Poly-ε-caprolactone microspheres as a drug delivery system for cannabinoid administration: development, characterization and in vitro evaluation of their antitumoral efficacy.

Cannabinoids show promise for the treatment of various medical conditions such as emesis, anorexia, pain, cancer, multiple sclerosis, Parkinson's disease and glaucoma. However, their high lipohilicity and instability complicate their handling and dosing, and restrict their use as pharmaceuticals. The objective of the present work was to assess the feasibility of developing cannabinoid loaded poly-ε-caprolactone (PCL) microparticles prepared by the oil-in-water emulsion-solvent evaporation technique as a suitable dosage form for their administration. Spherical microparticles with a size range of 20-50 µm, and high entrapment efficiency (around 100%) were obtained. Cannabidiol (CBD) dissolved in the polymeric matrix of the microspheres was slowly released in vitro within 10 days. In vitro cell viability studies demonstrated the antitumoral activity of CBD released from microparticles. After 4 and 7 days of incubation, CBD in microspheres significantly inhibited the growth of MDA-MB-231 cells by 60% as compared to the 50% attained with free drug. The results suggest that PCL microparticles could be an alternative delivery system for long-term cannabinoid administration, showing potential therapeutic advantages over free drug.

Comprimidos bucodispersables: ventajas terapéuticas y tecnológicas de elaboración / No disponible

Los comprimidos bucodispersables se definen como comprimidos no recubiertos destinados a ser colocados en la boca, donde se dispersan rápidamente antes de ser tragados. Estas formulaciones son conocidas por las siglas FDDT´s (Fast Dissolving Disintegrating Tablets). Son útiles para la administración a pacientes con dificultades en la deglución, presentan una elevada aceptación por parte del paciente, mejoran de la biodisponibilidad del principio activo y suponen una nueva alternativa para la industria farmacéutica. Dentro de sus inconvenientes destacan el poco conocimiento por parte del paciente, la baja resistencia mecánica, su mayor susceptibilidad a la degradación por temperatura y humedad; la falta, a veces, de bioequivalencia con las formulaciones convencionales, y la dificultad de obtener liberaciones prolongadas o retardadas del principio activo. A nivel tecnológico, existen varios procesos que se pueden aplicar en su elaboración. Con los métodos clásicos de elaboración de comprimidos, mediante la correcta selección de los excipientes y de las variables de la etapa de compresión se obtienen unos comprimidos en los que existe un equilibrio entre dureza y disgregación. Han surgido una serie de tecnologías novedosas: Flashtab, Wowtab, Orasolv y Durasolv. Otra opción es el empleo de técnicas de liofilización, aunque presenta como desventaja su alto coste. Algunas tecnologías especiales patentadas como son Lyoc, QuickSolv y Zydis. Por último, estos comprimidos se pueden elaborar por el método de los polímeros entrecruzados, también conocido como FlashDose y se basa en la formación de una matriz de hilos de azúcares entrelazados(AU)

Orally Disintegrating Tablets are defined as non-coated tablets that are placed in the mouth, where they are rapidly disintegrated before being swallowed. These formulations are known by the acronym FDDT's (Fast Dissolving Disintegrating Tablets). They are useful for administration to patients with difficulties in swallowing, present high acceptance by the patient, improve the bioavailability of the active pharmaceutical ingredient and represent a new alternative for the pharmaceutical industry. Among their disadvantages are the lack of knowledge by the patient, the low hardness and friability, their major degradation susceptibility by temperature and moisture environment, the non bioequivalence with the conventional formulations that sometimes happens and finally the difficulty to obtain prolonged or delayed drug release. From a pharmaceutical technological point of view, there are several processes that can be applied in their preparation. With the conventional tableting technology, choosing a proper role of excipients and variables in the compression stage, tablets with a good balance between hardness and disgregation must be obtained. A series of innovative technologies have been arisen: Flashtab, Wowtab, Orasolv and Durasolv. Another option is the use of freeze drying technique, although it high cost represents a significantly disadvantage. There are some special patented technologies such as Lyoc, QuickSolv and Zydis. Finally, these tablets can be produced by the method of interlocking polymers, also known as FlashDose base on the formation of a matrix of interwoven threads of sugar(AU)

Poly(epsilon-caprolactone) microparticles formed by the emulsion-evaporation method: effect of the variables of the different steps of the process on their size.

In the present work the influence of the variables of the microencapsulation procedure on the size of poly (epsilon-caprolactone) microparticles (PECL-MP) obtained by the solvent evaporation method is analysed. This study will allow to choose the work conditions necessary to obtain a suitable PECL-MP size for parenteral administration. Agitation rate in the emulsion formation step, polymer concentration and organic/aqueous phase volume ratio were the variables of the microencapsulation procedure that showed a highest influence on the PECL-MP size. High polymer concentrations and low internal phase volumes had a negative effect on the microencapsulation yield. Neither the conditions of the organic solvent evaporation nor the freeze-dry process (when a cryoprotector as threalose was used) influenced on PECL-MP size. The usefulness of this study was confirmed by getting PECL-MP loaded with naloxone and with a mean diameter within 30-40 microm, suitable for parenteral administration.

Statistical method for evaluation of dissolution stability in the formulation development of solid dosage forms: tablets of amonafide.

A statistical method for the evaluation of the dissolution stability results and for selecting the most stable formulation within a solid dosage form development is discussed. Three types of tablets of an antineoplastic drug, amonafide, stored at a relative humidities (RH), 45% and 75%, were used. The drug release from tablets was tested before and after storage. The experimental data were statistically fitted to empirical model equations. Furthermore, the best mathematical fit was the statistical comparison of the residuals. From the selected model equation, time-dependent dissolution (Q45 and DE45) and dissolved quantity-dependent parameters (t70, t100 and MDT) were calculated. A useful parameter to present and evaluate the results obtained in comparative stability studies was defined: the Modification Factor (MF). It allowed the selection of the most stable formulation in the easiest and fastest way: the most stable formulation should present the smallest modification of the studied characteristics, in other words, the smallest MF value. In this way, tablets II (manufactured by wet granulation and with Emcompress as main excipient) showed the greater dissolution stability of the three types of tablets studied. Amonafide tablets must be packaged in impermeable containers, since the environmental relative humidity strongly modifies their dissolution characteristics.

Procedure to evaluate the stability during processing and storage of a medicated premix and medicated farm feed: erythromycin thiocyanate.

In this paper, a stability study of a medicated premix and medicated farm feed containing erythromycin thiocyanate was planned. No drug degradation was detected during the medicated farm feed processing. In the medicated premix stability study, significant drug degradation was detected only at 40 degrees C and 75% relative humidity. Because after 2 years of storage at 25 degrees C and 60% relative humidity no degradation of erythromycin thiocyanate was detected, this period of time is proposed as the premix shelf life. In the medicated farm feed stability study, drug degradation was detected under accelerated conditions, but it was not detected under long-term storage conditions for 3 months. Therefore, the proposed shelf life of the medicated farm feed is 3 months, as this is time enough to be consumed. The planned stability study-storage conditions, testing frequency, and proposed data evaluation-allowed an easy and reliable evaluation of veterinary medicine stability.

Statistical evaluation for stability studies under stress storage conditions.

During the pharmaceutical development of a new drug, it is necessary to select as soon as possible the formulation with the best stability characteristics. The current International Commission for Harmonisation (ICH) regulations regarding stability testing requirements for a Registration Application provide the stress testing conditions with the aim of assessing the effect of severe conditions on the drug product. In practice, the well-known Arrhenius theory is still used to make a rapid stability prediction, to estimate a drug product shelf life during early stages of its pharmaceutical development. In this work, both the planning of a stress stability study to obtain a correct stability prediction from a temperature extrapolation and the suitable data treatment to discern the reliability of the stability results are discussed. The study was focused on the early formulation step of a very stable drug, Mitonafide (antineoplastic agent), formulated in a parenteral solution and in tablets. It was observed, for the solid system, that the extrapolated results using Arrhenius theory might be statistically good, but far from the real situation if the stability study is not designed in a correct way. The statistical data treatment and the stress-stability test proposed in this work are suitable to make a reliable stability prediction of different formulations with the same drug, within its pharmaceutical development.

Stability study of a sulfadimidine-containing medicated premix and its mixture with farm feed.

The objective of this paper was to study the stability of a medicated premix and a medicated farm feed containing sulfadimidine as the active ingredient. The medicated premix is supplied as powdered form and administered orally after mixing with animal feed. The sulfadimidine analytical method described in United States Pharmacopoeia 23 cannot be used to carry out the stability study because of its lack of specificity for different degradation products. Therefore, a high-performance liquid chromatography method was developed to assay sulfadimidine. This method was optimized and validated for the stability study. According to International Committee Harmonization (ICH) guidelines, the samples were stored under long-term testing and accelerated conditions for the stability study of the premix and the medicated farm feed. Sulfadimidine degradation was not detected in either form under any of the conditions studied.

Microbiological bioassay of erythromycin thiocyanate: optimisation and validation.

The validation of an analytical method for the quantitative determination of erythromycin thiocyanate formulated in an antibiotic preparation for veterinary use was carried out. This method is based on the microbiological method described in the European Pharmacopoeia to analyze erythromycin thiocyanate as a raw material. This erythromycin thiocyanate preparation is presented as a powder for oral administration after mixing with feed. For that reason, it was planned to validate the method for the quantitative determination of erythromycin thiocyanate incorporated both in the medicated premix and the mixture with feed. The microbiological method followed a linear model and was not proportional. The number of replicates needed to obtain a valid result was less than four in all cases. The small difference in concentration, expressed in natural logarithm detected by the method, was 0.1.

Pharmaceutical development of tablets of a new antineoplastic drug: mitonafide.

The pharmaceutical development of tablets of a 1,8 naphtalimide with antineoplastic activity is carried out in two steps. The preformulation step includes the study of those characteristics of the drug with special importance for the successful development of the formulation step. In this way, the low moisture, the low porosity and the good flowability of the drug as raw material allow direct compression to be taken into account, together with wet granulation as methods of tablet manufacture. As a result of the formulation studies, one formulation of tablets obtained by direct compression and another one obtained by wet granulation are selected. Both of them meet all the requirements imposed to a solid pharmaceutical form for oral administration.