Gaia Colombo

Pectin Matrix as Oral Drug Delivery Vehicle for Colon Cancer Treatment

Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.

Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres

&NA; There is interest in developing prolonged duration local anesthesics. Here we examine whether tetrodotoxin (TTX) can be used to prolong the block from bupivacaine microspheres with and without dexamethasone. Rats received sciatic nerve blocks with 75 mg of microspheres containing 0.05% (w/w) TTX, 50% (w/w) bupivacaine and/or 0.05% (w/w) dexamethasone. 0.1% (w/w) TTX microspheres were also tested. The carrier fluid contained 1:100,000 epinephrine. Nociceptive and motor blockade of the hindpaw were quantified. Nerves and adjacent muscles were harvested 2 weeks after injection for histological assessment by light microscopy. The median nociceptive block duration in hours from the microsphere groups were: bupivacaine=6.2, 0.05% TTX=0, bupivacaine+TTX=35.3, bupivacaine+dexamethasone=31.3, TTX+dexamethasone=8.1, TTX+bupivacaine+dexamethasone=221.7. Some animals receiving particles containing 0.05% TTX had deficits in the uninjected extremity; all animals receiving 0.1% (w/w) TTX particles died. Pockets of particles were associated with localized inflammation, and all samples showed some evidence of myotoxicity in the vicinity of the injection. The nerves themselves appeared intact. In summary, coencapsulation of TTX in controlled release devices containing bupivacaine and dexamethasone resulted in very prolonged nerve blocks. As formulated here, this preparation had a narrow margin of safety. While the myotoxicity appears consistent with the well‐known reversible myotoxicity associated with local anesthetics, its long‐term significance remains to be established.

Bioadhesive film for the transdermal delivery of lidocaine: in vitro and in vivo behavior

The aim of this work was to study, in vitro and in vivo, the behavior of a skin bioadhesive film containing lidocaine. The film characterization included drug transport studies through skin in vitro and in vivo tape stripping with and without iontophoresis. We studied the effect of drug loading in order to identify the release mechanism. Finally, the release rate was compared with a lidocaine commercial gel, to assess the therapeutic value. From the data obtained it can be concluded that the monolayer film acts as a water-permeable transdermal/dermal patch on application to the skin. The permeation kinetics across the skin was not linear, but the patch acted as a matrix controlling drug delivery. Additionally, the permeation rate increased with drug loading. The in vivo experiments with tape stripping indicated that the presence of water during film application is essential to achieve not only the proper adhesion but also an effective accumulation. The application of electric current to the patch can further increase the amount of drug accumulated in the stratum corneum.

Novel Platforms for Oral Drug Delivery

The aim of this review is to provide the reader general and inspiring prospects on recent and promising fields of innovation in oral drug delivery. Nowadays, inventive drug delivery systems vary from geometrically modified and modular matrices, more close to “classic” pharmaceutical manufacturing processes, to futuristic bio micro-electro-mechanical systems (bioMEMS), based on manufacturing techniques borrowed from electronics and other fields. In these technologies new materials and creative solutions are essential designing intelligent drug delivery systems able to release the required drug at the proper body location with the correct release rate. In particular, oral drug delivery systems of the future are expected to have a significant impact on the treatment of diseases, such as AIDS, cancer, malaria, diabetes requiring complex and multi-drug therapies, as well as on the life of patients, whose age and/or health status make necessary a multiple pharmacological approach.

Brain uptake of an anti-ischemic agent by nasal administration of microparticles

N(6)-cyclopentyladenosine (CPA) has neuronal anti-ischemic properties, but it is not absorbed into the brain from the bloodstream, where it shows poor stability and induces side effects. Microparticulate drug delivery systems designed for CPA nasal administration and constituted by mannitol or chitosan, were prepared by spray-drying and characterized. Mannitol-lecithin microparticles showed high CPA dissolution rate, whereas chitosan microparticles controlled its release rate. In vitro mucoadhesion studies indicated that CPA-loaded chitosan microparticles had higher mucoadhesive properties compared to mannitol particles. Ex vivo studies on sheep nasal mucosa showed that mannitol microparticles promoted CPA permeation across the mucosa, whereas chitosan microparticles controlled CPA permeation rate in comparison with CPA raw material. In vivo studies were carried out on rats. No CPA was detected in rat cerebrospinal fluid (CSF) and brain sections after intravenous administration. In contrast, after nasal administration of loaded microparticles CPA was found in the CSF at concentrations ranging from high nM to microM values and up to two order of magnitude higher than those obtained at systemic level. CPA was also found in the olfactory bulb at concentrations around 0.1 ng/mg of tissue. These results can open new perspectives for the employment of CPA against brain damages following stroke.

Dry powder inhalers of gentamicin and leucine: formulation parameters, aerosol performance and in vitro toxicity on CuFi1 cells

The high hygroscopicity of gentamicin (G) as raw material hampers the production of respirable particles during aerosol generation and prevents its direct use as powder for inhalation in patients suffering from cystic fibrosis (CF). Therefore, this research aimed to design a new dry powder formulation of G studying dispersibility properties of an aminoacid, L-leucine (leu), and appropriate process conditions. Spray-dried powders were characterized as to water uptake, particle size distribution, morphology and stability, in correlation with process parameters. Aerodynamic properties were analyzed both by Single Stage Glass Impinger and Andersen Cascade Impactor. Moreover, the potential cytotoxicity on bronchial epithelial cells bearing a CFTR F508/F508 mutant genotype (CuFi1) were tested. Results indicated that leu may improve the aerosol performance of G-dried powders. The maximum fine particle fraction (FPF) of about 58.3% was obtained when water/isopropyl alcohol 7:3 system and 15-20% (w/w) of leu were used, compared to a FPF value of 13.4% for neat G-dried powders. The enhancement of aerosol efficiency was credited both to the improvement of the powder flowability, caused by the dispersibility enhancer (aminoacid), and to the modification of the particle surface due to the influence of the organic co-solvent on drying process. No significant degradation of the dry powder was observed up to 6 months of storage. Moreover, particle engineering did not affect either the cell viability or cell proliferation of CuFi1 over a 24 h period.

Particles and powders: Tools of innovation for non-invasive drug administration

The paper briefly illustrates several approaches applied in delivering particulate drugs as powders. Microparticulate drug powders are difficult to manipulate with respect to dosage form preparation, particularly when they have very small size as this leads to poor flow and packing properties. When the dosage form performance resides in the presence of individual intact drug particles, the particle characteristics have to be retained in their original state, i.e., not altered during manufacturing and/or within the dosage form. There are several examples of dry powder dosage forms intended for different administration routes whose performance is strictly dependent on particle characteristics. In addition, the preparation of the finished dosage form is dependent on powder properties. The paper addresses dry powder formulations with special focus on oral powders mainly for elderly people or children, nasal powders and inhalation dry powders. These dosage forms are very attractive for both researchers and companies. Their formulation requires deep investigation, mainly in order to define particle structure and performance. Indeed, this makes for a new breakthrough in pharmaceutics and may lead to innovative products.

Brain distribution of ribavirin after intranasal administration

Ribavirin has proved to be effective in vitro against several RNA viruses responsible for encephalitis in humans and animals. However, the in vivo efficacy towards the cerebral viral load seems to be limited by the blood-brain barrier. Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we investigated here the distribution of ribavirin in the central nervous system (CNS) after intranasal administration. We first tested in vitro ribavirin diffusion from an aqueous solution across a biological membrane, using Franz cells and rabbit nasal mucosa. About 35% of ribavirin permeated in 4 h across the mucosa, after reaching steady-state flux in less than 30 min. In the first in vivo experiment, ribavirin aqueous solution was administered intranasally to Sprague Dawley rats (10 mg/kg). Animals were sacrificed at 10, 20 or 30 min after administration to collect brain areas (cerebellum, olfactory bulb, cerebral cortex, basal ganglia and hippocampus) and biological fluids (cerebrospinal fluid and plasma). Ribavirin, quantified by LC-MS/MS spectrometry, was detected at each time point in all compartments with the highest concentration in olfactory bulb and decreasing in rostro-caudal direction. Two subsequent in vivo experiments compared the nasal route (ribavirin solution) with the intravenous one and the nasal administration of ribavirin solution with ribavirin powder (10 mg/kg). It was found that 20 min after administration, ribavirin concentration in olfactory bulb was similar after intravenous or nasal administration of the ribavirin solution, whereas the powder led to significantly higher levels. Ribavirin was also present in deeper compartments, such as basal ganglia and hippocampus. Even if the mechanisms involved in ribavirin nose-to-brain transport are not clear, these results suggest a rapid extracellular diffusive flux from the nasal epithelium to the olfactory bulb and different CNS areas.

Spray dried amikacin powder for inhalation in cystic fibrosis patients: A quality by design approach for product construction

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructed by spray-drying in order to produce powders of pure drug having high respirability and flowability. An experimental design was applied as a statistical tool for the characterization of amikacin spray drying process, through the establishment of mathematical relationships between six Critical Quality Attributes (CQAs) of the finished product and five Critical Process Parameters (CPPs). The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefit the CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusion of 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirable function solutions indicated that the favourable concentration of amikacin in the feed solution had to be kept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase in the drying temperature to the maximum value (160 °C) was required to maintain good powder respirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose (ED) without affecting the desirable fine particle dose (FPD) values. The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD, well above the regulatory and scientific references. The finished product contained only the active ingredient, which keeps low the mass to inhale for dose requirement.

Module assemblage technology for floating systems: In vitro flotation and in vivo gastro-retention

The aim of this research was to study, in vitro by resultant-weight measurement and in vivo by gamma-scintigraphy experiments in humans, the floatation behavior of systems obtained by modules assembled in void configuration. The assembled system technology allowed the manufacturing of a system characterized by the presence of an internal void space that provided an apparent density lower than water. The gastro-retention times of floating assembled systems were determined in comparison with non-floating systems having the same mass and composition. In vitro the floatation of the system started immediately after immersion in water and lasted for more than 5 h. The in vivo studies confirmed that the in vitro floating ability of void configuration was maintained also in the human stomach where the system stayed for periods of time ranging from 2.5 to 5.0 h, depending on the food regimen and the sex of the subject. Reiterate eating and drinking further prolonged the stomach residence time.