Physicochemical stability of bortezomib solutions for subcutaneous administration.

For the majority of cytotoxic drug preparations, such as bortezomib, the unit dose information is not available. In addition, there is a lack of information on the physicochemical stability of the pharmaceutical preparation after opening; this information is crucial for its administration to patients in successive visits, and the per-patient cost can be affected. The purpose of our proposed physicochemical stability study is to determine the shelf life of the reconstituted liquid product under refrigeration and clinical practice conditions. This evaluation was extended to both vials and ready-to-use syringes prefilled with the contents of the open vial. The stability test design includes the specified storage conditions and the critical physicochemical parameters of reconstituted injectable bortezomib. Furthermore, this approach includes the determination of impurities, the monitoring of the purity of the mean peak using a photodiode array, the control of the mass balance, the monitoring of subvisible particles using a laser diffraction analyser, and the setting of stability specifications. For the chemical stability study, the amount of bortezomib and its degradation products were determined using a stability-indicating HPLC method. The physical inspection of the samples was performed throughout the stability study, and their pH values were also monitored. Bortezomib (2.5 mg/mL) in 0.9% sodium chloride remained stable for 7 days when stored in both polypropylene syringes and vials at 5 ± 3 °C (refrigeration) and shielded from light. Additionally, it exhibits stability for 24 h under storage conditions simulating clinical use (20-30 °C and protected from light). The proposed protocol provides the stability in the vials once reconstituted and in prefilled refrigerated syringes; this protocol can be used to reduce waste and increase cost savings.

Sellado antibiótico de reservorios subcutáneos: estabilidad de soluciones con vancomicina / Antimicrobial lock solutions for implantable central venous devices: stability of vancomycin solutions

Los reservorios subcutáneos son un tipo de catéter venoso central (CVC). Cuando se usan catéteres venosos centrales (CVC), el personal sanitario necesita evitar dos grandes riesgos: formación de coágulos e infecciones bacterianas. Para prevenir y evitar la contaminación de los catéteres en los pacientes hospitalizados y ambulatorios, se han implementado diversas alternativas, como el llamado “sellado antibiótico de catéteres” (SAC). De este modo, se ha sugerido la utilización de soluciones con agentes antimicrobianos, a las que se suelen adicionar sustancias con efecto anticoagulante y/o con efecto antibiofilm. Empero, se requiere que la estabilidad de dichas soluciones sea comprobada mediante técnicas como la cromatografía líquida de alta resolución (HPLC), además de las pruebas de eficacia antimicrobiana, para así poder establecer la seguridad de los pacientes. En este entorno, se plantea el presente trabajo de revisión bibliográfica, con el objetivo de incluir las investigaciones de mayor representación clínica a este respecto, para evidenciar el comportamiento de las soluciones de sellado antibiótico de catéteres en distintas condiciones de almacenamiento y uso. En particular, esta revisión se centra en soluciones con vancomicina. De acuerdo con los estudios consultados, las soluciones de vancomicina con citrato de sodio (agente quelante) son las que presentan las mejores características en cuanto a estabilidad físico-química y eficacia como soluciones de sellado.(AU)

Subcutaneous reservoirs are a type of central venous catheter. When using central venous catheters, healthcare workers need to avoid two major risks: clot formation and bacterial infections. To prevent and avoid catheter contamination in both hospitalized patients and outpatients, several strategies have been carried out, such as the so-called ” antibiotic-based catheter lock solution”. Therefore, it has been suggested to implement the use of solutions with antimicrobial agents, to which anticoagulant and/or antibiofilm substances are often added.However, the stability of such solutions needs to be tested by techniques such as high performance liquid chromatography (HPLC), in addition to antimicrobial efficacy testing, in order to establish patient safety. In consequence, this literature review aims to include the most clinically representative research towards these aspects, to demonstrate the behaviour of antibiotic-based catheter lock solutions under different conditions of storage and use. In particular, this review focuses on solutions containing vancomycin. According to the studies consulted, vancomycin solutions with sodium citrate (chelating agent) present the best stability characteristics in terms of physicochemical properties and efficacy.(AU)

Improving the therapeutic efficacy of prilocaine by PLGA microparticles: Preparation, characterization and in vivo evaluation.

A delivery system based on poly(lactic-co-glycolic acid) polymer (PLGA) microparticles has been developed for parenteral administration of the local anesthetic prilocaine in its free base form. Both drug-free and drug-loaded microparticles, prepared by a double-emulsion-evaporation method, were characterized for mean size by Laser Diffraction Analysis, while their morphology was investigated by scanning electron microscopy. The preparation technique allowed obtainment of homogeneous microparticles of about 25 µm diameter, suitable for subcutaneous administration. The encapsulation efficiency, determined by both direct and indirect methods, was around 36-38%. Differential Scanning Calorimetry was used to characterize the solid state of the raw materials, assess drug-polymer compatibility and miscibility and highlight possible modifications of the components induced by the preparation method. In vitro release studies showed a sustained release profile, with about 80% of drug released after the first 24 h. The anesthetic effect of the formulation was evaluated in vivo on rats, according to the test of cutaneous trunci muscle reflex. Administration of prilocaine base as PLGA microparticles allowed to significantly enhance both extent (60% AUC increase) and duration (100% increase) of the anesthetic effect in the animal model, in comparison with the equivalent dose of prilocaine hydrochloride aqueous solution.

Propuesta biotecnológica para el tratamiento del cáncer de cérvix uterino, empleando liposomas / Biotechnological proposal for cervical cancer treatment using liposomes

Los nanotransportadores de fármacos son una excelente opción para formar sistemas farmacéuticos eficientes y seguros. Interleucina 2 (IL-2) es eficaz en la terapia antitumoral, sin embargo su administración sistémica se ha limitado por su alta toxicidad. En el presente trabajo se aborda la investigación en animales del tratamiento antitumoral con IL-2 transportada en liposomas frente a IL-2 libre, y se aborda un paso imprescindible para el futuro uso de los liposomas con IL-2 como terapia biotecnológica para pacientes con carcinoma de cérvix: los primeros estudios de estabilidad farmacéutica

Drug nanosystems are an excellent option to form efficient and safe pharmaceutical systems. Our team has developed methodology based on the use of Interleukin 2 (IL-2) which has proven very effective in antitumor therapy, but systemic administration is limited by its high toxicity. The present work discusses in vivo evaluation of the tumor using IL-2 carried in liposomes against IL-2 free, and also addresses an important and necessary step for the future use of IL-2 liposomes in biotechnology therapy for patients with carcinoma of the cervix: the early pharmaceutical stability studies

Preparation and characterization of Δ(9)-tetrahydrocannabinol-loaded biodegradable polymeric microparticles and their antitumoral efficacy on cancer cell lines.

Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer, AIDS and multiple sclerosis), analgesics, and in the treatment of multiple sclerosis and cancer, among other conditions. However, despite their high clinical potential, only few dosage forms are available to date. In this paper, the development of Δ(9)-tetrahydrocannabinol (THC) biodegradable microspheres as an alternative delivery system for cannabinoid parenteral administration is proposed. Tetrahydrocannabinol was encapsulated into biodegradable microspheres by the oil-in-water (o/w) emulsion solvent evaporation method. Several formulations were prepared using different drug:polymer ratios. The influence of antioxidant (α-tocopherol acetate) concentration on the release of THC from the microparticles was studied. Elevated process yield and entrapment efficiencies were achieved. The in vitro drug release studies showed that the encapsulated drug was released over a two week period. As THC has shown therapeutic potential as anticancer drug, the efficacy of the microspheres was tested on different cancer cell lines. Interestingly, the microspheres were able to inhibit cancer cell proliferation during the nine-day study period. All the above results suggest that the use of biodegradable microspheres would be a suitable alternative delivery system for THC administration.

Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

Selection of PLA polymers for the development of injectable prilocaine controlled release microparticles: usefulness of thermal analysis.

The use of injectable local anaesthetics for the treatment of severe postoperative pain is limited by the short duration of the painkilling effect. Pre-formulation studies were carried out for the development of an injectable microparticle formulation for controlled release of prilocaine, an amino-amide type local anaesthetic suitable for intravenous, subcutaneous and intramuscular administration. To the best of our knowledge, the encapsulation of prilocaine into microparticles has not been investigated yet. Three different poly-lactic-acid (PLA) polymers were separately employed for the preparation of the microparticles. Thermal analyses by differential scanning calorimetry (DSC) were carried out for the characterization of the raw materials, to assess the drug-polymer compatibility and miscibility, to investigate the effects of the production process on the components. Empty and prilocaine loaded microparticles were prepared by double emulsion method. All formulations were fully characterized in terms of drug content, morphology, size and in vitro drug release. The preliminary value of PRL solubility in the polymer material determined by DSC was evaluated and discussed as a predictive value for encapsulation efficiency and controlled release. DSC analysis turned out to be a usefulness tool for a fast polymer selection. Microparticles prepared with PLA R202 and R203S showed desirable characteristics for subcutaneous administration and could represent two promising formulations for the development of innovative pharmacological tools in the treatment of postoperative pain.

Extraction and determination by liquid chromatography and spectrophotometry of naloxone in microparticles for drug-addiction treatment.

This paper discusses the development and validation of two analytical methods for the assay of naloxone in microparticles, as used in the therapy of opioid drug addiction (weaning). A UV-Vis spectrophotometric method is proposed to study drug loading and drug release, due to its ease and simplicity of performance, while a high performance liquid chromatographic method is developed as a means of stability-indication. Both analytical procedures were validated according to the International Committee for Harmonization (ICH) guidelines. Although the ranges and wavelengths were different for the two analytical methods, they were both found to be specific, linear, precise, and accurate under the determined conditions.

Globalización de los requisitos para la comercialización de medicamentos: importancia de la humedad ambiental en el diseño de los estudios de estabilidad / International requirements for drug marketing: relevance of environmental humidity in the design studies

Se revisan y analizan las condiciones de almacenamiento de las muestras para los estudios de estabilidad recogidas en la normativa elaborada por el ICH, y se propone incorporar un estudio a diferentes humedades relativas (una superior y otra inferior a la propuesta en las "condiciones de almacenamiento de las muestras") en el caso de medicamentos sólidos en envases semipermeables

The sstorage conditions of the samples in the stability studies according to ICH normative are revised and analysed. An additional study at different relative humidities (higher and lower than that proposed in "storage conditions of the samples") incase of drug products in semi permeable containers is proposed