Design and physicochemical stability studies of paediatric oral formulations of sildenafil

Abstract Personalized medicine is a challenging research area in paediatric treatments. Elaborating new paediatric formulations when no commercial forms are available is a common practice in pharmacy laboratories; among these, oral liquid formulations are the most common. But due to the lack of specialized equipment, frequently studies to assure the efficiency and safety of the final medicine cannot be carried out. Thus the purpose of this work was the development, characterization and stability evaluation of two oral formulations of sildenafil for the treatment of neonatal persistent pulmonary hypertension. After the establishment of a standard operating procedure (SOP) and elaboration, the physicochemical stability parameters appearance, pH, particle size, rheological behaviour and drug content of formulations were evaluated at three different temperatures for 90 days. Equally, prediction of long term stability, as well as, microbiological stability was performed. Formulations resulted in a suspension and a solution slightly coloured exhibiting fruity odour. Formulation I (suspension) exhibited the best physicochemical properties including Newtonian behaviour and uniformity of API content above 90% to assure an exact dosification process.

Design and physicochemical stability studies of paediatric oral formulations of sildenafil

Personalized medicine is a challenging research area in paediatric treatments. Elaborating new paediatric formulations when no commercial forms are available is a common practice in pharmacy laboratories; among these, oral liquid formulations are the most common. But due to the lack of specialized equipment, frequently studies to assure the efficiency and safety of the final medicine cannot be carried out. Thus the purpose of this work was the development, characterization and stability evaluation of two oral formulations of sildenafil for the treatment of neonatal persistent pulmonary hypertension. After the establishment of a standard operating procedure (SOP) and elaboration, the physicochemical stability parameters appearance, pH, particle size, rheological behaviour and drug content of formulations were evaluated at three different temperatures for 90 days. Equally, prediction of long term stability, as well as, microbiological stability was performed. Formulations resulted in a suspension and a solution slightly coloured exhibiting fruity odour. Formulation I (suspension) exhibited the best physicochemical properties including Newtonian behaviour and uniformity of API content above 90% to assure an exact dosification process.

Characterization, physicochemical stability, and evaluation of in vitro digestibility of solid lipid microparticles produced with palm kernel oil and tristearin

Solid lipid particles have been investigated by food researchers due to their ability to enhance the incorporation and bioavailability of lipophilic bioactives in aqueous formulations. The objectives of this study were to evaluate the physicochemical stability and digestibility of lipid microparticles produced with tristearin and palm kernel oil. The motivation for conducting this study was the fact that mixing lipids can prevent the expulsion of the bioactive from the lipid core and enhance the digestibility of lipid structures. The lipid microparticles containing different palm kernel oil contents were stable after 60 days of storage according to the particle size and zeta potential data. Their calorimetric behavior indicated that they were composed of a very heterogeneous lipid matrix. Lipid microparticles were stable under various conditions of ionic strength, sugar concentration, temperature, and pH. Digestibility assays indicated no differences in the release of free fatty acids, which was approximately 30% in all analises. The in vitro digestibility tests showed that the amount of palm kernel in the particles did not affect the percentage of lipolysis, probably due to the high amount of surfactants used and/or the solid state of the microparticles.

Physicochemical Stability of Poly(lactide-co-glycolide) Nanocapsules Containing the Local Anesthetic Bupivacaine

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Biological and physicochemical stability of ceftazidime and aminophylline on glucose parenteral solution

Ceftazidime is a broad spectrum antibiotic administered mainly by the parenteral route, and it is especially effective against Pseudomonas aeruginosa. The period of time in which serum levels exceed the Minimum Inhibitory Concentration (MIC) is an important pharmacodynamic parameter for its efficacy. One of the forms to extend this period is to administer the antibiotic by continuous infusion, after prior dilution in a Parenteral Solution (PS). The present work assessed the stability of ceftazidime in 5% glucose PS for 24 hours, combined or not with aminophylline, through High Performance Liquid Chromatography (HPLC). The physicochemical evaluation was accompanied by in vitro antimicrobial activity compared MIC test in the 24-hour period. Escherichia coli and Pseudomonas aeruginosa were the microorganisms chosen for the MIC comparison. The HPLC analysis confirmed ceftazidime and aminophylline individual stability on PS, while the MIC values were slightly higher than the mean described in the literature. When both drugs were associated in the same PS, the ceftazidime concentration by HPLC decreased 25% after 24 hours. Not only did the MIC values show high loss of antibiotic activity within the same period, but also altered MIC values immediately after the preparation, which was not detected by HPLC. Our results indicate that this drug combination is not compatible, even if used right away, and that PS might not be the best vehicle for ceftazidime, emphasizing the importance of the MIC evaluation for drug interactions.

Biological and physicochemical stability of ceftazidime and aminophylline on glucose parenteral solution

Ceftazidime is a broad spectrum antibiotic administered mainly by the parenteral route, and it is especially effective against Pseudomonas aeruginosa. The period of time in which serum levels exceed the Minimum Inhibitory Concentration (MIC) is an important pharmacodynamic parameter for its efficacy. One of the forms to extend this period is to administer the antibiotic by continuous infusion, after prior dilution in a Parenteral Solution (PS). The present work assessed the stability of ceftazidime in 5% glucose PS for 24 hours, combined or not with aminophylline, through High Performance Liquid Chromatography (HPLC). The physicochemical evaluation was accompanied by in vitro antimicrobial activity compared MIC test in the 24-hour period. Escherichia coli and Pseudomonas aeruginosa were the microorganisms chosen for the MIC comparison. The HPLC analysis confirmed ceftazidime and aminophylline individual stability on PS, while the MIC values were slightly higher than the mean described in the literature. When both drugs were associated in the same PS, the ceftazidime concentration by HPLC decreased 25% after 24 hours. Not only did the MIC values show high loss of antibiotic activity within the same period, but also altered MIC values immediately after the preparation, which was not detected by HPLC. Our results indicate that this drug combination is not compatible, even if used right away, and that PS might not be the best vehicle for ceftazidime, emphasizing the importance of the MIC evaluation for drug interactions.

Physicochemical Stability of Poly(lactide-co-glycolide) Nanocapsules Containing the Local Anesthetic Bupivacaine

This paper describes the preparation of poly(DL-lactide-co-glicolide) (PLGA) nanocapsules as a drug carrier system for the local anesthetic bupivacaine. The system was characterized and its stability investigated. The results showed a size distribution with a polydispersity index of 0.12, an average diameter of 148 nm, a zeta potential of -43.5 mV and an entrapment efficiency of 75.8%. The physicochemical properties of polymeric nanocapsule suspensions (average diameter, polydispersity, zeta potential and drug association efficiency) were evaluated as a function of time to determine the formulation stability. The formulation did not display major changes in these properties over the time, and it was considered stable up to 120 days of storage at room temperature. The results reported here which refer to the initial characterization of these new formulations for the local anesthetic bupivacaine show a promising potential for future in vivo studies.

The influence of different combinations of probiotic bacteria and fermentation temperatures on the microbiological and physicochemical characteristics of fermented lactic beverages containing soybean hydrosoluble extract during refrigerated storage

Lactic beverages containing probiotics were prepared with whole UHT milk, whey of Mozzarella cheese, soybean hydrosoluble extract and sugar. Three formulations were studied, each one containing a different combination of probiotic/starter bacteria, fermented at two different temperatures (37 and 45 °C). The aim of this work was to verify the influence of these variables on the viability of probiotic microorganisms and on the physicochemical stability of lactic beverages during storage under refrigeration (21 days at 7 °C). The results indicated that the fermentation temperature had a significant effect on the viability of probiotic bacteria. Counts for Lactobacillus acidophilus were affected by storage time, resulting appropriate after 21 days only for the beverage fermented at 37 °C. Physicochemical parameters did not exhibit drastic variations - proving the stability of formulations during storage. Cells of Bifidobacterium spp. showed high survival ability, probably due to the presence of growth promoters from soybean and cheese whey. The fermentation temperature of 37 °C allowed counts above the minimum limit for all the studied microorganisms, being preferred to the temperature of 45 °C. The inclusion of soybean hydrosoluble extract, a prebiotics source, resulted in a symbiotic product with more benefits to the health of consumers.

Stability and Local Toxicity Evaluation of a Liposomal Prilocaine Formulation

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Development of a topical formulation containing S. Lutea extract: Stability, in vitro studies and cutaneous permeation

Flavonoids have been widely incorporated into cosmetic and dermatological formulations, affording benefits such as antioxidant action, improved skin tone and fewer lines and wrinkles. Brazil has a huge biodiversity, with one of the richest flora in the world, and existing studies justify the quest for greater research efforts in this area. The cajazeira (Spondias lutea L.), a plant of the Anacardiaceae family from tropical America, is widely disseminated in Brazil. This plant was chosen because of the presence of flavonoids that exhibit antioxidant activity. The purpose of this research was to develop a stable topical formulation containing Spondias lutea extract with the aim of preventing skin diseases caused by UV radiation. Hydro ethanolic extract of Spondias lutea fruit was prepared and assayed for its the flavonoids content. The antioxidant activity was estimated by DPPH and superoxide assay. The physicochemical stability and skin permeation of the cream containing 8% (w/w) of extract were assessed. The results showed that the S. lutea extract possessed antioxidant activity, and that it is possible to obtain a stable cosmetic containing the extract, which is able to penetrate the skin. Thus, it is possible to use this extract to produce an anti-aging cosmetic.

Stability and Local Toxicity Evaluation of a Liposomal Prilocaine Formulation

This study reports a physicochemical stability evaluation of a previously reported liposomal prilocaine (PLC(LUV)) formulation (Cereda el al. J. Pharm. Pharmaceut. Sci. 7:235, 2004) before and after steam sterilization as well as its local toxicity evaluation. Prilocaine (PLC) was encapsulated into extruded unilamellar liposomes (LUVs) composed by egg phosphatidylcholine:cholesterol:alfa-tocopherol (4:3:0.07, mole %). Laser light-scattering analysis (p > 0.05) and thiobarbituric acid reaction (p > 0.05) were used to evaluate the liposomes physical (size) and chemical (oxidation) stability, respectively. The prilocaine chemical stability was followed by (1)H-nuclear magnetic resonance. These tests detected no differences on the physicochemical stability of PLC or PLCLUV, sterilized or not, up to 30 days after preparation (p > 0.05). Finally, the paw edema test and histological analysis of rat oral mucosa were used to assess the possible inflammatory effects of PLC(LUV). PLC(LUV) did not evoke rat paw edema (p > 0.05), and no significant differences were found in histological analysis, when compared to the control groups (p > 0.05). The present work shows that PLC(LUV) is stable for a 30-day period and did not induce significant inflammatory effects both in the paw edema test and in histological analysis, giving supporting evidence for its safely and possible clinical use in dentistry.

Batch purification of high-purity lysozyme from egg white and characterization of the enzyme modified by PEGylation

PEGylation is one of the most promising and extensively studied strategies for improving the pharmacological properties of proteins as well as their physical and thermal stability. Purified lysozyme obtained from hen egg white by batch mode was modified by PEGylation with methoxypolyethyleneglycol succinimidyl succinato (mPEG-SS, MW 5000). The conjugates produced retained full enzyme activity with the substrate glycol chitosan, independent of degree of enzyme modification, although lysozyme activity with the substrate Micrococcus lysodeikticus was altered according to the degree of modification. The conjugate with a low degree of modification by mPEG-SS retained 67% of its enzyme activity with the M. lysodeikticus substrate. The mPEG-SS was also shown to be a highly reactive polymer. The effects of pH and temperature on PEGylated lysozymes indicated that the conjugate was active over a wide pH range and was stable up to 50 degrees C. This conjugate also showed resistance to proteolytic degradation, remained stable in human serum, and displayed greater antimicrobial activity than native lysozyme against Gram-negative bacteria.

Metodologias para a qualificação de águas minerais naturais e águas de nascente

Dissertação de mestrado em Ordenamento e Valorização de Recursos Geológicos

Use of medicinal plant in the manufacturing of energetic cookies

Many nutrients provide energy and regulate physiological processes linked to exercise. This work aimed at using medicinal plant in the manufacturing of energetic cookie. An evaluation of microbiological and physicochemical stability was made within 180 days of the fabrication of the product. Sensorial analysis was performed in all stages with untrained tasters. The results were statistically tested. The evaluation of ergogenic effect of the product used the maximum volume of oxygen index as a parameter through the cooper track test (12 minutes) with 7 voluntaries. The participants received the consent form. This study was approved by the local ethics committee (N° CAAE - 0009.0.313.000-08). It was observed good stability for physicochemical and microbiological parameters. As for sensorial analysis there was a predominance of scores 6 to 8, characterizing good acceptance. It was verified increase in VO2 max after the intake of the cookies with or without the medicinal plants. However, the product with the medicinal plants presented a bigger value, 35.47 VO2 max mL/(kg.min)-1. The fraction of carbohydrate and the presence of medicinal plants can be considered as nutritional ergogenic substances. The lipid fraction favor the energetic aspect of the product. The proposed product presented energetic and ergogenic effect.

Quality of medicines stored together in multi-compartment compliance aids

Background and Objective: Dispensing medicines into compliance aids is a common practice in pharmacy contrary to manufacturers’ advice and studies have shown the appearance of light-sensitive tablets is compromised by such storage; we previously found evidence of reduced bioavailability at elevated temperature and humidity. Our objective was to examine the physicochemical stability of two generic atenolol tablets in different compliance aids and with aspirin co-storage at room temperature and at 40 °C/75% relative humidity. Methods: The physicochemical stability of atenolol tablets was evaluated after 28 days of storage and compared with controls by examining visual appearance, weight, disintegration, dissolution, friability and hardness to accepted standards and using a previously validated HPLC method for chemical assay. Results and Discussion: The response to storage was brand-dependent and not straightforward. With one make of atenolol (Alpharma), storage in compliance aids even at room temperature impacted on physical stability, reducing tablet hardness, with storage in Dosett® exerting a greater impact than storage in Medidos® (t-test P < 0·001). Co-storage at elevated temperature and humidity also impacted on the appearance of non-coated aspirin tablets (Angette™). The chemical stability of atenolol was not affected and we did not find evidence of changes to bioavailability with either make. Certainly data for one atenolol make (CP Pharmaceuticals) co-stored with aspirin (Angette™ and Nu-Seals) in both compliance aids at room temperature provided evidence of short-term stability. But medicines are dispensed into compliance aids in multi-factorial ways so our study highlights not only the lack of evidence but also a realization that evidence to support real practice may not be accomplished through research. Conclusion: Reassuring practitioners of the continued stability of medicines in compliance aids under the countless condition in which they are dispensed in practice may requires a different approach involving medical device regulators and more definitive professional guidance.