Stability of carboplatin infusion solutions used in desensitization protocol.

Carboplatin hypersensitivity reactions are one of the major clinical challenges in treating patients with relapse/recurrent ovarian malignancies. Desensitization protocols allow the continuation of treatment in patients who have presented hypersensitivity reactions by gradually re-introducing small amounts of the drug up to full therapeutic doses. Carboplatin desensitization protocol is based on three solutions that are usually prepared in the chemotherapy centralized units of hospital pharmacies. First and second solutions are diluted under the established concentration limit to guarantee the stability of the preparation. We developed a specific high-performance liquid chromatography assay to determine the stability of carboplatin infusion solutions that have been diluted to 0.2 mg/mL and 0.02 mg/mL in 250 mL of 5% dextrose in polypropylene infusion bags which were stored 24 h protected from light at room temperature. Samples were withdrawn at t = 0 h, 3 h, 6 h, and 24 h. The analytical column was a Zorbax eclipse XDB-C18 (150 mm × 4.6 mm; 5 µm particle size). The mobile phase had a flow rate of 1 mL/min under isocratic conditions of water-methanol (98:2, v/v). For 0.2 mg/mL solution, the high-performance liquid chromatography assay revealed no significant losses in carboplatin concentration. However, in 0.02 mg/mL solution remaining carboplatin was > 105% the initial dose after 3 h of storage at room temperature. The ultraviolet-visible spectra analysis showed that carboplatin remained intact during the study in 0.2 mg/mL solution, but some changes were detected in 0.02 mg/mL solution. Thus, 0.2 mg/mL carboplatin solution is stable for 24 h at room temperature in 5% dextrose polypropylene infusion bags but stability could not be proved for 0.02 mg/mL solution.

Nano and microparticulate chitosan-based systems for antiviral topical delivery.

Acyclovir (ACV) is one of the drugs of choice for the treatment of epidermal, ocular or systemic herpetic infections. Nevertheless, its trans-mucosal limited absorption and the scarce contact time of the formulation with the mucosal surface - especially in the ocular mucosa - constitute a big limitation of the antiviral efficiency. The most effective way to solve these problems is to increase the quantity and the residence time of the drug over the ocular surface. In order to cope with all these requirements, micro-particles (MPs) and nano-particles (NPs) containing ACV have been developed using cross-linked chitosan with tripolyphosphate (TPP) due to the biocompatibility, bio-adhesion ability and the potential power as penetration enhancer of this polymer. Particles were characterized by Fourier-transformed infrared (FTIR) spectroscopy, X-ray diffraction, SEM, Zeta potential and particle size. Encapsulation efficiency and release profiles in flow through diffusion cells were also determined. Besides the Slug Mucosal Irritation (SMI) assay has been applied as an alternative to the Draize test to predict the mucosal irritation of the selected formulation. FTIR and X-ray results suggested an electrostatic interaction ACV-Chitosan that made ACV be molecularly dispersed within the polymer matrix. Encapsulation efficiency was 75% for MP and 16% for NP. Release profiles in flow through diffusion cells were also determined. From the diffusion profiles, it was found that the amounts of ACV effectively diffused in 24h were 30, 430 and 80 µg for the ACV solution, MP and NP respectively. SMI results showed that chitosan-based particles induced moderate irritation and mild tissue damage, what supposes that ACV-MP constitute a promising alternative for further development of an antiviral formulation.

Evidence of the efficacy of alcohol lavage in the phenolization treatment of ingrown toenails.

BACKGROUND: For treatment of ingrown toenails, a phenolization is often chosen. Many reports describe an intra-operative irrigation or lavage of the wound with various types of alcohol to neutralize any residual phenol from this treatment. There are conflicting reports in the literature as to whether a true neutralization is required or merely effective removal of excess phenol. OBJECTIVE: The aim of our study was to analyse the suitability and effectiveness of the alcohol lavage step during the treatment of ingrown toenails with a phenolization procedure. METHODS: We performed an in vitro study using human skin and a diffusion cell apparatus to measure the amount of phenol remaining after various lavage washes. The effect of phenol evaporation was also examined. RESULTS: There was no measurable amount of phenol collected after each experiment, suggesting that diffusion of phenol through the skin does not exist. The open compartment test had significantly less phenol recovered compared with the occluded compartment test, indicating phenol evaporation. STUDY LIMITATIONS: None. CONCLUSIONS: An alcohol lavage step after the phenolization procedure can be a suitable and effective means of diluting and removing any excess or residual phenol from the exposed area.

Tape stripping on a human nail: quantification of removal.

BACKGROUND/PURPOSE: Tape stripping is commonly used to investigate the stratum corneum (SC). This study assesses if protein quantitative tape stripping method was suitable for human nails. METHOD: We used a colorimetric method to quantify proteins removed by the tape. Water barrier functions as a result of tape stripping were also observed by changes in transonychial water loss (TOWL) from the baseline. RESULTS: Using tape stripping, we observed no difference between nails in the protein quantity removed by tape stripping (P=0.39). The mean TOWL before and after tape stripping were 6.9 and 9.3 g/m2/h, respectively; this was significantly increased in tape stripped nails (P<0.0001). CONCLUSION: Tape stripping seems to be an effective method to extract proteins from human nail plate and may aid the study of nail structure and function. Further studies are needed to extend our results in terms of age, gender, ethnicity and disease.

Effect of pharmacotechnical design on the in vitro interaction of ketoconazole tablets with non-systemic antacids.

In certain polytherapy programs, ketoconazole can be administered with some antacids that could modify its dissolution rate and reduce its absorption leading to therapeutic failures. The aim of this work was to evaluate the influence of some excipients on this interaction in vitro. In this way, six formulations of directly compressible ketoconazole tablets were developed. The results confirmed that the dissolution rate of ketoconazole tablets was significantly reduced in the presence of antacids. Nevertheless this interaction was remarkably avoided in some of the formulations checked and in some conditions. In this way, the inclusion of a disintegrant (sodium starch glycolate) not only increased the dissolution rate of ketoconazole in the tablets, as expected, but it also modified the degree in which the dissolution rate was decreased in the presence of antacids. It was proved that a suitable selection of the excipients and therefore the modification in the rate in which the drug was released, could play an important role to modify a pharmacokinetic interaction based on a reduction of the solubility of the drug as a function of the pH value of the medium.

A stability study of tetracycline and tetracycline cyclodextrins in tablets using a new HPLC method.

A sensitive, rapid, reproducible, easy and precise reverse-phase high-performance liquid chromatographic assay for stability studies of tetracycline hydrochloride (TC.HCl) formulated with different excipients and techniques without using gradient elution, extraction methods, and at ambient temperature has been developed and validated. The method was especially developed for the analysis of TC.HCl and its main degradation product, 4-epi-anhydrotetracycline, due to its toxicity, in samples obtained from stability studies of solid dosage forms (tablets). The influence of the excipients used for the pharmaceutical design of the different tablet formulations and the use of hydroxypropyl-beta-cyclodextrin on the stability were evaluated. A significant improvement of the stability of TC.HCl was found in some tablet formulations. The precision and accuracy of the method was also studied for the encapsulated TC.HCl, and no significant interferences were found. The results obtained suggested that the developed HPLC method is selective and specific for the analysis of TC.HCl samples, and that it can be applied for long-term and accelerated protocols for stability studies.

Validation protocol of an automated in-line flow-through diffusion equipment for in vitro permeation studies.

Transdermal drug delivery experiments are often tedious and time consuming in terms of sampling, labor, etc. In this way, the automation of such experiments has increased in the last few years. A protocol suitable to validate an automated diffusion equipment with seven in-line flow-through cells is described. The proposed protocol was divided into two parts. First, validation of each component which makes up the whole equipment, including the study of the statistical variability of the internal volumes between the cells, the temperature into the different chambers, the time and sample volumes, etc. In the second part, a series of permeation studies were carried out comparing the performance of the system against a classical Franz-type diffusion cell. Ketoprofen was used as a model drug. It was proved the low variability of the replicates obtained with the automated flow-through diffusion cells. The best work conditions as flow rate into the receptor chamber, temperature, etc., as well as the best mathematical approach for the diffusion data, were determined. The advantages in terms of time saved and easiness of validation of the flow-through cell design in comparison to the Franz-type cell were evidenced.

Influence of pharmacotechnical design on the interaction and availability of norfloxacin in directly compressed tablets with certain antacids.

Norfloxacin is a fluorquinolone that can interfere with antacids that contain aluminum and magnesium salts by complexation and modification of its solubility, which reduces its absorption and may lead to therapeutic failures. The purpose of this work was to evaluate the effect of the pharmaceutical design on this interaction and to develop a formulation of norfloxacin tablets in which this process could be avoided. Norfloxacin tablets were designed in 28 formulations. The interaction was studied in terms of in vitro dissolution behavior (USP 23, apparatus 2) in simulated gastric fluid with different doses of four commercially available antacid preparations. It was observed that dissolution rates were markedly reduced in the presence of all antacids studied. This phenomenon was practically avoided with some formulations of norfloxacin tablets in which a disintegrant (sodium starch glycolate or crospovidone) was included. These results indicated that the chelation among metal ions and norfloxacin could be affected by the delivering ability of the drug in the tablet. It was demonstrated that the pharmacotechnical design could modify an interaction process. Some formulations of tablets, in which the reduced dissolution rates in the presence of nonsystemic antacids in vitro was practically avoided, were developed by direct compression.

Influence of chopper and mixer speeds and microwave power level during the high-shear granulation process on the final granule characteristics.

Although microwave drying technology has been used extensively, detailed studies in the pharmaceutical field are necessary to model the different operational parameters involved in microwave drying in combination with the high-shear granulation processes. The implications of the chopper and the mixer speeds during the granulation step and the microwave power level during the drying step on the final granule characteristics were investigated. alpha-Lactose monohydrate and microcrystalline cellulose were granulated at three different mixer and chopper speeds in a laboratory-scale high-shear mixer (Mi-Mi-Pro) and dried at three microwave power levels. The dried granules were characterized by friability tests, particle size analysis, bulk and tapped density studies, and porosimetry. Neither the mixer speed nor the chopper speed had a significant influence on the granule friability, which was low for all batches produced. The selected materials and experimental conditions induced a very robust granulation process, but the granule size distribution was influenced by the microwave power level. The reciprocal relationship between the dust formation and the microwave power level was analyzed using a central composite factorial design. The amount of dust remained low in all batches, but it influenced some of the inherent density properties and the volume reduction behavior of the granulation mass. In almost all cases, the Carr index decreased slightly with increasing microwave power. The major granule characteristics were not changed when different mixer or chopper speeds were changed, although the mixer speed did alter the intragranular pore size distribution.

Validation of a high-performance liquid chromatographic method for the determination of norfloxacin and its application to stability studies (photo-stability study of norfloxacin).

The development and validation study of a sensitive, rapid, reproducible, easy and precise reversed-phase high-performance liquid chromatographic assay for norfloxacin (NFLX) samples from photo-stability of solid dosage forms, without using gradient elution, extraction methods and without using counter-ion has been carried out. The method showed excellent linearity (r2> or =0.999) in the range 1-20 microg ml(-1) using a Lichrosorb-RP-8 column (10 microm, 20 cm x 4.6 mm) and UV-detection (278 nm) at ambient temperature. This method showed good efficiency for the analysis of photodegraded NFLX samples, and was applied to study the photo-stability of NFLX tablets under different conditions (direct sun light, ultraviolet light and fluorescent light). It was proven that the use of a disintegrant can increase the photo-stability of the NFLX in the tablets. This effect was studied in directly compressible tablets with microcrystalline cellulose (MCC) and mannitol for direct compression.

Modification of fluorescent properties of norfloxacin in the presence of certain antacids.

Modification of the fluorescent properties of norfloxacin samples in the presence of different antacids in terms of dissolution rates has been reported in a previous paper. The formation of chelates with Al3+ and Mg2+ ions has been previously suggested as a mechanism of interaction. In the present paper, the chelation was studied with different types and amounts of antacids and the stability of the non-absorbable chelates with each antacid was studied. Six dose fractions of each antacid were used in samples with the same norfloxacin concentration (9 microg ml(-1)). All samples were measured using both UV/Vis-spectrophotometry and spectrofluorimetry, and compared to a standard solution of norfloxacin (10 microg ml(-1)) without antacids, used as a reference in the calibration of the spectrofluorimeter. The results showed that the fluorescence signal features remarkable differences depending on the kind and the concentration of antacid, as well as on the time of contact. It was found that increasing amounts of antacids increased the fluorescence signal of norfloxacin samples. The evolution of the fluorescence signal in function of the antacid concentration showed a maximum and a posterior decrease. It was observed that, for a higher concentration of antacid in the medium, a higher signal was obtained and lower stability of the compound norfloxacin-antacid was observed. The data obtained strongly indicated that the binding of Al3+ and Mg2+ ions to the carboxylic groups of norfloxacin produced non-absorbable chelates. This effect might reduce the drug bioavailability.

The effect of photodegradation on the fluorescent properties of norfloxacin: (photodegradation and fluorescence of norfloxacin).

Norfloxacin (NFLX), a broad spectrum antibacterial quinolone, is a very thermostable but photosensitive drug, especially in solution leading to the formation of an ethylenediamine degradate. The modification of the fluorescent properties of NFLX in acid solution after exposure to fluorescent light and the degradation mechanisms were studied. Two analytical methods were previously developed and validated for NFLX, ultraviolet spectrophotometry (UV) and spectrofluorimetry (FL). Data obtained using both methods in the analysis of remaining NFLX in terms of percent recoveries revealed that there was no statistically significant modifications of the UV signal and of the recoveries obtained by the method. However, an important increase of the fluorescent signal after light exposure of NFLX solutions appeared, which led to an increase of the average recovery up to 270% over 15 months. Using a previously validated HPLC method for the photostability studies of NFLX, a loss of 5% with respect to the initial drug amount was observed. The study of UV and fluorescence spectra evidenced the formation of the degradation product, which induced significant modification of the fluorescent properties of NFLX samples. These results clearly indicated that FL analysis definitively is the method of choice and can be used to study the photodegradation of NFLX.

Determination of norfloxacin by fluorescence in the presence of different antacids: quantification of analytical interferences.

Norfloxacin is a fluorquinolone that can interfere with certain antacids (derivatives of Al and Mg) because its dissolution profiles are dependent on pH. Furthermore, it can form insoluble complexes that modify its absorption and bioavailability. Two sensitive and selective analytical methods using fluorescence (FL) and UV spectrophotometry (UV) have been developed to study the dissolution behaviour in gastric juice of different formulations of norfloxacin in tablets. There are no significant differences when the samples are measured by both methods and their ruggedness in the presence of some excipients is proven. From this, it is concluded that they are effective for this study. When different antacids are added to the dissolution medium, using UV and FL methods with the same samples, totally different dissolution profiles appear. Using FL, it would appear that up to 400% of the amount of norfloxacin in the tablet is released. These profiles are misleading because the uniformity of dosage units was tested before the dissolution studies. It is proven that the antacids dissolved in gastric juice do not produce fluorescence, but cause important analytical interferences with norfloxacin. This may be because their association with Al3+ or Mg2+ forms a new compound. Nevertheless, it is observed that this effect is more important in some antacids (Almagate, Magaldrate). This may be because their ability to deliver Al to the medium is greater.

Validation of a method to study the dissolution behaviour of norfloxacin tablets.

This experimental study examines the development and validation of a new method to evaluate the dissolution rate of norfloxacin tablets. The volume of dissolution medium used here is 100 ml. instead of the 750-900 ml used in the official methods. This smaller volume is closer to that in the human gastric tract. Our main aim is to validate a device which, requiring small volumes of medium, allows the addition of therapeutic amounts of antacids or other substances for in vitro interaction dissolution studies.