Enhancing ovarian cancer conventional chemotherapy through the combination with cannabidiol loaded microparticles.

In this work, we evaluated, for the first time, the antitumor effect of cannabidiol (CBD) as monotherapy and in combination with conventional chemotherapeutics in ovarian cancer and developed PLGA-microparticles as CBD carriers to optimize its anticancer activity. Spherical microparticles, with a mean particle size around 25 µm and high entrapment efficiency were obtained. Microparticles elaborated with a CBD:polymer ratio of 10:100 were selected due to the most suitable release profile with a zero-order CBD release (14.13 ± 0.17 µg/day/10 mg Mps) for 40 days. The single administration of this formulation showed an in vitro extended antitumor activity for at least 10 days and an in ovo antitumor efficacy comparable to that of CBD in solution after daily topical administration (≈1.5-fold reduction in tumor growth vs control). The use of CBD in combination with paclitaxel (PTX) was really effective. The best treatment schedule was the pre + co-administration of CBD (10 µM) with PTX. Using this protocol, the single administration of microparticles was even more effective than the daily administration of CBD in solution, achieving a ≈10- and 8- fold reduction in PTX IC50 respectively. This protocol was also effective in ovo. While PTX conducted to a 1.5-fold tumor growth inhibition, its combination with both CBD in solution (daily administered) and 10-Mps (single administration) showed a 2-fold decrease. These results show the promising potential of CBD-Mps administered in combination with PTX for ovarian cancer treatment, since it would allow to reduce the administered dose of this antineoplastic drug maintaining the same efficacy and, as a consequence, reducing PTX adverse effects.

Stability characteristics of cannabidiol for the design of pharmacological, biochemical and pharmaceutical studies.

Cannabidiol (CBD) is one of the most promising cannabinoids in therapeutics. Nevertheless, the reported stability testing has been carried out with plant extracts and not with CBD as a drug substance. The aim of this work was to evaluate the stability of CBD in solution. A High-Performance Liquid Chromatography (HPLC) analytical method, with CBD in ethanol, was previously validated for these stability studies. The resulting method was linear and proportional in a range of concentrations from 1 to 150 µg CBD/mL, as well as precise. It was also considered suitable to quantify CBD in aqueous medium as reported in accuracy studies. The stability of CBD was influenced by multiple factors. Temperature was one of the most critical parameters, with an activation energy of 92.19KJ/mol. At room temperature, CBD was highly unstable (t95 = 117.13 days). However, at 5 °C it was stable for at least 12 months. CBD was also sensitive to oxidation, with a short t95 of 1.77 days in oxidizing environments, as well as to light. The photolytic reaction seems to be oxidative. The solvent influences CBD stability, and the latter is more stable in ethanol than in aqueous medium. In fact, in simulated physiological conditions (pH 7.4 and 37 °C) 10% of CBD was degraded within 24 h. These studies indicate that CBD is highly unstable, and this should be taken into account in the development of in vitro and in vivo studies of CBD activity and in the pharmaceutical development of dosage forms.

CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer.

Cannabidiol (CBD) has emerged as a potential agent for breast cancer management. In this work, the potential use of cannabidiol in solution (CBDsol) and encapsulated in polymeric microparticles when combined with paclitaxel (PTX) and doxorubicin (DOX) in breast cancer treatment has been evaluated for the first time using MCF-7 and MDA-MB-231 cells. CBDsol, previously administered at suboptimal concentrations (cell death < 10%), enhanced the PTX and DOX effect in both breast cancer cells. The co-administration of CBDsol and PTX or DOX showed a synergistic effect. PLGA-502 was selected as the most suitable polymer to develop CBD-loaded microparticles. The developed formulation (CBD-Mps) was effective as monotherapy, showing extended antiproliferative activity for at least 10 days, and when combined with PTX or DOX. In fact, the use of CBD-Mps allows the combination of both, pre and co-administration strategies, with a single administration, also showing a significant increase in PTX and DOX antiproliferative activity. Finally, the anticancer effect of both CBDsol and CBD-Mps as monotherapy or in combination with PTX was also confirmed in ovo, usingMDA-MB-231-derived tumours. This data evidences the promising inclusion of CBD in conventional breast cancer chemotherapy and the use of CBD-Mps for the extended release of this cannabinoid, optimising the effect of the chemotherapeutic agents.

Current status of nanomedicine in the chemotherapy of breast cancer.

Despite the efforts that have been made in the field of breast cancer therapy, it is a leading cause of cancer death in women and a major health problem. The current treatments combine several strategies (surgery, radiotherapy, immunotherapy, hormone therapy, and chemotherapy) depending on cancer subtype and tumour stage. The use of chemotherapy is required in certain circumstances, like before or after surgery or in advanced stages of the disease. Chemotherapeutic regimens that include anthracyclines (e.g. doxorubicin), taxanes (e.g. paclitaxel), 5-fluorouracil and/or cyclophosphamide show, in general, a high toxicity that limit their clinical use. The use of targeted chemotherapy allows to get a selective location of the drug at tumour mass, decreasing the toxicity of these treatments. An increase of the antitumour efficacy can also be achieved. The use of nanocarriers containing anticancer drugs can be a good strategy to get targeted chemotherapy. In fact, several nanoformulations containing paclitaxel and doxorubicin have been approved or are under clinical trial for breast cancer therapy. The main advantage of these nanomedicines is their lower toxicity compared to conventional formulations, which can be attributed to the elimination of the solvents of the formulation (e.g. Cremophor-EL in paclitaxel conventional formulations) and the more selective location of the drug at tumour site (e.g. cardiotoxicity related to free doxorubicin). However, some adverse events (e.g. hand foot syndrome or infusion reactions) have been related to the administration of some nanomedicines, which have to be considered.

Phyto-, endo- and synthetic cannabinoids: promising chemotherapeutic agents in the treatment of breast and prostate carcinomas.

INTRODUCTION: The term 'cannabinoids' designates a family of compounds with activity upon cannabinoid receptors. Cannabinoids are classified in three groups: phytocannabinoids, endocannabinoids, and the synthetic analogues of both groups. They have become a promising tool in the treatment of cancer disease, not only as palliative agents, but also as antitumor drugs, due to their ability to inhibit the proliferation, adhesion, migration, invasion, and angiogenesis of tumour cells. Two of the cancers where they have shown high anticancer activity are breast and prostate tumours. Despite this potential clinical interest, several studies have also reported that cannabinoids can stimulate the proliferation of cancer cells at very low concentrations. Areas covered: The aim of this review is to evaluate the promising chemotherapeutic utility of phytocannabinoids, endocannabinoids, and synthetic cannabinoids in breast and prostate cancer. Expert opinion: Cannabinoids, in particular the non-psychoactive CBD, may be promising tools in combination therapy for breast and prostate cancer, due to their direct antitumor effects, their ability to improve the efficacy of conventional antitumor drugs and their usefulness as palliative treatment. Nevertheless, deeper studies to fully establish the mechanisms responsible for their antitumour and pro-tumour properties and their formulation in efficient delivery systems remain to be established.

Critical attributes of formulation and of elaboration process of PLGA-protein microparticles.

Low drug loading, burst effect during release and drug inactivation account for the main drawbacks of protein microencapsulation in poly(d,l-lactic-co-glycolic) acid (PLGA) matrix by the water-in oil-in water (W/O/W) solvent evaporation method. Thus, the current study was set to invest the critical attributes of formulation and of elaboration process which determine protein loading into microparticles as well as its further release, using albumin as protein model. NaCl concentration in the external aqueous phase, poly(vinyl alcohol) (PVA) concentration and mostly viscosity of both the internal aqueous phase and the organic phase were critical attributes for improving drug loading, with polymer molecular weight and hydrophobicity likewise directly related to albumin loading. In such a way, when using 0.5% PVA as internal aqueous phase the highest albumin loading was achieved. Optimized microparticles exhibited a sustained in vitro release of albumin over 130 days. The influence of the microencapsulation process on albumin stability and biological activity was evaluated by carrying out cell proliferation assays on PC12 cells with albumin released from microparticles. Such assay demonstrated that the microencapsulation procedure optimized in this study did not affect the biological stability of the microencapsulated protein.

Overcoming glucocorticoid resistances and improving antitumor therapies: lipid and polymers carriers.

PURPOSE: To improve chemotherapy protocols of lymphoid malignancies, by using polymeric and lipid microparticles as controlled delivery systems of dexamethasone, part of all combined chemotherapy protocols for its strong-inducing effect on malignant lymphoblasts. METHODS: Polymeric microparticles were prepared by the oil-in-water-emulsion cosolvent evaporation method, andlipid microparticles by spray drying. Their cytotoxic effects on GC-sensitive PC12 cells and GC-resistant PC3 cells were characterized by cell proliferation and apoptosis assays. RESULTS: Both elaboration methods rendered optimal-sized microparticles for parenteral administration with high drug loading. In vitro assays showed sustained dexamethasone release from polymeric microparticles over a month, whereas 100% dexamethasone release from lipid microparticles was achieved within 24 h. Similar PC12 cell death to that obtained with dexamethasone solution administered every 48 h was achieved with dexamethasone polymeric microparticles in 26-days assays. Dexamethasone solution and loaded polymeric microparticles induced apoptosis around 15.8 and 19.9%, respectively, after 2 days of incubation. Lipid microparticles increased further apoptosis induction in PC12 cells and, unlike dexamethasone solution and polymeric microparticles, showed antiproliferative effects on PC3 cells. CONCLUSIONS: Dexamethasone polymeric microparticles constitute an alternative to current dexamethasone administration systems in combined chemotherapy, whereas dexamethasone lipid microparticles represent a potential tool to revert glucocorticoid resistance.

Objective: tumor. Strategies of drug targeting at the tumor mass level.

Concurrent with the development of new antitumor drugs, there is intensive research to develop strategies and systems to optimize the efficacy of well-known anticancer agents. The main research lines are: (a) reduction in toxicity, (b) improvement of administration and (c) overcoming drug resistance. Drug targeting systems allow us to act on these three points. The best way to increase efficacy and reduce toxicity of an anticancer agent is targeting the drug at the level of the tumor masses and maintaining its concentration there for enough time to optimize its therapeutic action. Numerous strategies have been developed to achieve this second order targeting, based on the use of polymeric-drug conjugates, polymeric micelles, liposomes and albumin conjugates and nanoparticles, whose main features of toxicity, efficacy and administration are discussed in this review.

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.

Polímeros en medicamentos de administración oftálmica / Polymers in ocular drug formulations

No disponible

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.

Photolability evaluation of the new cytostatic drug mitonafide.

A qualitative and quantitative study on the stability of the new cytostatic drug mitonafide (N-[2-(dimethyl-amino) ethyl]-3-nitronaphthalimide, CAS 54824-17-8) against UVA, UVC and visible radiations was carried out. Initially a test with controlled lighting on samples from mitonafide solution is carried out. This test include the determination of the protector effect of different kinds of glasses (clear and amber glass). The results achieved are verified by means of a test in normal lighting conditions (direct sun light, normal laboratory lighting and darkness). High mitonafide photodecomposition, deeper against UVA radiation, requires conservation of raw material in darkness. Similarly UV sterilizing radiations must be avoided in sterile rooms during manufacture. The use of amber glass ampoules is not enough to protect parenteral solutions from radiations. Direct sunlight must be avoided in the manufacture, control tests and administration in perfusion of pharmaceutical dosage forms, although artificial light can be used during short periods of time.