encapsulating and delivering bioactivators.


Assuntos
Lipossomos , Fosfolipídeos , Ácido Ascórbico/análogos & derivados , Estabilidade de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/química , Fosfolipídeos/química , Polifenóis
2.
Malar J ; 21(1): 256, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068561

RESUMO

BACKGROUND: Artesunate is recommended by the World Health Organization (WHO) for parenteral treatment of severe Plasmodium falciparum malaria. However, artesunate is inherently unstable in an aqueous solution and hydrolyses rapidly after its preparation for injection. Therefore, the aim of the study was to evaluate the stabilizing effects of phosphate buffer and mannitol against short-term (ex-tempore) artesunate hydrolysis. METHODS: A HPLC-UV isocratic method was developed using a reversed-phase fused core column (HALO RP-C18) and a mobile phase consisting of a mixture of 45% ammonium formate 10 mM in water (pH 4.5) and 55% methanol. Artesunate was formulated as aqueous solutions using a design of experiment (DOE) to investigate the artesunate stabilizing effects of pH (8-10), phosphate buffer strength (0.3-0.5 M), and mannitol (0-0.22 mmol/mL). The solutions were incubated at predefined temperatures (5, 25, and 40 °C) with subsequent analysis. Arrhenius equation was applied to model and evaluate the stability results. RESULTS: The developed HPLC-based method using fused-core stationary phase allowed to selectively quantify artesunate in the presence of its main hydrolysis degradants; namely ß-dihydroartemisinin (ß-DHA) and α-dihydroartemisinin (α-DHA) within 10 min. By applying the Arrhenius equation, the rate of hydrolysis of the drug increased approximately by 3.4 as the temperature raised by 10 °C. Buffer strength was found to be the main factor affecting the hydrolysis rate constants at 5 and 25 °C (p < 0.05), the activation energy (p = 0.009), and the frequency factor (p = 0.045). However, the effect of the buffer was predominant on the activation energy and hydrolysis rate constants, revealing its stabilizing effect on the drug at lower buffer strength (0.3 M). Within the investigated range (pH = 8-10), pH was found to influence the activation energy, with a positive stabilizing effect in the pH range of 8-9. The addition of mannitol as stabilizing agent into artesunate aqueous formulation did not show an improved response. CONCLUSION: Phosphate buffer was the main stability determining factor of artesunate in the aqueous intravenous (i.v.) formulation and was found to be more effective in stabilizing artesunate at a buffer strength of 0.3 M in pH 8-9, while mannitol lacked stabilizing effect.


Assuntos
Artemisininas , Artesunato , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Injeções Intravenosas , Cinética , Manitol , Fosfatos , Água
3.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4365-4371, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046863

RESUMO

This study was designed to explore the potential of gypenosides as a novel natural stabilizer for the production of nanosuspensions. The gypenosides-stabilized quercetin nanosuspensions(QUE-NS) were prepared using the high-speed shearing and high-pressure homogenization method with quercetin as a model drug, followed by their in vitro evaluation.Based on the measured mean particle size and polydispersity index(PDI) of QUE-NS,the single factor experiment was conducted to optimize the preparation process parameters.The freeze-drying method was used to transform QUE-NS into freeze-dried powders, whose storage stability and saturation solubility were then studied.Moreover, the effects of pH and ionic strength on the physical stability of the nanosuspension system were examined.According to the results, the optimized process parameters were listed as follows: shear rate 13 000 r·min~(-1),shear time 2 min, homogenization pressure 100 MPa, and homogenization frequency 12 times.The mean particle size of QUE-NS prepared under the optimum process conditions was(461.9±2.4) nm, and the PDI was 0.059±0.016.During the two months of storage at room temperature, the freeze-dried QUE-NS powders remained stable.The saturation solubility of freeze-dried QUE-NS powders was proved higher than those of quercetin and the physical mixture.The results of stability testing demonstrated that QUE-NS stabilized with gypenosides exhibited good stability within the pH range of 6 to 8,while coalescence was prone to occur in the presence of salt.Overall, gypenosides is expected to become a new natural stabilizer for the preparation of nanosuspensions.


Assuntos
Nanopartículas , Quercetina , Estabilidade de Medicamentos , Gynostemma , Tamanho da Partícula , Extratos Vegetais , Pós , Solubilidade , Suspensões
4.
AAPS PharmSciTech ; 23(7): 248, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056201

RESUMO

This study aimed to formulate and optimize solid-dispersion of meloxicam (MX) employing response-surface-methodology (RSM). RSM allowed identification of the main effects and interactions between studied factors on MX dissolution and acceleration of the optimization process. 33 full factorial design with 27 different formulations was proposed. Effects of drug loading percentage (A), carriers' ratio (B), method of preparation (C), and their interactions on percent MX dissolved after 10 and 30 min (Q10min & Q30min) from fresh and stored samples were studied in distilled water. The considered levels were 2.5%, 5.0%, and 7.5% (factor A), three ratios of Soluplus®/Poloxamer-407 (factor B). Physical mixture (PM), fusion method (FM), and hot-melt-extrusion (HME) were considered factor (C). Stability studies were carried out for 3 months under stress conditions. The proposed optimization design was validated by 3-extra checkpoints formulations. The optimized formulation was selected via numerical optimization and investigated by DSC, XRD, PLM, and in vitro dissolution study. Results showed that HME technique gave the highest MX dissolution rate compared to other techniques (FM & PM). At constant level of factor (C), the amount of MX dissolved increased by decreasing MX loading and increasing Soluplus in carriers' ratio. Actual responses of the optimized formulation were in close consistency with predicted data. Amorphous form of MX in the optimized formulation was proved by DSC, XRD, and PLM. Selected factors and their levels of the optimization design were significantly valuable for demonstrating and adapting the expected formulation characteristics for rapid dissolution of MX (Q10min= 89.09%) from fresh and stored samples.


Assuntos
Química Farmacêutica , Tecnologia de Extrusão por Fusão a Quente , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Temperatura Alta , Meloxicam , Solubilidade
6.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077212

RESUMO

In this paper, we thoroughly investigated the physical stability of the anti-inflammatory drug etoricoxib, which has been reported earlier to be resistant to recrystallization in its glassy and supercooled states at ambient pressure. Our unique application of the standard refractometry technique showed that the supercooled liquid of the drug was able to recrystallize during isothermal experiments in atmospheric conditions. This enabled us to determine the crystallization onset timescale and nucleation energy barrier of etoricoxib for the first time. As the physical instability of etoricoxib requires working out an efficient method for improving the drug's resistance to recrystallization to maintain its amorphous form utility in potential pharmaceutical applications, we focused on finding a solution to this problem, and successfully achieved this purpose by preparing binary mixtures of etoricoxib with octaacetylmaltose. Our detailed thermal, refractometry, and molecular dynamics studies of the binary compositions near the glass transition revealed a peculiar behavior of the glass transition temperatures when changing the acetylated disaccharide concentration in the mixtures. Consequently, the anti-plasticization effect on the enhancement of physical stability could be excluded, and a key role for specific interactions in the improved resistance to recrystallization was expected. Invoking our previous results obtained for etoricoxib, the chemically similar drug celecoxib, and octaacetylmaltose, we formulated a hypothesis about the molecular mechanisms that may cause an impediment to crystal nuclei formation in the amorphous mixtures of etoricoxib with octaacetylmaltose. The most plausible scenario may rely on the formation of hydrogen-bonded heterodimers of the drug and excipient molecules, and the related drop in the population of the etoricoxib homodimers, which disables the nucleation. Nevertheless, this hypothesis requires further investigation. Additionally, we tested some widely discussed correlations between molecular mobility and crystallization properties, which turned out to be only partially satisfied for the examined mixtures. Our findings constitute not only a warning against manufacturing the amorphous form of pure etoricoxib, but also evidence for a promising outcome for the pharmaceutical application of the amorphous compositions with octaacetylmaltose.


Assuntos
Simulação de Dinâmica Molecular , Vitrificação , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Etoricoxib , Excipientes/química
7.
ACS Appl Mater Interfaces ; 14(36): 40698-40710, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36054111

RESUMO

Preventing crystallization is a primary concern when developing amorphous drug formulations. Recently, atomic layer coatings (ALCs) of aluminum oxide demonstrated crystallization inhibition of high drug loading amorphous solid dispersions (ASDs) for over 2 years. The goal of the current study was to probe the breadth and mechanisms of this exciting finding through multiple drug/polymer model systems, as well as particle and coating attributes. The model ASD systems selected provide for a range of hygroscopicity and chemical functional groups, which may contribute to the crystallization inhibition effect of the ALC coatings. Atomic layer coating was performed to apply a 5-25 nm layer of aluminum oxide or zinc oxide onto ASD particles, which imparted enhanced micromeritic properties, namely, reduced agglomeration and improved powder flowability. ASD particles were stored at 40 °C and a selected relative humidity level between 31 and 75%. Crystallization was monitored by X-ray powder diffraction and scanning electron microscopy (SEM) up to 48 weeks. Crystallization was observable by SEM within 1-2 weeks for all uncoated samples. After ALC, crystallization was effectively delayed or completely inhibited in some systems up to 48 weeks. The delay achieved was demonstrated regardless of polymer hygroscopicity, presence or absence of hydroxyl functional groups in drugs and/or polymers, particle size, or coating properties. The crystallization inhibition effect is attributed primarily to decreased surface molecular mobility. ALC has the potential to be a scalable strategy to enhance the physical stability of ASD systems to enable high drug loading and enhanced robustness to temperature or relative humidity excursions.


Assuntos
Óxido de Alumínio , Polímeros , Cristalização , Estabilidade de Medicamentos , Polímeros/química , Pós/química , Solubilidade
8.
J Vis Exp ; (186)2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-36036623

RESUMO

Lipid-based excipients (LBEs) are low-toxic, biocompatible, and natural-based, and their application supports the sustainability of pharmaceutical manufacturing. However, the major challenge is their unstable solid-state, affecting the stability of the pharmaceutical product. Critical physical properties of lipids for their processing-such as melt temperature and viscosity, rheology, etc.-are related to their molecular structure and their crystallinity. Additives, as well as thermal and mechanical stress involved in the manufacturing process, affect the solid-state of lipids and thus the performance of pharmaceutical products thereof. Therefore, understanding the alteration in the solid-state is crucial. In this work, the combination of powder x-ray diffraction and differential scanning calorimetry (DSC) is introduced as the gold standard for the characterization of lipids' solid state. X-ray diffraction is the most efficient method to screen polymorphism and crystal growth. The polymorphic arrangement and the lamella length are characterized in the wide- and small-angle regions of x-ray diffraction, respectively. The small-angle x-ray scattering (SAXS) region can be further used to investigate crystal growth. Phase transition and separation can be indicated. DSC is used to screen the thermal behavior of lipids, estimate the miscibility of additives and/or active pharmaceutical ingredients (API) in the lipid matrix, and provide phase diagrams. Four case studies are presented in which LBEs are either used as a coating material or as an encapsulation matrix to provide lipid-coated multiparticulate systems and lipid nanosuspensions, respectively. The lipid solid-state and its potential alteration during storage are investigated and correlated to the alteration in the API release. Qualitative microscopical methods such as polarized light microscopy and scanning electron microscopy are complementary tools to investigate micro-level crystallization. Further analytical methods should be added based on the selected manufacturing process. The structure-function-processability relationship should be understood carefully to design robust and stable lipid-based pharmaceutical products.


Assuntos
Química Farmacêutica , Excipientes , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Excipientes/química , Lipídeos/química , Espalhamento a Baixo Ângulo , Difração de Raios X
9.
J Pharm Biomed Anal ; 220: 114962, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-35963017

RESUMO

Drug formulations such as spray drying are often required to improve the physicochemical properties and bioavailability of hydrophobic drugs. However, excipients often carry contaminants/ impurities and may also increase moisture levels in solid formulations, which can have detrimental effects on the drugs, including drug degradation and stability. Hence, achieving adequate shelf life of drug products has been among the most challenging issues for pharmaceuticals. Here we report a case study where we systematically studied the oxidative degradation of a pharmaceutical compound GENE-A, spray-dried and dispersed in hydroxypropyl methylcellulose-acetate succinate polymer matrix. Three different oxidative degradation products were observed, and their mechanisms of formation were investigated via forced degradation studies. Finally, we used several antioxidants based on their mechanisms of action to reduce/ prevent the drug degradation process. Propyl gallate alone and in combination with Ethylenediaminetetraacetic acid completely prevented the formation of two degradation products, whereas there was no significant impact observed on the third one. The results showed that both metal chelators and free radical terminators most effectively prevented drug degradation. This study may address some of the key issues that pharmaceutical companies encounter and offer appropriate solutions to counter the oxidative degradation process of pharmaceuticals.


Assuntos
Excipientes , Galato de Propila , Quelantes , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Ácido Edético , Excipientes/química , Derivados da Hipromelose/química , Estresse Oxidativo , Polímeros/química , Succinatos
10.
Rev Lat Am Enfermagem ; 30: e3620, 2022.
Artigo em Português, Inglês, Espanhol | MEDLINE | ID: mdl-35920542

RESUMO

OBJECTIVE: to verify the stability of vancomycin hydrochloride in antimicrobial seal solutions with and without association of heparin sodium according to temperature and association time. METHOD: an experimental study designed for the analysis of hydrogenionic potential and concentration by means of high-efficiency liquid chromatography of vancomycin hydrochloride (n=06) and vancomycin hydrochloride and heparin sodium (n=06). The solutions studied were submitted to absence of light, as well as to 22°C and 37°C. Analyses in triplicate (n=192) were performed at the initial moment (T0) and three (T3), eight (T8) and 24 hours (T24) after preparation. The data were submitted to analysis of variance (p≤0.05). RESULTS: concentration of the antimicrobial at 22°C presented a reduction (T0-T8) and a subsequent increase (T24); hydrogenionic potential decreased significantly over time. At 37°C, the concentration increased up to T3 and decreased at T24, with a reduction of hydrogenionic potential up to 24 hours. Concentration of the vancomycin hydrochloride and heparin sodium solutions varied with a reduction at 22°C, accompanied by increased hydrogenionic potential. Precipitate formation was observed by visual inspection of the vancomycin hydrochloride-heparin sodium association (T3). CONCLUSION: pharmacological stability of vancomycin hydrochloride (5 mg/mL) and physical incompatibility with heparin sodium (100 IU/mL) were evidenced after three hours of association in the antimicrobial seal solutions studied.


Assuntos
Cateteres Venosos Centrais , Vancomicina , Antibacterianos , Estabilidade de Medicamentos , Heparina , Humanos , Vancomicina/química
11.
Drugs R D ; 22(3): 225-234, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35933639

RESUMO

AIM: The purpose of this study was to evaluate the extended physicochemical and biological stability of Sandoz Rixathon®/Riximyo® (SDZ-RTX) after exposure to out-of-fridge (OOF) conditions. MATERIALS AND METHODS: The impact of the short-term temperature excursion on stability parameters of SDZ-RTX was simulated by subsequently exposing the three batches of SDZ-RTX (100 and 500 mg) to OOF conditions, (I) 25 ± 2 °C/60 ± 5% relative humidity (RH) and (II) 30 ± 2 °C/65 ± 5% RH, for up to 21 days after more than the claimed 36-month shelf-life storage in long-term conditions (5 ± 3 °C). Analytical methods used included the cation exchange chromatography (CEX), size exclusion chromatography (SEC), and non-reducing capillary electrophoresis-sodium dodecyl sulfate (nrCE-SDS), as well as biological activity by complement-dependent cytotoxicity (CDC)-bioactivity as well as further methods, for example, related to identity and pharmacopoeia test methods. RESULTS: No notable changes were observed across all batches with respect to identity (charge and primary structure), pharmaceutical tests (clarity, visible and subvisible particles analytics, container appearance, degree of coloration, pH, osmolality, extractable volume, and container closure integrity testing), protein content by UV and microbiological parameters (sterility and bacterial endotoxins) under both OOF conditions. Only minor changes were observed for parameters evaluated via SEC, CEX, and nrCE-SDS. For potency (CDC-bioactivity) only one of the batches showed a relevant change. Even for these stability-indicating test methods, all analyzed parameters complied with the shelf-life specifications. CONCLUSION: SDZ-RTX is safe for use even under worst-case conditions, for example, after subjecting it for up to 21 days at OOF conditions (25 ± 2 °C/60 ± 5% RH or 30 ± 2 °C/65 ± 5% RH) after the batches had reached an age that was already beyond the claimed shelf-life.


Assuntos
Medicamentos Biossimilares , Medicamentos Biossimilares/química , Estabilidade de Medicamentos , Humanos , Rituximab/química , Temperatura
12.
Int J Pharm ; 625: 122098, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35961416

RESUMO

Amorphous pharmaceutical solids (APS) are single- or multi-component systems in which drugs exist in high-energy states with long-range disordered molecular packing. APSs have become one of the most effective and widely used pharmaceutical delivery approaches for poorly water-soluble drugs in the last several decades. Considerable efforts have been made to investigate the physical stability and dissolution behaviors of APSs, however, the underlying mechanisms remain imperfectly understood. Recent studies reveal that surface and interface properties of APSs could strongly affect the physical stability and dissolution behaviors. This paper provides a comprehensive overview of recent studies focusing on the physical stability and dissolution behaviors of APSs from both surface and interface perspectives. We highlight the role of surface or interface properties in nucleation, crystal growth, phase separation, dissolution, and supersaturation. Meanwhile, the challenges and scope of research on surface and interface properties in the future are also briefly discussed. This review contributes to a better understanding of the surface- and interface-facilitated processes, which will provide more efficient and rational guidance for the design of APSs.


Assuntos
Água , Cristalização , Estabilidade de Medicamentos , Preparações Farmacêuticas/química , Solubilidade , Água/química
13.
Eur J Pharm Biopharm ; 178: 105-116, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35917864

RESUMO

The ability to deliver stable and active dried protein therapeutics from biopharmaceutical drug delivery systems is critical for solid dosage formulation development. Spray dried formulations with carefully selected excipients provide a unique opportunity in amorphous phase stabilization of the therapeutic proteins. Herein, we discuss the role of hydroxypropyl methylcellulose acetate succinate (HPMCAS) derivatives as polymeric excipients for stabilizing a model fragment antibody (Fab2) during high temperature processing and in possible low pH environments of a drug delivery platform. The effects of high temperature processing and microenvironmental pH sensitivity are of particular interest to us due to their adverse impact on stability of molecules that demonstrate temperature and pH dependent inactivation within drug delivery devices. It appears in solid state at 90 °C and 37 °C and within low pH micro-environment HPMCAS protects protein against aggregation. The high temperature performance of HPMCAS is comparable to that of a disaccharide excipient like trehalose in spray dried protein powder. Simultaneously, inside a poly(lactic-co-glycolic acid) (PLGA) based delivery system HPMCAS provides protection to a pH sensitive protein against acidic degradation products from aqueous hydrolysis of PLGA.


Assuntos
Excipientes , Metilcelulose , Anticorpos , Estabilidade de Medicamentos , Excipientes/química , Concentração de Íons de Hidrogênio , Derivados da Hipromelose , Metilcelulose/química , Temperatura
14.
Eur J Pharm Biopharm ; 178: 82-93, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35932965

RESUMO

Co-amorphous strategy has been extensively investigated to improve the dissolution of hydrophobic drugs. Here, epigallocatechin-3-gallate (EGCG) was exploited as a co-former in co-amorphous systems based on its unique structure including phenyl rings, phenolic hydroxyl groups and the galloyl moiety. Two model BCS class II drugs, simvastatin (SIM) and nifedipine (NIF), were selected to be co-amorphized with EGCG. All drug-EGCG systems at three molar ratios became amorphous by the means of spray drying and showed high physically stable either under dry condition and 75 % RH at 40 °C or under dry conditions at 25 °C. The optimal feed molar ratios of both EGCG based co-amorphous systems fabricated were determined to be three, under which the significant increases were obtained in the maximum apparent concentrations of 4.90-fold for SIM at 1 h and 106.03-fold for NIF at 0.25 h compared to crystalline drugs by non-sink dissolution studies. The underlying molecular mechanisms of two co-amorphous systems formation were involved in molecular miscibility, hydrogen bonds and π-π stacking interactions unraveled by means of DSC, FTIR and molecular dynamics simulations. More to the point, oral pharmacokinetic studies in rats demonstrated that co-amorphous SIM-EGCG and NIF-EGCG systems at 1:3 have a significant increase in Cmax of 1.81- and 5.69-fold, and AUC 0-24h of 1.62- and 4.57-fold compared with those of corresponding crystalline drugs, respectively. In conclusion, EGCG is proved to be a promising co-former in co-amorphous systems.


Assuntos
Nifedipino , Sinvastatina , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Catequina/análogos & derivados , Estabilidade de Medicamentos , Nifedipino/química , Ratos , Sinvastatina/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
15.
Artigo em Inglês | MEDLINE | ID: mdl-35993995

RESUMO

The aqueous solubility of active drug moiety plays a crucial role in the development of an efficacious formulation. The poor aqueous solubility of BCS class II and IV drugs is manifested as poor bioavailability. Preparation of cyclodextrin inclusion complex to improve the solubility, stability, and bioavailability is a well-established technique. The latest trend in cyclodextrin research is focused on ternary complexes wherein an auxiliary agent such as water-soluble polymers, organic ions, metals, or amino acids is incorporated in the inclusion complex. The cyclodextrin-based supramolecular ternary complex offers significant advantages over binary complex specifically for oral drug delivery. Compared with the binary complex, the ternary complex exhibits better complexation efficiency and stability constant. Moreover, the ternary complex has a major advantage of reducing the concentration of cyclodextrin required to achieve maximum solubility and stability. Lately, in silico molecular modeling has gained tremendous attention as a preliminary tool to evaluate the cyclodextrin-based ternary or binary complex which has been discussed. This review gives an insight into various ternary agents explored worldwide, significant observations, safety, and clinical studies carried out on ternary cyclodextrin complexes.


Assuntos
Ciclodextrinas , beta-Ciclodextrinas , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Ciclodextrinas/química , Estabilidade de Medicamentos , Humanos , Preparações Farmacêuticas/química , Solubilidade , Água/química , beta-Ciclodextrinas/química
16.
J Pharm Biomed Anal ; 219: 114955, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-35917732

RESUMO

Cariprazine hydrochloride is a second-generation antipsychotic drug and has been approved by the US Food and Drug Administration and the European Medicines Agency. Herein, we have reported a stability-indicating assay method for the Cariprazine hydrochloride and characterization of its major degradation products using LC-HRMS/MS. The drug substance Cariprazine hydrochloride was subjected to acid, base, oxidation, thermal and photolytic stress degradation. A total of five novel degradation products (DP-1 to DP-5) of Cariprazine hydrochloride drug substance were formed under various acid, base and oxidative conditions. In silico toxicity of the degradation products was evaluated using Leadscope prediction platform. We successfully separated Cariprazine Hydrochloride peak from degradation products (DP-1 to DP-5) by using gradient elution on an Inertsil C18 column (150 × 4.6 mm, 5 µm). The drug substance was found to be labile to acidic, alkaline hydrolytic, and oxidative conditions and stable to photolytic and thermal stress conditions. The degradation pathways were delineated by explaining the putative mechanism of degradation in various conditions. The stability-indicating assay method was validated according to the ICH guideline and hence can be used for routine quality control and stability study analysis of Cariprazine hydrochloride in pharmaceutical industries and research laboratories.


Assuntos
Piperazinas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Estabilidade de Medicamentos , Hidrólise , Espectrometria de Massas/métodos , Oxirredução , Fotólise
17.
J Agric Food Chem ; 70(33): 10075-10089, 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-35968926

RESUMO

Lactoferrin (LF) is a naturally present iron-binding globulin with the structural properties of an N-lobe strongly positively charged terminus and a cage-like structure of nano self-assembly encapsulation. These unique structural properties give it potential for development in the fields of electrostatic spinning, targeted delivery systems, and the gut-brain axis. This review will provide an overview of LF's unique structure, encapsulation, and targeted transport capabilities, as well as its applications in immunity and gut microbiota regulation. First, the microstructure of LF is summarized and compared with its homologous ferritin, revealing both structural and functional similarities and differences between them. Second, the electrostatic interactions of LF and its application in electrostatic spinning are summarized. Its positive charge properties can be applied to functional environmental protection packaging materials and to improving drug stability and antiviral effects, while electrostatic spinning can promote bone regeneration and anti-inflammatory effects. Then the nano self-assembly behavior of LF is exploited as a cage-like protein to encapsulate bioactive substances to construct functional targeted delivery systems for applications such as contrast agents, antibacterial dressings, anti-cancer therapy, and gene delivery. In addition, some covalent and noncovalent interactions of LF in the Maillard reaction and protein interactions and other topics are briefly discussed. Finally, LF may affect immunological function via controlling the gut microbiota. In conclusion, this paper reviews the research advances of LF in electrostatic spinning, nano self-assembly, and immune and gut microbiota regulation, aiming to provide a reference for its application in the food and pharmaceutical fields.


Assuntos
Microbioma Gastrointestinal , Lactoferrina , Estabilidade de Medicamentos , Fatores Imunológicos , Lactoferrina/química , Eletricidade Estática
18.
ACS Appl Mater Interfaces ; 14(33): 37410-37423, 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-35968684

RESUMO

Insulin, the oldest U.S. Food and Drug Administration (FDA)-approved recombinant protein and a World Health Organization (WHO) essential medicine for treating diabetes globally, faces challenges due to its storage instability. One approach to stabilize insulin is the addition of poly(trehalose methacrylate) (pTrMA) as an excipient. The polymer increases the stability of the peptide to heat and mechanical agitation and has a low viscosity suitable for injection and pumps. However, the safety and stabilizing mechanism of pTrMA is not yet known and is required to understand the potential suitability of pTrMA as an insulin excipient. Herein is reported the immune response, biodistribution, and insulin plasma lifetime in mice, as well as investigation into insulin stabilization. pTrMA alone or formulated with ovalbumin did not elicit an antibody response over 3 weeks in mice, and there was no observable cytokine production in response to pTrMA. Micropositron emission tomography/microcomputer tomography of 64Cu-labeled pTrMA showed excretion of 78-79% ID/cc within 24 h and minimal liver accumulation at 6-8% ID/cc when studied out to 120 h. Further, the plasma lifetime of insulin in mice was not altered by added pTrMA. Formulating insulin with 2 mol equiv of pTrMA improved the stability of insulin to standard storage conditions: 46 weeks at 4 °C yielded 87.0% intact insulin with pTrMA present as compared to 7.8% intact insulin without the polymer. The mechanism by which pTrMA-stabilized insulin was revealed to be a combination of inhibiting deamidation of amino acid residues and preventing fibrillation, followed by aggregation of inactive and immunogenic amyloids all without complexing insulin into its hexameric state, which could delay the onset of insulin activity. Based on the data reported here, we suggest that pTrMA stabilizes insulin as an excipient without adverse effects in vivo and is promising to investigate further for the safe formulation of insulin.


Assuntos
Excipientes , Trealose , Animais , Estabilidade de Medicamentos , Excipientes/química , Insulina/química , Metacrilatos , Camundongos , Polímeros/química , Distribuição Tecidual , Tomografia Computadorizada por Raios X , Trealose/química
19.
Molecules ; 27(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36014329

RESUMO

Due to the growing demand for patient-friendly subcutaneous dosage forms, the ability to increasing protein solubility and stability in formulations to deliver on the required high protein concentrations is crucial. A common approach to ensure protein solubility and stability in high concentration protein formulations is the addition of excipients such as sugars, amino acids, surfactants, approved by the Food and Drug Administration. In a best-case scenario, these excipients fulfil multiple demands simultaneously, such as increasing long-term stability of the formulation, reducing protein adsorption on surfaces/interfaces, and stabilizing the protein against thermal or mechanical stress. 2-Hydroxylpropyl-ß-cyclodextrin (derivative of ß-cyclodextrin) holds this potential, but has not yet been sufficiently investigated for use in protein formulations. Within this work, we have systematically investigated the relevant molecular interactions to identify the potential of Kleptose®HPB (2-hydroxylpropyl-ß-cyclodextrin from Roquette Freres, Lestrem, France) as "multirole" excipient within liquid protein formulations. Based on our results three factors determine the influence of Kleptose®HPB on protein formulation stability: (1) concentration of Kleptose®HPB, (2) protein type and protein concentration, and (3) quality of the protein formulation. Our results not only contribute to the understanding of the relevant interactions but also enable the target-oriented use of Kleptose®HPB within formulation design.


Assuntos
Excipientes , beta-Ciclodextrinas , Estabilidade de Medicamentos , Excipientes/química , Humanos , Estabilidade Proteica , Proteínas/química , Solubilidade , beta-Ciclodextrinas/química
20.
Int J Pharm ; 624: 122025, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35850185

RESUMO

Modified oligosaccharides with cyclic topology seem to be promising excipients for the preparation of Amorphous Solid Dispersions (ASDs), especially with those Active Pharmaceutical Ingredients (APIs), which have a strong crystallization tendency from the amorphous/glassy state. Herein, the usefulness of two acetylated cyclodextrins (ac-α-CD and ac-ß-CD) with various molecular weights (Mw) as stabilizers for the supercooled metronidazole (Met) has been discussed. X-ray diffraction (XRD) studies carried out on Met-acCDs mixtures (prepared in molar ratios from 1:2 to 5:1) showed that the system with ac-α-CD containing the highest amount of API (5:1 m/m) crystallizes immediately after preparation, whereas all Met-ac-ß-CD ASDs remain stable. What is more, long-term XRD measurements confirmed that the Met-ac-α-CD 2:1 m/m system crystallizes after 100 days of storage in contrast to the same system containing ac-ß-CD. The non-isothermal calorimetric data revealed that the activation barrier for crystallization (Ecr) in ASDs with the oligosaccharide having a greater Mw (i.e., composed of seven acGLU molecules) is slightly higher. Finally, to explain the differences in behavior between the mixtures with both acCDs, infrared studies, DFT calculations and Molecular Dynamics simulations were performed. All methods excluded the scenario of API incorporation inside the acCDs' core. On the other hand, obtained results suggested that in comparison to ac-α-CD, the greater amount of Met molecules might be bounded on the outside surface of ac-ß-CD. Therefore, this modified saccharide is a better stabilizer of the examined API.


Assuntos
Ciclodextrinas , Metronidazol , Varredura Diferencial de Calorimetria , Cristalização/métodos , Estabilidade de Medicamentos , Excipientes/química , Solubilidade , Difração de Raios X
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