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Natural products are promising drug candidates with various pharmacological effects. However, they can be difficult to use due to poor bioavailability or low stability. In this experiment, while developing topical formulations containing 0.1% Agrimonia pilosa extract, a simple and rapid method of analyzing flavonoid glucuronides, which are representative ingredients, was developed and validated, and the physicochemical properties and stability of flavonoid glucuronides were observed. As a result, an optimized cream formulation was developed. The oil phase comprised tween 60, liquid paraffin, propylene glycol, cetanol, stearyl alcohol, span 60, benzyl alcohol, and A. pilosa extracts, and the water phase comprised water and citric acid hydrate. Then, physicochemical and microbial stability tests of the formulation were conducted under long-term (12 months) and accelerated conditions (6 months). It was thus confirmed that both physicochemical and biological properties were stable during the test period. Consequently, an optimized formulation for the extract was developed and stability was confirmed.

Previously our laboratory first reported that dropping of freeze-dried monoclonal antibody (mAb) formulations could cause protein degradation and aggregation (J Pharm Sci, 2021, 1625). In this manuscript, we evaluated effects of secondary package on stability of several freeze-dried biopharmaceutical formulations during dropping. The degradation of mAb-Y during dropping with different secondary packages was determined by the sensitive particle analyzing techniques micro-flow imaging (MFI) and dynamic light scattering (DLS). Electron paramagnetic resonance (EPR) was used to detect free radicals after repeated dropping in different secondary packages. The amount of free radicals and SbVPs was correlated to the sample temperature as well as the secondary package during dropping. Our observations suggest that secondary packaging has significant effect on freeze-dried biopharmaceutical stability during dropping and therefore should be thoroughly screened and optimized to assure high product quality even for the presumed highly stable freeze-dried biopharmaceuticals.

Fluconazole is an important drug in the treatment of cutaneous and systemic mycoses. The Hospital de Clínicas de Porto Alegre performs a derivation of fluconazole capsules to obtain an oral liquid formulation that is easily administered and whose dose can be adjusted. In order to replace the derivation for a formulation produced from an active pharmaceutical ingredient, this study sought to develop a liquid oral formulation, evaluate its physical chemical and microbiological stability and demonstrate suitability of the analytical method for the formulation assay. Seven different formulations of pharmaceutical suspension form were produced and evaluated for pH, viscosity, sedimentation volume and assay. The analytical method by High Performance Liquid Chromatography was demonstrated. Two most promising formulations were manipulated in the Farmácia Semi-Industrial do Hospital de Clínicas de Porto Alegre and stored in amber PET bottles under three different conditions: room temperature, under refrigeration (2 to 8 ºC) and in an oven (40 ° C). Samples were collected after 0, 7 and 14 days to evaluate physical-chemical stability, assay, pH and macroscopic aspects. Samples were collected after 0 and 21 days to evaluate microbiological stability. It was possible to demonstrate stability for one of the formulations for a 14-day period. Throughout the study, the chosen formulation presented adequate quantification of fluconazole, constant pH, no organoleptic changes and no microbial growth. The results suggest the incorporation of a new formulation for fluconazole to the Farmacia Semi-Industrial portfolio).

The food and beverage industry often need to encapsulate hydrophobic functional ingredients in their products, including colors, flavors, lipids, nutraceuticals preservatives, and vitamins. Encapsulation can improve the handling, water-dispersibility, chemically stability, and efficacy of these functional ingredients. In this review article, we focus on the design of nanoemulsion-based delivery systems to encapsulate, protect, and deliver non-polar bioactive agents, such as vitamin A, D and E, β-carotene, lycopene, lutein, curcumin, resveratrol, and coenzyme Q10. Initially, the challenges associated with incorporating these different bioactives into foods are highlighted. The relative merits and drawbacks of different nanoemulsion fabrication methods are then discussed. Finally, examples of the application of nanoemulsions for improving the stability and bioavailability of various kinds of hydrophobic vitamins and nutraceuticals are provided.

Objectives: The aim of current research was to formulate limonene selfnanoemulsified delivery system (SNEDS) by spontaneous emulsification method. Methods: The optimization was carried out through the construction of a pseudo-ternary phase diagram. Limonene-based self- nanoemulsifying system was optimized by evaluating its droplet characteristic; namely; size, polydispersity, zeta potential, in addition, its morphology was assessed through the use of transmission electron microscopy. Moreover, the formulation stability under different storage conditions for three months was examined. Results: The obtained results showed that the optimized limonene-based self-nanoemulsifying system was characterized by a small droplet size, low polydispersity index, high percentage transmittance and optimal zeta potential with uniform spherical droplets. The selected formulation with 50% w/w limonene, 40% w/w Tween 80 and 10% w/w propylene glycol had a droplet size of 113.3±1.18nm with bluish transparent appearance and a zeta potential value of -19.13±0.38 mV. The developed formula was stable against pH change. The stored limonenebased SNEDS showed acceptable stability at 4°C and 0°C compared to 25°C. Conclusion: The formulated self-nanoemulsifying system showed an improved aqueous dispersibility, patient acceptability and stability of limonene, representing a promising carrier for lipophilic drugs.

Formulation screening for biotherapeutics can cover a vast array of excipients and stress conditions. These studies consume quantities of limited material and, with higher concentrated therapeutics, more material is needed. Here, we evaluate the use of crystal zenith (CZ) microtiter plates in conjunction with FluoroTec-coated butyl rubber mats as a small-volume, high-throughput system for formulation stability studies. The system was studied for evaporation, edge effects, and stability with comparisons to type 1 glass and CZ vials for multiple antibodies and formulations. Evaporation was minimal at 4°C and could be reduced at elevated temperatures using sealed, mylar bags. Edge effects were not observed until 12 weeks at 40°C. The overall stability ranking as measured by the rate of change in high molecular weight and percent main peak species was comparable across both vials and plates at 4°C and 40°C out to 12 weeks. Product quality attributes as measured by the multi-attribute method were also comparable across all containers for each molecule formulation. A potential difference was measured for subvisible particle analysis, with the plates measuring lower particle counts than the vials. Overall, CZ plates are a viable alternative to traditional vials for small-volume, high-throughput formulation stability screening studies.

Meglumine antimoniate (MA) is a pentavalent antimony (SbV) drug recommended for the treatment of leishmaniasis. It is known that the trivalent antimony (SbIII) present as a residue in MA contributes to the drug side effects. In this article, multivariate optimization was used in the synthesis of MA in order to obtain a drug with low levels of SbIII. Four variables (source of antimony, temperature, water volume and pH) were preliminarily evaluated by 24-1 fractional factorial design. Central composite design (CCD) was used to determine the optimal synthesis conditions, using two different sources of SbV and the significant variables selected in a fractional factorial design. Response surface methodology obtained by CCD provided a model with non-significant regression (p = 0.05) for the synthetic route via KSb(OH)6. On the other hand, synthetic route via SbCl5 reached minimum value of SbIII content of 0.172% and significant regression, and it was selected for further evaluations. The analysis of MA formulations synthesized with SbCl5 under optimized conditions revealed the efficiency of multivariate optimization to reduce SbIII content. In addition, the monitoring of some physicochemical parameters of these formulations maintained at 40 ºC for 90 days, showed that stability was not altered at 95% confidence level.

Minor depression and sleep disorders are common problems in modern societies. There are prescription medicines and herbal remedies to ease the symptoms. St. John-s wort is often used to treat mild depression and valerian root is recommended as a sedative for centuries. Nowadays there is an increasing interest for herbal medicines and therefore the herbal products are becoming more and more popular. As dietary supplement retailers selling low quality products -or even don-t contain what-s claimed on the label- quality becomes the major concern. The legislation to conventional medicines applies to traditional herbal medicines too, which makes registered herbal medicines reliable in production and quality. A CTD application dossier which contains quality data in module 3 should be provided while registering a herbal medicine in EU. In this study we developed a stable formulation and validated two separate methods to quantify the herbal extract amounts in solid oral dosage forms which contains St. John-s Wort and valerian dry extract as active ingredients to comply CTD module 3 requirements.

Cosmetic treatments aim at improving skin appearance through vehicles of good sensory properties. Those vehicles are mainly emulsions and gels designed to deliver safe and effective compounds to skin. Creams and serums are widely used to achieve these goals, but recently a new type of formulation known as organogels triggered scientific attention, particularly in the design of both topical and cosmetic formulations. It has been established that the lipophilic nature of organogels makes it an excellent candidate for the delivery of cosmetic molecules through skin. In this review, we discuss the properties and characteristics of organogels and present the advantages of the application of these systems in cosmetics.Les traitements cosmétiques visent à améliorer l'apparence de la peau grâce à des véhicules dotés de bonnes propriétés sensorielles. Ces véhicules sont principalement des émulsions et gels conçus pour livrer des composants sûrs et efficaces à la peau. Crèmes et sérums sont largement utilisés pour atteindre ces objectifs mais un nouveau type de formulation appelé organogels a récemment attiré l'attention des scientifiques, en particulier en ce qui concerne la conception de formulations à la fois topiques et cosmétiques. Il a été établi que la nature lipophile des organogels en fait d'excellents candidats pour la livraison de molécules cosmétiques à la peau. Dans cette analyse, nous discutons des propriétés et des caractéristiques des organogels, et présentons les avantages de l'utilisation de ces systèmes dans la cosmétique.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

Previously, a liposomal formulation of a chemotherapeutic agent melphalan (Mlph) incorporated in a fluid lipid bilayer of natural phospholipids in the form of dioleoylglyceride ester (MlphDG) was developed and the antitumor effect was confirmed in mouse models. The formulation composed of egg phosphatidylcholine (ePC), soybean phosphatidylinositol (PI), and MlphDG (8:1:1, by mol) showed stability in human serum for at least 4–5 h. On the contrary, replacing PI with pegylation of the liposomes, promoted fast dissociation of the components from the bilayer. In this work, interactions of MlphDG-liposomes with the most abundant plasma protein—albumin—in function of the presence of PI in the formulation were explored using Fourier transform infrared spectroscopy. The release of MlphDG from the liposomes was studied by asymmetrical flow field-flow fractionation (AF4) using micelles formed by a polyethylene glycol conjugate with phosphatidylethanolamine to mimic the physiological lipid sink like lipoproteins. Our results show that PI actually protects the membrane of MlphDG-liposomes from the protein penetration, presumably due to pairing between the positively charged MlphDG and negatively charged PI, which compensates for the heterogeneity of the lipid bilayer. The AF4 technique also evidences high stability of the formulation as a drug carrier.

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior O antimoniato de meglumina (AM) é um fármaco de antimônio pentavalente (SbV) recomendado para o tratamento da leishmaniose. Sabe-se que o antimônio trivalente (SbIII), presente como resíduo no AM, contribui para os efeitos colaterais e para o desenvolvimento de resistência a antimoniais. Neste trabalho, planejamento de experimentos (DOE) foi utilizado na síntese de AM para a obtenção de um fármaco com baixos níveis de SbIII residual. Quatro variáveis (fonte de SbV, temperatura, volume de água e pH) e suas interações foram avaliadas preliminarmente através de um planejamento fatorial fracionário 24-1. O planejamento composto central (CCD) foi empregado para determinar as condições ideais de duas rotas sintéticas, usando fontes diferentes de SbV. A análise de formulações de AM sintetizadas em condições otimizadas, revelou a eficiência do DOE para reduzir os níveis de SbIII residual. Além disso, o monitoramento de alguns parâmetros físico-químicos, i.e., teor de SbIII, pH e osmolaridade dessas formulações, mantidas a 40 oC por 90 dias, mostrou com 95% de confiança que a estabilidade não foi alterada. Teor de SbIII, em relação à quantidade de Sb total, presente nos compostos de AM foi usado como resposta no DOE e na avaliação da estabilidade de formulações de AM. Para esse fim, foi desenvolvido e validado um procedimento para especiação de Sb inorgânico em AM empregando espectrometria de absorção atômica por geração de hidretos (HG-AAS). A especiação do Sb ocorre em duas etapas: 1) quantificação de Sb total usando um agente redutor (KI); 2) quantificação de SbIII pela geração seletiva de estibina (SbH3) com o uso de ácido cítrico, em meio com elevada concentração de SbV. A concentração de ácido cítrico utilizada no método otimizado foi de 4 a 20 vezes menor do que a recomendada na literatura, evitando o entupimento do capilar da célula de quartzo T. Os limites de quantificação (LQ) foram calculados em 0,48 μg L-1 para Sb total e 0,17 μg L-1 para SbIII. Os valores de desvio padrão relativo (DPR) variaram de 3,1 a 19,6% e 9,1 a 20,1%, enquanto a recuperação variou de 95,6 a 102,3% e 89,1 a 108,1%, para Sb total e SbIII, respectivamente. Meglumine antimoniate (MA) is a pentavalent antimony (SbV) drug recommended for the treatment of leishmaniasis. It is known that the trivalent antimony (SbIII) present as a residue in MA contributes to the drug side effects and to the development of antimonial drug resistance. In this work, design of experiments (DOE) was used in the synthesis of MA in order to obtain a drug with low levels of SbIII. Four variables (source of SbV, volume, temperature, water volume and pH) and their interactions were preliminarily evaluated by 24-1 fractional factorial design. Central composite design (CCD) was used to determine the optimal conditions of two synthetic routes, using different sources of SbV. The analysis of MA formulations synthesized under optimized conditions revealed the efficiency of DOE to reduce SbIII content. In addition, the monitoring of some physicochemical parameters, i.e., SbIII content, pH and osmolarity of these formulations maintained at 40 oC for 90 days, showed that stability was not altered at 95% confidence. The SbIII content, in relation to the amount of total Sb, present in MA compounds was used as a response in the DOE and in the evaluation of the MA formulations stability. For this purposte, a procedure for speciation of inorganic Sb in MA was developed and validated using hydride generation atomic absorption spectrometry (HG-AAS). The Sb speciation occurs in two stages: 1) quantification of total Sb using a reducing agent (KI); 2) quantification of SbIII by the selective generation of stibin (SbH3) with the use of citric acid, in medium with higher SbV concentration. The concentration of citric acid used in the optimized method was 4 to 20-fold lower than that recommended in the literature, preventing clogging of the capillary of the T quartz cell. The limits of quantification (LOQ) were calculated at 0.48 μg L-1 for total Sb and 0.17 μg L-1 for SbIII. The relative standard deviation (RSD) values ranged from 3.1 to 19.6% and 9.1 to 20.1%, while recovery ranged from 95.6 to 102.3% and 89.1 to 108.1%, for total Sb and SbIII, respectively.

Nanoparticles (NPs) offer noteworthy advantages in the treatment of several diseases by prompting, among other benefits, the site-specific delivery of drugs. Ultra-small nanostructured lipid carriers (usNLCs) are no exception. These correspond to a class of NPs composed of a blend of solid and liquid lipids, the latter usually in a higher proportion, which promotes a less ordered solid lipid matrix, providing a higher drug loading capacity, drug release modulation, and improved stability in comparison with other lipid nanoparticles. Several manufacturing methods have been described for obtaining usNLCs. However, a comprehensive understanding of the process is imperative to warrant the final quality of the NPs. In the present work, the hot high pressure homogenization (HPH) method, which is characterized by easy scaling-up, simplicity and ease of use, was used for the development of highly concentrated small size NLCs. Critical process parameters (CPPs) and critical material attributes (CMAs) were evaluated to investigate the manufacturing process reproducibility, inter-batch consistency, long-term formulation stability, drug loading capacity and drug release. To gain a broader understanding of this method, multivariate analysis was applied to investigate how the physicochemical properties of the usNLC are affected by the variation in CPPs/CMAs. CPPs include HPH-time, and HPH-pressure, while CMAs, such as lipid content, are also taken into consideration. The results show that a high lipid content (15% w/w), an intermediate pressure and a short HPH time seem to be the crucial parameters to obtain both a small particle size ( |30| mV).

Small angle neutron scattering (SANS) studies of a model pharmaceutical formulation reveal how formulation stability depends on the compatibility of individual components. Solutions of two common protein formulation excipients, polysorbate 80 (PS80), a nonionic surfactant that prevents aggregation, and m-cresol, an antimicrobial agent for multi-dose injectable formulations, are investigated. The addition of m-cresol to PS80 solutions leads to solution turbidity and irreversibly alters PS80 micelle morphology. This slow preservative-induced destabilization of PS80 micelles progresses over days or even weeks, which highlights the essential role that aggregation kinetics plays in preservative-surfactant interactions. The temperature-dependence of PS80 micelle growth kinetics is quantified by SANS in the presence of m-cresol. Aggregation is a two-step process, where initial formation of small aggregates is followed by a period of monotonic power-law growth, providing evidence for the mechanism. Total aggregate mass stays constant after initial aggregate formation, and addition of a pH-regulating citrate buffer dramatically accelerates aggregation kinetics.

The compatibility of formulation components is crucial for safe and high-quality medicines. To detect the potential for incompatibility and to assess formulation stability, it is beneficial to conduct a compatibility study during the drug development phase. The therapy of tuberculosis normally consists of two or more medicines taken together. Consequently, different antituberculotic fixed-dose combination (FDC) formulations have been developed. Isoniazid is first-line medicine and present in several FDCs. Low bioavailability due to the active substances’ incompatibility in acidic medium was reported for some of these FDC forms. Rifabutin, also a first- line antituberculotic, is available in the market as a single component formulation. This study presents compatibility testing of these two active substances for a new FDC and evaluates the impact of the most common solid dosage forms’ excipients on the stability of two active substances. The potential for interaction between the formulation components was analyzed by the UHPLC method. One degradation product and one interaction product were observed and further characterized by high- resolution mass spectrometry. Still, significant degradation of two active substances, such as reported in marketed FDC formulations was not detected for this combination. The stability and drug delivery of the proposed combination were confirmed by the dissolution test in acidic medium.

One of the major challenges in formulation development of biopharmaceuticals is improving long-term storage stability, which is often achieved by addition of excipients to the final formulation. Finding the optimal excipient for a given protein is usually done using a trial-and-error approach, due to the lack of general understanding of how excipients work for a particular protein. Previously, preferential interactions (binding or exclusion) of excipients with proteins were postulated as a mechanism explaining diversity in the stabilisation effects. Weak preferential binding is however difficult to quantify experimentally, and the question remains whether the formulation process should seek excipients which preferentially bind with proteins, or not. Here, we apply solution NMR spectroscopy to comprehensively evaluate protein-excipient interactions between therapeutically relevant proteins and commonly used excipients. Additionally, we evaluate the effect of excipients on thermal and colloidal protein stability, on aggregation kinetics and protein storage stability at elevated temperatures. We show that there is a weak negative correlation between the strength of protein-excipient interactions and effect on enhancing protein thermal stability. We found that the overall protein-excipient binding per se can be a poor criterion for choosing excipients enhancing formulation stability. Experiments on diverse set of excipients and test proteins reveal that while excipients affect all of the different aspects of protein stability, the effects are very much protein specific, and care must be taken to avoid apparent generalizations if a smaller dataset is being used.

In this work, we compared the formulation, stability and bioaccessibility of ergocalciferol nanodispersions using modified lecithin (ML) and sodium caseinate (SC) as natural emulsifiers. The mean particle size of nanodispersions stabilized by ML (56 nm) was much smaller than those stabilized by SC (112 nm). The ML-stabilized nanodispersions were stable over a wide range of pH, NaCl concentrations and heating, but became unstable with slight increase in particle size when exposed to CaCl 2 solution. In comparison, SC-stabilized nanodispersions were relatively unstable to particles aggregation at pH 4 and 5, CaCl 2 addition and heating. Long-term stability for ergocalciferol were observed in both ML- and SC-stabilized nanodispersions. In the absence of milk, the ergocalciferol bioaccessibility was strongly dependent on the emulsifier type, with ML providing much higher bioaccessibility than SC. During in vitro gastrointestinal digestion, the incorporation of milk into nanodispersions could increase the bioaccessibility and stability for ergocalciferol.

Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight.

A new institutional clinical trial assessed the improvement of sleep disorders in 40 children with autism treated by immediate-release melatonin formulation in different regimens (0.5 mg, 2 mg, and 6 mg daily) for one month. The objectives of present study were to (i) prepare low-dose melatonin hard capsules for pediatric use controlled by two complementary methods and (ii) carry out a stability study in order to determine a use-by-date. Validation of preparation process was claimed as ascertained by mass uniformity of hard capsules. Multicomponent analysis by attenuated total reflectance Fourier transformed infrared (ATR-FTIR) of melatonin/microcrystalline cellulose mixture allowed to identify and quantify relative content of active pharmaceutical ingredients and excipients. Absolute melatonin content analysis by high performance liquid chromatography in 0.5 mg and 6 mg melatonin capsules was 93.6%±4.1% and 98.7%±6.9% of theoretical value, respectively. Forced degradation study showed a good separation of melatonin and its degradation products. The capability of the method was 15, confirming a risk of false negative, Graphical abstract fx1

High protein titers are gaining importance in biopharmaceutical industry. A major challenge in the development of highly concentrated mAb solutions is their long-term stability and often incalculable viscosity. The complexity of the molecule itself, as well as the various molecular interactions, make it difficult to describe their solution behavior. To study the formulation stability, long- and short-range interactions and the formation of complex network structures have to be taken into account. For a better understanding of highly concentrated solutions, we combined established and novel analytical tools to characterize the effect of solution properties on the stability of highly concentrated mAb formulations. In this study, monoclonal antibody solutions in a concentration range of 50–200 mg/ml at pH 5–9 with and without glycine, PEG4000, and Na2SO4 were analyzed. To determine the monomer content, analytical size-exclusion chromatography runs were performed. ζ-potential measurements were conducted to analyze the electrophoretic properties in different solutions. The melting and aggregation temperatures were determined with the help of fluorescence and static light scattering measurements. Additionally, rheological measurements were conducted to study the solution viscosity and viscoelastic behavior of the mAb solutions. The so-determined analytical parameters were scored and merged in an analytical toolbox. The resulting scoring was then successfully correlated with long-term storage (40 d of incubation) experiments. Our results indicate that the sensitivity of complex rheological measurements, in combination with the applied techniques, allows reliable statements to be made with respect to the effect of solution properties, such as protein concentration, ionic strength, and pH shift, on the strength of protein-protein interaction and solution colloidal stability.

Today, there is a rising demand and ongoing search for novel plant-derived phytochemicals in the cosmetic market owing to the growing consumer expectations worldwide for green and natural health products. Various plant ingredients, including polyphenols, oils, volatile oils, vitamins and other herbal extracts, have been extensively used in herbal cosmetics. Recent advances in encapsulation technologies have greatly improved their chemical stability, biocompatibility, skin permeability and dermocosmetic efficiency when applied topically. This comprehensive review summarizes the up-to-date information on encapsulated plant ingredients tailored for dermocosmetic application with a focus on the development of novel delivery systems. An overview of the commonly used techniques for carrier characterization, performance-related properties and toxicological evaluation is also included, which might provide guidance for researchers to select or develop appropriate assay systems.Aujourd'hui, face aux attentes croissantes des consommateurs à travers le monde pour les produits écologiques et naturels, la demande et les recherches sur les nouveaux ingrédients phytochimiques d’origine végétable augmentent de façon substantielle sur le marché des cosmétiques. Divers ingrédients végétaux, notamment des polyphénols, huiles, huiles essentielles, vitamines et d’autres extraits de plantes, ont été largement utilisés en cosmétique à base de plantes. La stabilité chimique, la biocompatibilité, la perméabilité cutanée et l’efficacité dermo-cosmétique ont été considérablement améliorées grâce aux derniers progrès des techniques d’encapsulation, lorsqu’elles sont appliqués par voie topique. Cet examen complet résume les informations les plus récentes sur les ingrédients végétaux encapsulés utilisés pour une application dermo-cosmétique en se concentrant sur le développement de nouveaux systèmes de libération. Le rapport fournit également un aperçu des techniques couramment utilisées pour la caractérisation des supports, les propriétés liées aux performances et l'évaluation toxicologique, ce qui pourrait guider des chercheurs dans la sélection ou la mise au point de systèmes de dosage appropriés.

Background: Ampicillin (AMP) is frequently administered parenterally in critically ill patients with meningitis or endocarditis. Many of them require parallel infusion of total parenteral nutrition (TPN) admixtures. The aim of the study was to determine the physicochemical stability of AMP in TPN admixtures. Methods: AMP was added to two formulations of TPN admixtures differing in the lipid emulsion (Lipofundin&reg, MCT/LCT 20% or LIPIDem&reg, ). Samples were stored at 4 &plusmn, 1 &deg, C with light protection, and at 25 &plusmn, C with and without light protection to assess the impact of temperature and light on formulation stability. Every 24 h the pH, zeta potential, mean droplet diameter (MDD) of a lipid emulsion, and AMP concentration using HPLC method were determined. The assessment of stability and compatibility of TPN admixtures with vitamins and trace elements was carried out immediately after preparation and after 24 h of storage. Results: The addition of AMP as well as vitamins and trace elements to the TPN admixtures did not affect their physical stability. An increase in the pH value of approx. 0.6 and reduction of zeta potential were observed. The MDD of the lipid emulsions was below the limit of 500 nm (dynamic light scattering (DLS) method) and no fat droplets greater than 525 nm were observed (light diffraction (LD) method). The content of AMP after the first 24 h was within the acceptable limit of 90% for TPN admixtures stored at 4 &plusmn, C and 25 &plusmn, C with light protection. Conclusions: The results showed that co-administration of AMP in the same bag with TPN admixture at the tested dose is possible when used ex tempore and with light protection.

Premenstrual syndrome (PMS) is a common condition that affects 90% of menstruating women on emotions, behaviours and physical health. Vitex agnus-castus L. also known as chasteberry or chaste tree is long being used for its health benefits on feminine problems like PMS and hyperprolactinemia. There are also some prescription medicines to ease the symptoms of PMS. While dietary supplements containing medicinal plants could be found everywhere with the lack of quality and standardisation, there are only a few registered traditional herbal medicinal products available on the market containing agnus-castus fruit extract. In this study we developed a stable film coated oral formulation and fully validated the analytical methods to quantify the extract in dosage forms to fulfil the requirements of CTD module 3 while registering the traditional herbal medicinal product according to European Union legislations.

The mucosal surfaces represent the major site of entry of many pathogens, and major challenges in vaccine development include safety and stability in a suitable dosage form. Micro- and nanocarrier-based delivery systems as nasal vaccines induce humoral, cellular, and mucosal immunity. The nasal route of vaccination could also offer immunity at several distant mucosal sites (oral, rectal, vaginal, and pulmonary), which is considered a simplified and cost-effective mode of vaccination with enhanced patient compliance. Most of the nasal vaccine delivery systems in the form of microparticulates, nanoparticulates, and liposomes are currently under development and prove to offer immunity in animal models. The importance and potential of the nasal route of administration for vaccines is unexplored, and this chapter outlines the opportunities, challenges, and potential delivery solutions to facilitate the development of improved nasal vaccines for infectious diseases.

The present paper shows the effects of added sugars and sweeteners on the clearing temperature of a highly water dilutable fatty acid salt microemulsion used as a model of a beverage concentrate. There is a twofold interest in this work. The first one is practical and relates to the fact that many fatty acid salt surfactants can be used in food without major regulatory restrictions. As is shown here, they allow making highly stable microemulsions even at neutral and acidic pH. The second one is more of scientific interest. The model system can be used to study the effect of sugars and sweeteners on the formulation stability depending on their charges, amphiphilic properties, and localization in the microemulsion interfacial film. An important practical result is the discovery of the possibility to formulate highly dilutable microemulsions at neutral or slightly acid pH with a good taste in presence of sucralose. Further, a significant decrease of the pKA of the fatty acid is observed in presence of stevia, thus allowing transparent, fairly stable systems at neutral pH.

The objective of this study was to use pinhão derivatives, starch and coat extract, as new natural ingredients to develop cosmetic formulations. Two types of formulation, gel and emulgel, and their controls were developed. The formulations were characterized by stability studies using thermal stress. The parameters analyzed were resistance to centrifugation, pH, spreadability, rheology, content of phenolic compounds and antioxidant activity. Sensory analysis was also performed to verify the acceptability of the ingredients to potential consumers. The pH was kept the same after heating/freezing cycles for all formulations, and the formulations showed stability by resistance to centrifugation. The formulations did not induce any skin irritation or cutaneous pH alteration. The pinhão starch addition improved spreadability stability and increased viscosity when compared with control formulations. The pinhão coat extract used in these formulations is a good source of phenolic compounds and antioxidant activity. Moreover, sensory analysis indicates that the emulgel formulation is the best vehicle for adding pinhão starch and pinhão coat extract.

SynopsisBACKGROUND: Acetyl aspartic acid (A-A-A) was discoveredthrough gene array analysis with corresponding connectivity map-ping (Cmap). Using an in silico and in vitro approach, A-A-A wasfound increased keratinocyte regeneration, inhibited dermal expres-sion of MMP making this compound a potential active ingredientfor cosmetic application.OBJECTIVES: To determine the conditions to successfully formu-late A-A-A for skin delivery investigation and in vivo clinical assess-ment by the systematic approach of pre-formulation testing of theactive, screening of formulation type on active delivery and stabilityevaluations.METHODS: Analytical evaluation of A-A-A was undertaken usingLC-MS ESI method. Formulation stability was evaluated usingBrookfield viscometer, pH analysis, optical microscopy andorganoleptic evaluations.RESULTS: Analytical evaluation of A-A-A shows that pH signifi-cantly impacts chemical stability of the molecule. A-A-A containingformulae show minimal differences to vehicle product throughoutthe testing.CONCLUSION: A-A-A is an active that can be successfully formu-lated in a cosmetic o/w emulsion within defined pH considerations.ResumeCONTEXTE: l’acide acetyl aspartique (A-A-A) a ete identifie parl’analyse de l’expression genique couplee avec le ‘connectivity map-ping (Cmap)’. En combinant une approche in silico et in vitro, nousavons montre que A-A-A augmentait la regeneration cellulaire surkeratinocyte et inhibait l’expression de metalloproteinase der-miques, confirmant une activite anti-^age potentielle de ce nouveaucompose.OBJECTIFS: Determiner les conditions optimums pour formuler A-A-A en vue d’etude d’absorption percutanee et d’etudes cliniquespar une approche systematique de tests de pre-formulations, laselection de formulations et l’evaluation de sa stabilite chmique.METHODES: L’analyse de A-A-A a eterealisee en utilisant lachromatographie liquide couplee a la spectrometrie de masse. Lesetudes de stabilite des formulations ont ete menees avec un vis-cosimetre Brookfield, un pH-metre et un microscope optique enlumiere polarisee et par des evaluations organoleptiques.RESULTATS: L’analyse de A-A-A montre que le pH influence sig-nificativement la stabilite chimique de la molecule. Les formulescontenant A-A-A montrent une faible influence sur l’absorptionpercutanee.CONCLUSION: A-A-A est un nouveau ingredient actif qui peut^etre assez ais ement formule dans des emulsions cosmetiques H/Edans une gamme definie de pH.IntroductionCosmetic products have been used throughout the ages to improveskin appearance and comes in many different forms depending onthe aspect of improvement that is desired by the consumer. By defi-nition, these are limited to preparations with or without activematerials which are applied to the skin to affect a change in theappearance, protect or keep the skin in good condition [1].The cosmetic cream, lotion, serum, ointment, etc. have beenshown to provide a degree of efficacy for moisturization and protec-tion or improvement of the skin barrier function [2]; however,when considering benefits beyond these aspects, it is generally con-sidered to be a vehicle for the active ingredient(s) to be aestheticallydelivered to the skin.The active ingredient is included to provide benefits such asanti-wrinkle, firmness, UV-protection and pigmentation manage-ment beyond any placebo effect which could be provided by a sim-ple vehicle.When considering an active, these are diverse in their propertiesand as such will require differing formulation strategies to incorpo-rate in the cosmetic product. The ideal active would have good sol-ubility, stability and delivery, have no effect on formulationproperties, be multifunctional and be effective at low levels and lowcost, would that such a material exists. The first key aspect tounderstand is the polarity of the active as this will determine therelative solubility in aqueous, hydroxylic or lipidic media. Solubilityis a key parameter for both delivery of an active and to ensurecrystallization processes do not occur in a formula [3], concurrentwith solubility in aqueous media is the ionization state of the activeif it has acid or basic functionality. Relative stability of the activein neat or solubilized form to light, oxygen, temperature or mois-ture is the next consideration as these impact the ability to success-fully work with the material without investigating protectivestrategies such as encapsulation [4], protective packaging or inertatmosphere [5].Following the characterization of the active properties, it thenneeds to be formulated into a cosmetic vehicle to validate deliv

The aim of this study was to produce a hydro-alcoholic safe antioxidant Malus pumila Miller cv Annurca peel extract (APE) useful as functional ingredient in an oil-in-water emulsion. Results showed that APE contains a hydroxycinnamic acid (chlorogenic acid), flavonol glycosides (quercetin derivatives) and a dihydrochalcone, phloridzin (phloretin-2-O-glucoside). The isoquercitrin (quercetin-3-O-glucoside) content was quantified in 0.3% w/w of extract. APE showed a significant and concentration-dependent free-radical scavenging activity correlated to its polyphenols content. No cytotoxic effect was observed in primary human epidermal keratinocyte adults and dermal fibroblast cell lines. The formulative approach led to produce a stable emulsion able to load a high amount of APE, up to 6.0% w/w. The homogenous distribution of APE in the emulsion was clearly demonstrated by fluorescence microscopy analysis. The emulsion resulted able to enhance the in vitro release rate of APE through synthetic membranes with respect to the raw material.

Introduction. In today's world, oral tablets is the most convenient and widely used in medical practice dosage form. The patients prefers solid dosage forms due to their ease of transportation, capability of self-dosage drug dose and painless application. However, some categories of patients, especially elderly patients, have difficulties in swallowing dosage forms in the solid form. For these categories of patients developed sublingual tablet form - a drug that combines practicality and convenience of the pill and dissolves quickly in the mouth and easily enters the gastrointestinal tract. In addition, numerous clinical studies have shown that the therapeutic effect for sublingual tablets comes earlier than for traditional tablets that dissolve in the stomach of the patient because drug absorption through the mucous begins immediately after oral administration. [1-4]. "Korvalol" drops used for treatment of temporary nervous system disorders, disorders of the autonomic nervous system, cardiovascular system, spastic pain [5]. The product is aimed for the elderly patients, for whom need immediate help, so the most appropriate is development sublingual tablets, similar to "Korvalol" drops. For drugs used in medical practice in addition to the requirements of efficiency and safety are increased pharmacopoeial requirements for quality. Drugs should remain effective throughout the all period of storage, so stability is one of the main requirements for the quality of drugs [6]. The purpose of these studies was stability studies and determining the shelf life of the drug "Korvalol" in the form of sublingual tablets during the long-term storage. Materials and Methods: Stability studies conducted for three pilot batches: 10910, 20910, 30910 for sublingual tablets "Korvalol" manufactured on JSC "Farmak". Tests were conducted for tablets in the package for sale (polyvinyl chloride light-shielded film and aluminum foil with printing). To determine the shelf life long-term stability researches were conducted at a temperature of 15 to 25 0 C and relative humidity of 60 ± 5%, control points were 0, 3, 6, 9, 12, 18, 24 months. The study of accelerated stability was conducted at 40 ±2 0 C and relative humidity of 75 ± 5%, control points were 0, 3, 6 months. Results and discussion As a result, the study found that during two years of storage in the original packaging at a temperature of 15 to250Cand relative humidity of 60 ± 5% three researched batches of sublingual tablets "Korvalol" showed formulation stability throughout all of the period. Quantitative and qualitative indicators of the quality of the drug are within acceptable norms throughout all of the studied period. Packaging provides protection from external influence of the drug, microbiological parameters did not change and fully meet the requirements of the specification. Results of the study of long-term stability demonstrate the rationality of the drug composition, and optimal manufacturing technology. Excipients were chosen according to technological, physico-chemical and functional characteristics. Conclusions Researched long-term and accelerated stability of sublingual tablets "Korvalol" Physicochemical and pharmacological studies of sublingual tablets "Korvalol" completed. The research results are included to the specification of the drug. Proved stability of the drug in the proposed package for two years storage at a temperature of 15 to 25 0 C and relative humidity of 60 ± 5%.

Background: Microemulsions are attractive delivery systems for therapeutic proteins and peptides due to their ability to enhance bioavailability. Although different proteins and peptides have been successfully delivered through such ternary systems, no information can be found about protein loading and the formulation stability when such microemulsions are prepared with pharmaceutically-approved oils and surfactants. The aim of this work was to optimise a ternary system consisting of water/ethyl oleate/SpanO 80-TweenO 80 and to determine its protein loading capacity and stability, using bovine serum albumin (BSA) as a model of biomolecule. Methods: The optimization was carried out using a Central Composite Design and all the prepared formulations were characterised through dynamic light scattering, rheology, optical and polarized microscopy. Subsequently, the maximum loading capacity was determined and the stability of the final microemulsion with the highest content of protein was followed over six months. To investigate the structural features of the protein, BSA was recovered from the microemulsion and analysed through fluorescence spectroscopy. Results: After incorporation of the protein in the microemulsion, a decrease of its aqueous solubility was observed. However, the formulation remained stable over six months and the native-like state of the recovered protein was demonstrated by fluorescence spectroscopy Conclusion: This study demonstrated the feasibility of preparing microemulsions with the highest content of protein and their long-term stability.

The mucosal surfaces represent the major site of entry of many pathogens, and major challenges in vaccine development include safety and stability in a suitable dosage form. Micro- and nanocarrier-based delivery systems as nasal vaccines induce humoral, cellular, and mucosal immunity. The nasal route of vaccination could also offer immunity at several distant mucosal sites (oral, rectal, vaginal, and pulmonary), which is considered a simplified and cost-effective mode of vaccination with enhanced patient compliance. Most of the nasal vaccine delivery systems in the form of microparticulates, nanoparticulates, and liposomes are currently under development and prove to offer immunity in animal models. The importance and potential of the nasal route of administration for vaccines is unexplored, and this chapter outlines the opportunities, challenges, and potential delivery solutions to facilitate the development of improved nasal vaccines for infectious diseases.

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

This review work focuses mainly on the formulation, characterization, physicochemical properties and parameters of stability of emulsions stabilized by solid particles (Pickering emulsions). This concept of emulsions stabilized by particles strong knows a renewed interest in our days saw the benefits they present: good stability, protection of the environment, safety of users, types of particles etc. The adsorption of the solid particles at the oil-water interface is almost irreversible and strong, leading to the formation of a dense film, creating a barrier around the droplets and thus making the droplets very resistant to coalescence. Recently, the possibilities of application of emulsions stabilized by particles are considered in the pharmaceutical industry. This type of formulation may be a potential system of encapsulation of the active ingredients, allowing controlled and targeted release of the active ingredient from the internal phase.

Probiotics are live microorganisms that administered through the digestive tract, have a positive impact on the hosts health. In this study research has shown that extraction method (encapsulation in alginate systems) can be used as an effective method for preparation of immobilized Lactobacillus acidophilus. All formulas were studied, from characterization, encapsulation yield, particle size measurement and mechanical stability of microcapsules in simulated gastric conditions which resulted that alginate – starch microcapsules gave the best results. based on this finding that starch – alginate can be used to protect living microbes, alginate starch microcapsules has been further studied for: efficacy of cell release, thermal stability ( refrigeration and shelf life ) which achieved good results. Finally the selected formula was added to standard anti- Helicobacter pylori therapy (triple therapy) in a parallel clinical study (42 patients) which showed that the addition of Lactobacillus acidophilus has a significant effect in increasing the eradication rate of Helicobacter pylori.

The potential of fat-crystal stabilised W1/O emulsions containing salt to be incorporated into a W1/O/W2 double emulsion was studied. 30% W1/O emulsions stabilised by monoglyceride and triglyceride crystals, and containing 1.6% KCl in the W1 phase, have been mixed with equal amounts of oil and incorporated into double emulsions (W1/O/W2), where the W2 phase contained different levels of different types of emulsifiers (e.g. Na-caseinate). The resulting double structures were monitored over the course of 8 weeks. It was found that double emulsions remain relatively stable during this time depending on the species used to stabilise the external o/w2 interface.

Nonclinical dose formulation analysis methods are used to confirm test article concentration and homogeneity in formulations and determine formulation stability in support of regulated nonclinical studies. There is currently no regulatory guidance for nonclinical dose formulation analysis method validation or sample analysis. Regulatory guidance for the validation of analytical procedures has been developed for drug product/formulation testing; however, verification of the formulation concentrations falls under the framework of GLP regulations (not GMP). The only current related regulatory guidance is the bioanalytical guidance for method validation. The fundamental parameters for bioanalysis and formulation analysis validations that overlap include: recovery, accuracy, precision, specificity, selectivity, carryover, sensitivity, and stability. Divergence in bioanalytical and drug product validations typically center around the acceptance criteria used. As the dose formulation samples are not true “unknowns”, the concept of quality control samples that cover the entire range of the standard curve serving as the indication for the confidence in the data generated from the “unknown” study samples may not always be necessary. Also, the standard bioanalytical acceptance criteria may not be directly applicable, especially when the determined concentration does not match the target concentration. This paper attempts to reconcile the different practices being performed in the community and to provide recommendations of best practices and proposed acceptance criteria for nonclinical dose formulation method validation and sample analysis.

O trabalho aborda a aplicação dos métodos de biofísica no estudo de eficácia de produtos dermocosméticos. A qualidade de um produto cosmético engloba a segurança de seu uso, a estabilidade da formulação, o aspecto, o sensorial e a sua eficácia. As técnicas de biofísica têm sido amplamente empregadas na avaliação do efeito de formulações dermocosméticas, principalmente devido ao fato de possibilitarem a avaliação de produtos em suas reais condições de uso, ou seja, na pele humana. A comprovação dos efeitos de produtos cosméticos e a elucidação de seu mecanismo de ação por meio de protocolos experimentais devidamente elaborados, que utilizem as técnicas de biofísica da pele, dentre outras, tornam-se de fundamental importância e, assim, a serem amplamente exploradas e ainda bastante desenvolvidas, visando à melhoria da qualidade de vida dos usuários de tais produtos.The authors consider the application of biophysical techniques in the study of cosmetics effectiveness. The quality of a cosmetic product includes the safety of its use, the formulation stability , the visual and other sensorial aspects, and its effectiveness. The biophysical techniques have been widely used in the evaluation of the effect of formulations of topical use, mainly due to the fact of facilitating the evaluation of products in its real use conditions, that is to say, directly in the human skin. The confirmation of the effects of cosmetic products and its action mechanism, by means of experimental protocols properly elaborated using the skin biophysics is of fundamental importance. It should be thoroughly explored and quite developed seeking the improvement of the life quality of users of such products.

Objectives Effective vaccines against the highly pathogenic influenza A/H5N1 virus are being developed worldwide. In Japan, two adjuvanted, inactivated, whole-virion influenza vaccines were recently developed and licensed as mock-up, pre-pandemic vaccine formulations by the Ministry of Health and Labor Welfare of Japan. During the vaccine design and development process, various obstacles were overcome and, in this report, we introduce the non clinical production, immunogenicity data in human and development process that was associated with egg-derived adjuvanted, inactivated, whole-virion influenza A (H5N1) vaccine. Design Pilot lots of H5N1 vaccine were produced using the avirulent H5N1 reference strain A/Vietnam/1194/2004 (H5N1) NIBRG-14 and administered following adsorption with aluminum hydroxide as an adjuvant. Quality control and formulation stability tests were performed before clinical trials were initiated (phase I-III). The research foundation for microbial diseases of Osaka University (BIKEN) carried out vaccine production, quality control, stability testing and the phase I clinical trial in addition to overseeing the licensing of this vaccine. Mitsubishi Chemical Safety Institute Ltd. carried out the non clinical pharmacological toxicity and safety studies and the Japanese medical association carried out the phase II/III trials. Phase I-III trials took place in 2006. Results The production processes were well controlled by established tests and validations. Vaccine quality was confirmed by quality control, stability and pre-clinical tests, and the vaccine was approved as a mock-up, pre-pandemic vaccine by the Ministry of Health and Labor Welfare of Japan. Conclusions Numerous safety and efficacy procedures were carried out prior to the approval of the described vaccine formulation. Some of these procedures were of particular importance e.g., vaccine development, validation, and quality control tests that included strict monitoring of the hemagglutinin (HA) content of the vaccine formulations. Improving vaccine productivity, shortening the production period and improving antigen yield of the avirulent vaccine strains were also considered important vaccine development criteria.