RESUMEN

Despite the advances in targeted therapies and immunotherapy for non-small cell lung cancer (NSCLC) patients, the intravenous administration of carboplatin (CARB) and paclitaxel (PTX) in well-spaced cycles is widely indicated for the treatment of NSCLC from stage II to stage IV. Our strategy was to add a controlled-release cisplatin-based dry-powder for inhalation (CIS-DPI-ET) to the conventional CARB-PTX-IV doublet, administered during the treatment off-cycles to intensify the therapeutic response while avoiding the impairment of pulmonary, renal and haematological tolerance of these combinations. The co-administration of CIS-DPI-ET (0.5 mg/kg) and CARB-PTX-IV (17-10 mg/kg) the same day showed a higher proportion of neutrophils in BALF (35 ± 7% vs 1.3 ± 0.8%), with earlier regenerative anaemia than with CARB-PTX-IV alone. A first strategy of CARB-PTX-IV dose reduction by 25% also induced neutrophil recruitment, but in a lower proportion than with the first combination (20 ± 6% vs 0.3 ± 0.3%) and avoiding regenerative anaemia. A second strategy of delaying CIS-DPI-ET and CARB-PTX-IV administrations by 24 h avoided both the recruitment of neutrophils in BALF and regenerative anaemia. Moreover, all these groups showed higher cytotoxicity (LDH activity, protein content) with no higher renal toxicities. These two strategies seem interesting to be assessed in terms of antitumor efficacy in mice.

Asunto(s)

RESUMEN

Despite recent advances, platinum-based chemotherapy (partially composed of cisplatin, CIS) remains the backbone of non-small-cell lung cancer treatment. As CIS presents a cumulative and dose-limiting nephrotoxicity, it is currently administered with an interruption phase of 3-4 weeks between treatment cycles. During these periods, the patient recovers from the treatment side effects but so does the tumour. Our strategy is to increase the treatment frequency by delivering a cisplatin controlled-release dry powder for inhalation (CIS-DPI) formulation during these off-cycles to expose the tumour environment for longer to CIS, increasing its effectiveness. This is promising as long as the pulmonary and renal toxicities remain acceptable. The aim of the present investigation was to evaluate the pulmonary and renal tolerance of CIS-DPI (three times per cycle) and CIS using the intravenous (IV) route (CIS-IV) (one time per cycle) as monotherapies and to optimize their combination in terms of dose and schedule. At the maximum tolerated dose (MTD), combining CIS-DPI and CIS-IV impaired the pulmonary and the renal tolerance. Therefore, pulmonary tolerance was improved when the CIS-IV dose was decreased by 25% (to 1.5 mg/kg) while maintaining the MTD for CIS-DPI. In addition to this dose adjustment, a delay of 24 h between CIS-DPI and CIS-IV administrations limited the acute kidney injury.

Asunto(s)

RESUMEN

The main objective of this work was to explore the feasibility to print monoclonal antibody (mAb)-loaded implantable systems using fused-deposition modelling (FDM) to build complex dosage form designs. Indeed, to our knowledge, this work is the first investigation of mAb-loaded devices using FDM. To make this possible, different steps were developed and optimized. A mAb solution was stabilized using trehalose (TRE), sucrose (SUC), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), sorbitol or inulin (INU) in order to be spray dried (SD). Printable filaments were then made of poly(lactide-co-glycolide) (PLGA) and mAb powder (15% w/w) using hot melt extrusion (HME). The FDM process was optimized to print these filaments without altering the mAb stability. TRE was selected and associated to L-leucine (LEU) to increase the mAb stability. The stability was then evaluated considering high and low molecular weight species levels. The mAb-based devices were well-stabilized with the selected excipients during both the HME and the FDM processes. The 3D-printed devices showed sustained-release profiles with a low burst effect. The mAb-binding capacity was preserved up to 70% following the whole fabrication process. These promising results demonstrate that FDM could be used to produce mAb-loaded devices with good stability, affinity and sustained-release profiles of the mAb.

Asunto(s)

RESUMEN

This study assesses the feasibility of printing implantable devices using 3D printing Fused deposition modeling (FDM) technology. The influence of the deposition temperature, the deposition rate and the layer thickness on the printing process and the physical properties of the devices were evaluated. The filaments were composed of neat poly(lactic acid) (PLA) and blends of different plasticizers (polyethylene glycol 400 (PEG 400), triacetine (TA), acetyltriethyl citrate (ATEC) and triethyl citrate (TEC)) at 10% (w/w). The assessment of thermomechanical characteristics and morphology of both filaments and devices (cylinders and dog bones) were performed. The influence of each parameter was evaluated using a design of experiment (DoE) and the significance of the results was discussed. A large amount of data about the evaluation of FDM process parameters are already available in the literature. However, specific insights needed to be increased into the impact of the use of PLA and plasticized PLA raw material on the feasibility of printing devices in three dimensions. To conclude, the ductility was improved with a high layer thickness, low temperature and using ATEC. Whereas, adhesion was promoted with an increase in temperature, a lower layer thickness and adding TA.

Asunto(s)

RESUMEN

Background Many tools exist to document drug-related problems (DRP), such as the Pharmaceutical Care Network Europe (PCNE) classification. However, none have been adapted and published for French-speaking Belgian community pharmacies. Settings French-speaking Belgian Community pharmacies. Objective The objective was to translate and adapt the PCNE V6.2 classification to the Belgian pharmacy practice and legal setting and to assess the content validity, daily use and inter-rater reliability of this classification. Main Outcome Measure Validation of the French-language adapted PCNE v6.2 classification in Belgium. Method The first step translated and adapted the PCNE V6.2 classification to the Belgian setting. Thereafter academic and community pharmacists evaluated the content validity, which involved six criteria and concerned the instruction manual (clarity, helpfulness) and the registration form (representativeness, logical design, completeness and uniqueness). The next step was the DRP collection, using the PCNE tool daily. Compliance with the instructions and the time needed to solve a DRP were evaluated. Finally, the inter-rater reliability was evaluated by comparing DRP codings done by pharmacist volunteers. Results The classification was translated into French and adapted by adding 16 items. The classification showed a high content validity for the academics and the community pharmacists. A total of 109 DRP forms were coded, with an average resolution time of 5 min. Regarding the inter-rater reliability, 74 tool items out of the set of 83 showed high consistency in coding. Conclusion This study showed that the tool adaptation to a French-speaking Belgian context was reliable and has adequate validity for daily use.

Asunto(s)

RESUMEN

Despite severe adverse effects, chemotherapy is still widely used in the treatment of lung tumors, including primary lung tumors and metastases. In order to reduce the risk of harm and to intensify treatment responses, several strategies have been described recently. These include the use of nanomedicine-based chemotherapies and pulmonary drug delivery. However, to treat lung tumors, inhalation cannot be effective and safe without an adaptation of current inhalation techniques, i.e. inhalation devices and drug formulations. This can be very challenging. This review presents recent preclinical developments that could address the limitations observed with aerosolized chemotherapy. The solutions involve the use of dry powder inhalers and advanced drug formulations, such as controlled and sustained release formulations and nanomedicine-based formulations.

Asunto(s)

RESUMEN

Lung tumours have a high incidence and cause many deaths worldwide. Despite progresses in treatment with targeted therapies and immunotherapies, the global 5-year survival rate remains low. In this context, inhaled chemotherapy could provide a means to intensify current therapeutic modalities. This review is based on clinical studies of inhaled chemotherapy against lung tumours. The advantages of this approach in terms of pharmacokinetic ratio and therapeutic index are presented as well as the limitations including contraindications and pulmonary side effects. Moreover, the challenges linked to technical aspects around administration are identified (inhalation device and facilities to limit aerosol propagation and exposure of healthcare professionals). The current developments proposed to overcome these challenges are described briefly. Also discussed are the potential applications for the distribution of the inhaled anticancer drug into tumour-bearing respiratory tracts and finally the potential indications for current therapeutic modalities.

Asunto(s)

RESUMEN

Aim Aims are: 1] Identify causes of Drug Related Problems (DRPs), interventions performed by pharmacists and results of corticosteroid- related problems and 2] distinguish between problems related to inhaled and general corticosteroids. Methods During 5 days of their internship, 534 final year students of pharmaceutical sciences in six Belgian universities collected DRPs encountered in community pharmacies, as well as related interventions performed by pharmacists and the result of the intervention. The DRPs' electronic registration was done through an adapted tool for Belgium based on the classification of Pharmaceutical Care Network Europe [PCNE- v 6.2]. Findings The frequency of DRPs is 24,8%. 766 DRPs (4,8%) related to corticosteroids, of which 351 were inhaled corticosteroids. The most common causes of corticosteroid-related problems (53- 59%) were technical causes. The most represented category of clinical causes was the inappropriate choice of drug [33-41%]. Pharmacists' intervention was similar for inhaled and general corticosteroids. Pharmacists intervened orally with patients in 38-40% of total interventions, and in writing in 16% of interventions. Pharmacists did not react in 16% of corticosteroid-related problems. 81-83% of PLMS were resolved partially or completely. Conclusion In conclusion, DRPs detected in community pharmacies related to corticosteroid are infrequent (4,8% of DRPs) but 82% of detected problems have been resolved. Furthermore, the study shows the importance for the Belgian health system to introduce an official DRPs classification and software facilitating their documentation in community pharmacies.

Asunto(s)

RESUMEN

Chitosan and chitosan derivative-based nanoparticles loaded with insulin were prepared by self-assembly, via electrostatic interactions between the negatively charged drug and the positively charged polymers. In the investigated chitosan derivatives, the amine groups were substituted to different extents (33, 52 or 99%) by 2-hydroxypropyl-3-trimethyl ammonium groups, rendering the polymers permanently positively charged, irrespective of the pH. This is an important property for this type of advanced drug delivery system, since the pH value changes throughout the gastrointestinal tract and electrostatic interactions are of crucial importance for the stability of the nanoparticles. Permanent positive charges are also in favor of mucoadhesion. In contrast, the electric charges of chitosan molecules depend on the pH of the surrounding medium. Since the solubility of the chitosan derivatives increased due to the introduction of quaternary ammonium groups, sodium tripolyphosphate (TPP) was added to the systems to create supplementary cross-links and stabilize the nanoparticles. The presence of TPP influenced both the dissolution of the polymer matrix as well as the resulting release kinetics. The underlying drug release mechanisms were found to be more complex than simple diffusion under constant conditions, likely involving also ionic interactions and matrix dissolution. The most promising formulation was based on a chitosan derivative with 33% substitution degree and characterized by a Z-average of 142 ± 10 nm, a zeta potential of 29 ± 1 mV, an encapsulation efficacy of 52 ± 3% and, most importantly, the release of insulin was sustained for more than 210 min.

Asunto(s)

RESUMEN

Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer(®) RG505 and Resomer(®) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5 ± 3°C, 25 ± 2°C/60% RH and 40 ± 2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5 ± 3°C and that the Resomer(®) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres.

Asunto(s)

RESUMEN

Osteoarthritis is characterized by slow degenerative processes in the articular cartilage within synovial joints. It could be interesting to develop a sustained-release formulation that could be effective on both pain/inflammation and restoration of mechanical integrity of the joint. Recently, an injectable system based on glycerol monooleate (GMO), containing clonidine as a model hydrophilic analgesic/anti-inflammatory drug and hyaluronic acid as a viscoelastic scaffold, showed promising potential as a biodegradable and biocompatible preparation to sustain the drug activity. However, drug release from the system is relatively fast (complete within 1 week) and the underlying drug release mechanisms not fully understood. The aims of this study were: (i) to significantly improve this type of local controlled drug delivery system by further sustaining clonidine release, and (ii) to elucidate the underlying mass transport mechanisms. The addition of FDA-approved inactive ingredients such as sodium oleate or purified soybean oil was found to be highly effective. The release rate could be substantially reduced (e.g., 50% release after 10 days), due to the increased hydrophobicity of the systems, resulting in slower and reduced water uptake and reduced drug mobility. Interestingly, Fick's second law of diffusion could be used to quantitatively describe drug release.

Asunto(s)

RESUMEN

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with (99m)Tc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h. Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC0₋360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate. The two formulations showed interesting pharmacokinetic profiles (T(max) of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.

Asunto(s)

RESUMEN

The aim of this study was to encapsulate ethylhexyl methoxycinnamate (EMC), a commonly used UVB filter, in a solid lipid matrix in order to obtain microparticles and then nanoparticles to reduce its photo-instability under UV light exposure. Glyceryl behenate, rice bran wax and ozokerite were investigated for encapsulating EMC. The suspensions of nanoparticles contained 70% encapsulated EMC (relative to the lipid mass). The absorbance level at 310 nm of suspensions containing nanoparticles was more than twice that of those containing microparticles. So, decreasing the size of particles improved the efficiency of light protection, regardless of the lipid material used. Moreover, free EMC presented a 30% loss of its efficiency after 2 h of irradiation, whereas the three NLC formulations showed a loss of absorbency between 10% and 21%. The in vitro cutaneous penetration test did not show a higher potential penetration for EMC contained in nanosuspensions compared to free EMC.

Asunto(s)

RESUMEN

This review describes the different drug delivery systems containing levodopa that are used in the treatment of Parkinson's disease. Their composition, process of preparation, advantages, disadvantages and limitations are discussed as well as the major objective in the management of Parkinson's disease according to the pathology of the disease.

Asunto(s)

RESUMEN

The aim of this study was to evaluate the possible penetration through human skin of organic and inorganic filters contained in sunscreen emulsions packaged in aerosol cans, using an in vitro method. Experiments were carried out on two different types of emulsion: W/Si and W/O. This study was conducted using static diffusion cells (Franz cells). The determination of organic UV filters [Methylene Bis Benzotriazolyl Tetramethylbutylphenol (MBBT); Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (BEMT); Diethylamino Hydroxybenzoyl Hexyl Benzoate (DHHB); Ethylhexyl Methoxycinnamate (EMC); and 2-Ethylhexyl Dimethyl PABA (ED-PABA)] was performed by High Performance Liquid Chromatography (HPLC). Therefore, it was important to develop a single analytical method for the quantification of the five organic filters with the aim of facilitating the experiment. The determination of inorganic filters [titanium dioxide (TiO(2)) and zinc oxide (ZnO)] was performed using an emission spectrometric analysis method (ICP-OES). The HPLC and ICP-OES methods were validated. After a penetration test of 24 h duration, the results showed very low penetration only for two of the organic filters (maximum penetration of 1.21 microg cm(-2) h(-1) for EMC and 0.14 microg cm(-2) h(-1) for MBBT) and no penetration for the inorganic filters. Moreover, more than 50% of each sunscreen agent stayed on the surface on the skin. These results are consistent with those in the literature that presents similar experiments. This study showed that the sprayable sunscreen products developed, which contained high concentrations of UV filters, presented a low level of skin penetration.

Asunto(s)

RESUMEN

This article reports the development and evaluation of two nano-emulsions (F45T-03/HFB and F15T-03/PFOB) containing fluorinated trityl radicals dissolved in perfluorocarbons. Preparation with a high-pressure homogenizer conferred sub-micronic size to both nano-emulsions. In vitro and in vivo EPR spectroscopy showed that the nano-emulsions had much greater oxygen sensitivity than the hydrophilic trityl, CT-03. In vivo experiments in rodents confirmed the ability of the nano-emulsions to follow the changes in oxygen concentration after induced ischemia. Histological evaluation of the tissue injected with the nano-emulsions revealed some acute toxicity for the F45T-03/HFB nano-emulsion but none for the F15T-03/PFOB nano-emulsion. These new formulations should be considered for further EPR oximetry experiments in pathophysiological situations where subtle changes in tissue oxygenation are expected.

Asunto(s)

RESUMEN

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

Asunto(s)

RESUMEN

This article describes the in vitro evaluation and the enhancement of the floating properties of coated sustained release (SR) minitablets (MTs). The evaluated system consisted of a 3-mm drug-containing gas-generating core prepared by melt granulation and subsequent compression, which was then coated with a flexible polymeric membrane. Eudragit RL30D and acetyl triethylcitrate were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (wt/wt). The optimally coated floating MTs floated within 10 min and remained buoyant for more than 13 h, regardless of the pH of the test medium. By evaluating the dissolution profiles of levodopa at different pH, it was found that the release of levodopa was sustained for more than 12 h regardless of the pH, even if the coating did not cancel the effect of the pH-dependent solubility of the active drug. Finally, the robustness of the coated floating MTs was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.

Asunto(s)

RESUMEN

The aim of this study was to develop a new coated multiple-unit sustained-release floating system that is able to float over an extended period of time. Levodopa was used as a model drug. The system consisted of a 3mm drug-containing gas-generating core, prepared by melt granulation and subsequent compression, and coated with a flexible polymeric membrane. Eudragit RL30D and ATEC were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (w/w). The floating lag time decreased as the proportion of effervescent agents increased. The optimized coated floating minitablets could float within 20min and remained buoyant for more than 13h. In addition, a sustained release of levodopa for more than 20h was observed.

Asunto(s)

RESUMEN

The purpose of this study was to evaluate the possible influence of different formulation and technological parameters such as sunscreen type and concentration, viscosity, propellant gas, actuator and valve type on size and size distribution of droplets in emulsions of waterproof sunscreens conditioned in aerosol cans. Different kinds of emulsion, W/Si and W/O, were prepared with high concentrations of organic and inorganic UV-filters. These formulations were incorporated in aerosol cans with gas (a blend of butane, propane and isobutane). The size and size distribution of the droplets were analysed by laser diffraction using a Malvern Spraytec. The results showed that the sprayability of the formulation and the particle size characteristics of the emitted sprays are dependent on the physicochemical properties of the formulations. Sprayable waterproof sunscreen emulsions, with a high sun protection factor and negligible percentage of emitted droplets below 30 mum, were successfully developed by optimizing formulation parameters and using appropriate actuators and valves.