Synergistics of Carboxymethyl Chitosan and Mangosteen Extract as Enhancing Moisturizing, Antioxidant, Antibacterial, and Deodorizing Properties in Emulsion Cream.

Carboxymethyl chitosan (CMCH) from native chitosan of high molecular weight (H, 310-375 kDa) was synthesized for improving water solubility. The water solubility of high-molecular-weight carboxymethyl chitosan (H-CMCH) was higher than that of native chitosan by 89%. The application of H-CMCH as enhancing the moisturizer in mangosteen extract deodorant cream was evaluated. Different concentrations of H-CMCH (0.5-2.5%) were investigated in physicochemical characteristics of creams, including appearance, phase separation, pH, and viscosity, by an accelerated stability test. The different degrees of skin moisturizing (DM) on pig skin after applying H-CMCH solution, compared with untreated skin, water, and propylene glycol for 15 and 30 min using a Corneometer®, were investigated. The results showed that the 0.5% H-CMCH provided the best DM after applying the solution on pig skin for 30 min. Trans-2-nonenal, as an unsatisfied odor component, was also evaluated against components of the mangosteen extract deodorant cream, which were compared to the standard, epigallocatechin gallate (EGCG). In addition, DPPH and ABTS radical scavenging activity, ferric reducing antioxidant power (FRAP), and antibacterial activities were examined for the mangosteen extract deodorant cream using 0.5% H-CMCH. Results indicated that the mangosteen extract synergized with H-CMCH, which had a good potential as an effective skin moisturizing agent enhancer, deodorizing activity on trans-2-nonenal odor, antioxidant properties, and antibacterial properties.

Accelerated stability test of sustained-release thienorphine loaded microspheres for injection / 药学学报

In order to meet the clinical needs of long-acting sustained-release thienorphine, injectable thienorphine loaded microspheres were developed, and the accelerated stability study was carried out to explore the suitable storage and transportation conditions of the microspheres. Using poly(lactic-co-glycolic acid) (PLGA) as carrier material, 3 batches of microspheres were prepared in pilot scale with emulsion solvent evaporation method. By investigating the in vitro release of thienorphine loaded microspheres at 37, 45, 52, and 60 ℃, and applying the Arrhenius equation, the linear relationship between the release rate constant (lgk) and the temperature (1/T) was established to obtain the equation: lgk = -8.073/T + 24.35 (R2 = 0.985 3), which showed that the release of microspheres at high temperature can be used to predict the release in vitro at 37 ℃, and 52.0 ± 0.5 ℃ was selected as the accelerated release condition in vitro. The quality research methods were established to investigate the changes of critical quality attributes such as microsphere morphology, drug loading, particle size and distribution, polymer molecular weight, and the related substances under accelerated conditions. The difference factor f1 and similarity factor f2 were used to assess the similarity of release behavior under accelerated conditions. The results showed that under the accelerated experimental conditions of 25 ± 2 ℃ and relative humidity (RH) 60% ± 5%, the critical quality attributes of injectable thienorphine loaded microspheres had no significant change in 6 months, suggesting that the long-term storage condition could be 5 ± 3 ℃.

Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) are important formulation strategies for improving the dissolution process and oral bioavailability of poorly soluble drugs. Physical stability of a candidate drug must be clearly understood to design ASDs with superior properties. The crystallization tendency of small organics is frequently estimated by applying rapid cooling or a cooling/reheating cycle to their melt using differential scanning calorimetry. The crystallization tendency determined in this way does not directly correlate with the physical stability during isothermal storage, which is of great interest to pharmaceutical researchers. Nevertheless, it provides important insights into strategy for the formulation design and the crystallization mechanism of the drug molecules. The initiation time for isothermal crystallization can be explained using the ratio of the glass transition and storage temperatures (Tg/T). Although some formulation processes such as milling and compaction can enhance nucleation, the Tg/T ratio still works for roughly predicting the crystallization behavior. Thus, design of accelerated physical stability test may be possible for ASDs. The crystallization tendency during the formulation process and the supersaturation ability of ASDs may also be related to the crystallization tendency determined by thermal analysis. In this review, the assessment of the crystallization tendency of pharmaceutical glasses and its relevance to developmental studies of ASDs are discussed.

Microstructural Distinction of Electrospun Nanofibrous Drug Delivery Systems Formulated with Different Excipients.

The electrospun nanofiber-based orally dissolving webs are promising candidates for rapid drug release, which is due to the high surface area to volume ratio of the fibers and the high amorphization efficacy of the fiber formation process. Although the latter is responsible for the physical and/or chemical instability of these systems. The primary aim of the present study was to elucidate how the addition of polysorbate 80 (PS80) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) influenced the electrospinning process, the properties, and the behavior of the obtained nanofibers. In order to reveal any subtle changes attributable to the applied excipients, the prepared samples were subjected to several state of the art imaging and solid state characterization techniques at both macroscopic and microscopic levels. Atomic force microscopy (AFM) revealed the viscoelastic nature of the fibrous samples. At relatively low forces mostly elastic deformation was observed, while at higher loads plasticity predominated. The use of polysorbate led to about two times stiffer, less plastic fibers than the addition of cyclodextrin. The 1H-13C nuclear magnetic resonance (NMR) cross-polarization build-up curves pointed out that cyclodextrin acts as an inner, while polysorbate acts as an outer plasticizer and, due to its "liquid-like" behavior, can migrate in the polymer-matrix, which results in the less plastic behavior of this formulation. Positron annihilation lifetime spectroscopy (PALS) measurements also confirmed the enhanced mobility of the polysorbate and the molecular packing enhancer properties of the cyclodextrin. Solid-state methods suggested amorphous precipitation of the active ingredient in the course of the electrospinning process; furthermore, the nature of the amorphous systems was verified by NMR spectroscopy, which revealed that the use of the examined additives enabled the development of a molecularly dispersed systems of different homogeneities. An accelerated stability study was carried out to track physical state related changes of the incorporated drug and the polymeric carrier. Recrystallization of the active ingredient could not be observed, which indicated a large stress tolerance capacity, but time-dependent microstructural changes were seen in the presence of polysorbate. Raman mapping verified homogeneous drug distribution in the nanofibrous orally dissolving webs. The performed dissolution study indicated that the drug dissolution from the fibers was rapid and complete, but the formed stronger interaction in the case of the PVA-CD-MH system resulted in a little bit slower drug release, compared to the PS80 containing formulation. The results obviously show that the complex physicochemical characterization of the polymer-based fibrous delivery systems is of great impact since it enables the better understanding of material properties including the supramolecular interactions of multicomponent systems and consequently the rational design of drug-loaded nanocarriers of required stability.

Physicochemical stability and aerosolization performance of dry powder inhalation system containing ciprofloxacin hydrochloride.

Antibiotic delivery in form of dry powder inhalation has been studied for possible clinical treatment of respiratory tract infection in the recent years. Dry powder inhalation of ciprofloxacin hydrochloride (CIP) assures local antibacterial activity and comfort of easy application. The aim of this work was to test the stability of co-spray-dried CIP in carrier free system. Since the microparticles in the dry powder system are amorphous and do not contain any stabilizer, the effects of temperature and relative humidity (RH) on the physicochemical properties and aerosolization behavior are very important. Therefore investigation of the role of excipients (such as polyvinyl alcohol (PVA), l-leucine (LEU) and hydroxypropyl-beta-cyclodextrin (CD)) on physicochemical stability and aerosolization performance is essential element prior designing the final dosage form. Stability tests (stress and accelerated) were performed at 40±2°C and 75±5% RH during 6 months. Particle characterization and size measurement - as the most important parameters in aerodynamic behavior - were done by the laser diffraction method, the surface morphology of microparticles was evaluated by scanning electron microscopy (SEM). The physiochemical properties of microparticles were investigated by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The resulting aerodynamic behavior of microparticles was studied by Andersen cascade impactor. The overall stability results (against RH and temperature) showed that microparticles containing CIP and LEU alone and in combination with the other excipients were more stable than those containing PVA or CD alone. In relation to fine particle fraction and mass median aerodynamic diameter (determining the aerosolization parameters), it was found that the particle size and particle shape did not show significant changes after the storage. Among the excipients LEU was found to have many advantages, including relatively simple formulation, enhanced aerosolization behaviour, convenient portability and inherently improved stability. Such a composition may serve as an innovative drug delivery system for the local treatment of respiratory tract infection and cystic fibrosis.

Effect of lentil proteins isolate concentration on the formation, stability and rheological behavior of oil-in-water nanoemulsions.

The formation, stability and rheology of 5wt% oil-in-water nanoemulsions as a function of lentil protein isolate concentration (0.5-5wt%) at pH 3.0 was investigated for 28days. All nanoemulsions, except 1wt% protein, showed bimodal droplet size distribution where the larger diameter peak was ascribed to protein aggregates and entrapped oil droplets. The average droplet size for all nanoemulsions measured from the lower diameter peak ranged from 161 to 357nm, which did not change over 28days. Stable flowable nanoemulsions were formed at 1-2wt% protein concentrations. Nanoemulsions with 3 and 5wt% protein formed strong non-flowable gels which showed a two-step yielding behavior during strain-sweep rheology, indicating gel formation by interconnected clusters of proteins and oil droplets. This study demonstrated that lentil protein has a potential to be utilized as an emulsifier in nanoemulsions, as well as in the formation of emulsion gels at higher protein concentrations.

Shelf-life of a 2.5 percent sodium hypochlorite solution as determined by arrhenius equation

Accelerated stability tests are indicated to assess, within a short time, the degree of chemical degradation that may affect an active substance, either alone or in a formula, under normal storage conditions. This method is based on increased stress conditions to accelerate the rate of chemical degradation. Based on the equation of the straight line obtained as a function of the reaction order (at 50 and 70 ºC) and using Arrhenius equation, the speed of the reaction was calculated for the temperature of 20 ºC (normal storage conditions). This model of accelerated stability test makes it possible to predict the chemical stability of any active substance at any given moment, as long as the method to quantify the chemical substance is available. As an example of the applicability of Arrhenius equation in accelerated stability tests, a 2.5 percent sodium hypochlorite solution was analyzed due to its chemical instability. Iodometric titration was used to quantify free residual chlorine in the solutions. Based on data obtained keeping this solution at 50 and 70 ºC, using Arrhenius equation and considering 2.0 percent of free residual chlorine as the minimum acceptable threshold, the shelf-life was equal to 166 days at 20 ºC. This model, however, makes it possible to calculate shelf-life at any other given temperature.

Testes acelerados de estabilidade são indicados para avaliar, em um curto período de tempo, o grau de degradação química que poderá afetar uma substância química, isoladamente ou quando inserida em uma fórmula, sob condições normais de armazenamento. Este método está fundamentado na intensificação das condições de estresse para acelerar a velocidade de degradação química. Baseando-se na equação da reta obtida e na ordem de reação determinada (a 50 e 70 ºC) e usando a equação de Arrhenius, a velocidade de reação foi calculada para a condição de temperatura de 20ºC (condições normais de armazenamento). Este modelo de teste acelerado de estabilidade torna possível a predição da estabilidade química de qualquer substância, em qualquer tempo, desde que o método de quantificação da substância química esteja disponível. Como exemplo da aplicabilidade da equação de Arrhenius em teste acelerado de estabilidade, uma solução de hipoclorito de sódio a 2,5 por cento foi analisada por ser quimicamente instável. A quantificação do cloro residual livre foi determinada através de titulação iodométrica. A partir dos dados obtidos decorrentes das amostras submetidas às temperaturas de 50 e 70 ºC e com o emprego da equação de Arrhenius, o tempo de prateleira obtido foi de 166 dias em temperatura de 20 ºC, considerando como limite inferior a concentração de 20 mg/mL de cloro residual livre. Este modelo, entretanto, possibilita o cálculo de tempo de prateleira em qualquer outra temperatura de interesse.

Estabilidade e estudo de penetração cutânea in vitro da rutina veiculada em uma emulsão cosmética através de um modelo de biomembrana alternativo / Stability and in vitro penetration study of rutin incorporated in a cosmetic emulsion through an alternative model biomembrane

A rutina é empregada como antioxidante e na prevenção da fragilidade capilar. Estudos de penetração in vitro através da pele humana seria a situação ideal, entretanto, há dificuldades de sua obtenção e manutenção de sua viabilidade. Entre os demais modelos de membrana, a muda de pele de cobra se apresenta como estrato córneo puro, fornecendo barreira similar ao humano e é obtida sem a morte do animal. Os objetivos desta pesquisa foram desenvolver e avaliar a estabilidade de uma emulsão cosmética contendo rutina e, como promotor de penetração cutânea, o propilenoglicol; e avaliar a penetração e a retenção cutânea in vitro da referida substância ativa da formulação, empregando um modelo de biomembrana alternativo. A emulsão foi desenvolvida com rutina e propilenoglicol, ambos a 5,0 por cento p/p. Quantificou-se a rutina das emulsões por espectrofotometria a 361,0 nm, método previamente validado. A penetração e retenção cutânea in vitro foram realizadas em células de difusão vertical com muda de pele de cobra de Crotalus durissus, como modelo de biomembrana alternativo, e água destilada e álcool etílico absoluto 99,5 por cento (1:1), como fluido receptor. O experimento foi conduzido em um período de seis horas, a 37,0 ± 0,5 ºC e agitação constante de 300 rpm. Empregou-se o método espectrofotométrico validado a 410,0 nm para a quantificação da rutina após penetração e retenção cutânea. A emulsão não promoveu a penetração cutânea da rutina através da muda de pele de C. durissus, retendo 0,931 ± 0,0391 mg de rutina/mg de muda de pele de cobra. Nas condições de armazenamento a 25,0 ± 2,0 ºC; 5,0 ± 0,5 ºC e 45,0 ± 0,5 ºC, a emulsão apresentou-se quimicamente estável durante 30 dias. De acordo com os resultados, a emulsão não favoreceu a penetração cutânea da rutina, mas apenas sua retenção no estrato córneo de C. durissus, condição considerada estável no período de 30 dias.

Rutin is employed as antioxidant and to prevent the capillary fragility and, when incorporated in cosmetic emulsions, it must target the action site. In vitro cutaneous penetration studies through human skin is the ideal situation, however, there are difficulties to obtain and to maintain this tissue viability. Among the membrane models, shed snake skin presents itself as pure stratum corneum, providing barrier function similar to human and it is obtained without the animal sacrifice. The objectives of this research were the development and stability evaluation of a cosmetic emulsion containing rutin and propylene glycol (penetration enhancer) and the evaluation of rutin in vitro cutaneous penetration and retention from the emulsion, employing an alternative model biomembrane. Emulsion was developed with rutin and propylene glycol, both at 5.0 percent w/w. Active substance presented on the formulation was quantified by a validated spectrophotometric method at 361.0 nm. Rutin cutaneous penetration and retention was performed in vertical diffusion cells with shed snake skin of Crotalus durissus, as alternative model biomembrane, and distilled water and ethanol 99.5 percent (1:1), as receptor fluid. The experiment was conducted for six hours, at 37.0 ± 0.5 ºC with constant stirring of 300 rpm. Spectrophotometry at 410.0 nm, previously validated, determined the active substance after cutaneous penetration/retention. Emulsion did not promote rutin cutaneous penetration through C. durissus skin, retaining 0.931 ± 0.0391 mg rutin/mg shed snake skin. The referred formulation was chemically stable for 30 days after stored at 25.0 ± 2.0 ºC, 5.0 ± 0.5 ºC and 45.0 ± 0.5 ºC. In conclusion, it has not been verified the active cutaneous penetration through the model biomembrane, but only its retention on the Crotalus durissus stratum corneum, condition considered stable for 30 days.

Accelerated chemical stability data of O/W fluid emulsions containing the extract of Trichilia catigua Adr. Juss (and) Ptychopetalum olacoides Bentham

Development of topical dosage forms requires physical, physicochemical and chemical assays that provide, as soon as possible, the formulation with the best stability profiles. This study evaluated the stability of O/W fluid emulsions, by total flavonoids determination, expressed in rutin, containing the standardized extract of Trichilia catigua Adr. Juss (and) Ptychopetalum olacoides Bentham. Samples were evaluated for 90 days stored at 24.0 ± 2.0 ºC, 5.0 ± 0.5 ºC and 40.0 ± 0.5 ºC, following a protocol for the assessment of accelerated chemical stability assay, also known as Normal Stability Test. A sensitive UV-spectrophotometric method at 361.0 nm was previously validated for the determination of the active substance. By Normal Stability Test, the O/W fluid emulsions presented acceptable chemical stability, for at least 90 days, when the samples were stored at 24.0 ± 2.0 ºC and 5.0 ± 0.5 ºC. The storage condition at 40.0 ± 0.5 ºC has accelerated the degradation process of the total flavonoids, consequently, those O/W emulsions containing this kind of natural active substance or a similar preparation must not be stored at elevated temperatures.

O desenvolvimento de formas farmacêuticas tópicas necessita ensaios físicos, físico-químicos e químicos que selecionem rapidamente a formulação de melhor desempenho de estabilidade. Este estudo avaliou a estabilidade de emulsões O/A fluidas, por meio da determinação de flavonóides totais, expressos em rutina, contendo o extrato padronizado de Trichilia catigua Adr. Juss (e) Ptychopetalum olacoides Bentham. As amostras foram armazenadas a 24,0 ± 2,0 ºC; 5,0 ± 0,5 ºC e 40,0 ± 0,5 ºC durante 90 dias e foram avaliadas segundo o protocolo para a determinação da estabilidade acelerada, conhecida como Teste de Estabilidade Normal. A quantificação da substância ativa foi determinada por espectrofotometria na região do ultravioleta a 361,0 nm, previamente validado. Após os ensaios de estabilidade, as emulsões O/A fluidas apresentaram estabilidade adequada, pelo menos, no período de 90 dias, quando armazenadas a 24,0 ± 2,0 ºC e 5,0 ± 0,5 ºC. A condição de armazenamento a 40,0 ± 0,5 ºC acelerou a cinética de degradação dos flavonóides totais, expressos em rutina, portanto, preparações possuindo esta categoria de substância ativa natural ou formulações similares não devem ser armazenadas em temperaturas elevadas.

Apply the accelerated stability test to predict the self-life of national standard serum tetanus antitoxin

Accelerated stability test has been applied for predicting self-life of national standard serum tetanus anti-toxin (SAT). Samples of the tetanus antitoxin were kept at - 20°C, 4°C, 22°C, 37°C and 45°C for 6 months and their potency was estimated by using the toxin neutralization method on mice. There was relationship between the potency change and the self- life of serum tetanus antitoxin by using Arrhenius equation. The results demonstrated that the self-life of the national standard serum tetanus antitoxin was 9 years and 6 months when stored at -20°C.