Development of implantation substrates for the collection of radionuclides of medical interest produced via ISOL technique at INFN-LNL.

Accelerator-based techniques with electromagnetic mass separation are considered among the most innovative and promising strategies to produce non-conventional radionuclides for nuclear medicine. Such approach was successfully used at CERN, where the dedicated MEDICIS facility was built, and at TRIUMF, where the ISAC radioactive beam facility was used to produce unconventional α-emitters. In such framework, the Legnaro National Laboratories of the Italian Institute of Nuclear Physics (INFN-LNL) proposed the ISOLPHARM project (ISOL technique for radioPHARMaceuticals), which will exploit radionuclides producible with the SPES (Selective Production of Exotic Species) ISOL (Isotope Separation On-Line) facility to develop novel radiopharmaceuticals. The ISOL technique utilizes the irradiation with a primary beam of particles/nuclei of a production target where radionuclides are produced. A radioactive ion beam is subsequently extracted from the production target unit, and transported up to an analyzing magnet, where non-isobaric contaminants are filtered out. The so-obtained purified radioactive beam is dumped onto an implantation substrate, referred as collection target. Then, the desired nuclides can be chemically harvested from the collected isobars, and the isotopically pure atom collection can be employed to radiolabel high specific activity radiopharmaceuticals. Metallic deposition targets in the form of coated metal foils were mostly used at TRIUMF and CERN. At ISOLPHARM, a different approach is under investigation which foresees the use of soluble cold-pressed collection targets, possibly facilitating the chemical purification process of the collected radionuclides. In this study, the production and characterization of some of the ISOLPHARM collection targets is presented, in particular, soluble salts (NaCl and NaNO3) and organic materials widely used for pharmaceutical tablets production are considered. All such materials proved to be potentially suitable as collection targets, since solid samples were easily produced and resulted compatible with the vacuum conditions required for the ion implantation process. Furthermore, some of the selected substrates were used for proof-of-concept deposition tests with stable silver, to prove their suitability as ISOLPHARM deposition substrates for silver-111, a promising candidate for radiotherapy. Such tests highlighted possible scenarios useful for the development of new alternative materials, as the use of insoluble organic targets.

A preliminary study for the production of high specific activity radionuclides for nuclear medicine obtained with the isotope separation on line technique.

Radiopharmaceuticals represent a fundamental tool for nuclear medicine procedures, both for diagnostic and therapeutic purposes. The present work aims to explore the Isotope Separation On-Line (ISOL) technique for the production of carrier-free radionuclides for nuclear medicine at SPES, a nuclear physics facility under construction at INFN-LNL. Stable ion beams of strontium, yttrium and iodine were produced using the SPES test bench (Front-End) to simulate the production of 89Sr, 90Y, 125I and 131I and collected with good efficiency on suitable targets.

High shear mixer granulation using food grade binders with different thickening power.

Mixer agglomeration, in particular high shear wet granulation, is a unit operation typically used in the pharmaceutical industry to improve the flowability, the compressibility, the dosing accuracy during tableting or the content uniformity of a blend. Thanks to its advantages (production of spherical and dense granules, reduction of production time), this technique can be potentially successful also in the food industry as for example in the production of dietary supplements. In this work four thickening agents (povidone, maltodextrin, k-carrageenan and xanthan gum) have been tested to study their effects on the granule growth behavior and on some technologically relevant granule properties (size, shape, strength and flowability). Experiments highlighted the full feasibility of the process and the possibility of using these agents to get products with satisfactory technological properties. The dependence of product properties on the formulation variables (water and binder amount) has been analyzed according to a multivariate approach and a robust predictive tool for the granule size has been developed. Furthermore it was observed that a reduced amount of binding liquid (water) can be used in the presence of strongly thickening binders with a reduction up to 25%. This would decrease drying time and energy requirement and be beneficial especially in the food and food supply industry where products have generally lower added value than in the pharmaceutical one and reducing production costs is critical.

Effect of the surfactant on the availability of piroxicam as a poorly hydrosoluble drug from suppositories.

The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.

The effect of Na(2)CO(3), NaF and NH(4)OH on the stability and release behavior of sol-gel derived silica xerogels embedded with bioactive compounds.

Stability, defined as the reproducible behavior of a device upon its storage, is an important issue in pharmaceutical formulation. Silica xerogels obtained through the sol-gel route are relatively new as matrices for the controlled release of drugs. In some cases, it was observed that their behavior changes upon storage, so that they cannot always be defined as "stable". This occurs especially when gel processing is performed at mild temperatures, a procedure that may have to be used to prevent degradation of the embedded drug. This work investigated the use of inorganic catalysts as potential xerogel stability inducers when gel curing by heating is not applicable. Three compounds known to accelerate sol-gel polymerization, namely ammonia, sodium fluoride and sodium carbonate, were introduced during the polymerization of low-temperature processed inorganic and organically modified gels, and the effect of each compound on xerogel stability and drug release was monitored. The use of carbonate leads to formulations with good retention properties, as opposed to ammonia and NaF, which lead to poorly retentive xerogels in accordance with their known ability to increase porosity. Ammonia was shown to be a poor stability promoter independently of gel composition, as opposed to fluoride and carbonate, which both displayed stabilizing properties in a dose-dependent manner. No correlation was found between xerogel stability and drug release properties. An attempt was also made to correlate stability data with polymerization rates and wet gel syneresis time evolution with the purpose of identifying one or more synthesis parameters that could act as stability predictors for pre-formulation studies. No correlation was found between stability and syneresis data. A similar trend in the curve of gel time vs. catalyst concentration was observed for the two stabilizing catalysts, which was different for the non-stabilizing ammonia. It was concluded that the trend of this curve could potentially provide an indicator of catalyst stabilizing efficacy.

Effects of surfactant characteristics on drug availability from suppositories.

The addition of surfactants to suppository formulations is referred to in the scientific literature, but their effects on drug availability remain uncertain. Surfactants are reported to improve drug dispersion into hard fatty excipients, to increase the spreading of the melted suppository on the rectal mucosa leading to a greater contact surface, to reduce the viscosity of the molten mass and to reduce the pathway of drug particles to the interface. In the present study a systematic investigation based on tensiometric and rheological methods was carried out to evaluate the effects of nonionic surfactants with different HLBs (hydrophilic-lipophilic-balance) on drug availability and to clarify the possible mechanisms involved in the release process. The relationship between the melted suppositories and a membrane simulating the rectal barrier were investigated in the course of the in vitro release test by measuring their energy characteristics. At the same time, the potential influences of such interactions on drug release were investigated in suppositories formulated with different kinds and concentrations of surfactant additives. Drug availability was influenced not only by the interaction between the suppository and the rectal membrane but also by the interaction between surfactant, lipophilic excipient and suspended drug particles. Such interactions appear to greatly influence drug release from suppositories, which, in turn, is the main parameter determining drug availability.

In vitro methods for the evaluation of drug availability from suppositories: comparison between biological and artificial membranes.

Drug availability from suppositories is currently evaluated in vitro by means of a model consisting of a dialysis tube (porous membrane) or isolated biological membrane (animal rectum). We propose a new alternative in vitro method to determine drug availability from suppositories consisting of an artificial membrane soaked with n-octanol, coupled with a filter paper sheet soaked with phosphate buffer. This method provides for an integrated hydro-lipophilic simulation of the biological membrane, including the mucus layer adhering to the rectal mucosa. By simply using the porous membrane, the amount of drug released varied directly according to its solubility for formulations with lipophilic excipients. For formulations with hydrophilic excipients, drugs with low/intermediate solubility in water showed increased availability in comparison to lipophilic excipients. The in vitro rat rectum model provided overall results that were similar to those obtained with the porous membrane method, although the percentage values of AUC were lower. The new model of in vitro simulated absorption produced a degree of drug availability that was lower in comparison to both previous methods. However, the simulated model appeared to give a pattern of drug availability closer to that of the model of in vitro rat rectum. The new in vitro artificial model thus appears to be useful in suppositories preformulation studies, allowing for an estimate of drug availability and the choice of the most adequate excipient.

Influence of synthesis and processing conditions on the release behavior and stability of sol-gel derived silica xerogels embedded with bioactive compounds.

The influence of processing parameters and synthetic strategies in the properties of sol-gel derived silica matrices intended for the release of bioactive compounds was investigated. The time-evolution of the matrix properties during its aging at room temperature in the dry and wet forms was investigated by measuring some of its physical and drug retaining properties. The results indicate that long term gel aging in the wet form is fundamental for the obtainment of dry matrices that are stable upon storage, a fundamental requirement for any practical application. In the case of hybrid matrices obtained by replacing part of the tetraethoxysilane precursor with mono-methyl trimethoxysilane, the order of addition of the reaction component is also important in determining the properties of the final dry gel, probably by influencing the polymer structural properties. This parameter acts synergistically with the matrix composition in determining the release properties of xerogels embedded with bioactive compounds.

The "bubble point" for validation of drug release or simulated absorption tests for ointments.

The aim of the present study was to design a test to ascertain the behaviour and reliability of a membrane used in drug release and simulated absorption tests in order to arrive at useful indications for simulating topical as well as gastro-intestinal absorption. The membrane can be used in two different conditions: a) as a simple porous membrane placed between the ointment and an accepting liquid phase, generally water phase; b) as a membrane soaked in a lipophilic liquid phase to simulate the horny layer between the ointment and accepting water phase. In this study the "bubble point test" was used to test the integrity of the soaking film as well as the membrane, during and after drug release and simulated absorption tests with different types of ointment. In the case of a drug release test from an ointment, the bubble point test may determine the test conditions, that is the ointment applied to either a dry or hydrated membrane. Only the use of a previously hydrated membrane can guarantee constant conditions in the in vitro model. Use of a dry membrane may lead to infiltration of liquid components of the ointment base, thus altering the contact conditions between the two phases of the cutaneous compartment model (lipogel and W/O creams). The use of a hydrated membrane may also lead to interactions between the two phases of the compartment, with osmotic exchanges between the acceptor phase and ointment sample (hydrogel, PEG gel, O/W creams). The hydrated membrane is therefore reliable only for comparison between lipophilic base ointments. In a simulated absorption test, determination of the bubble point makes it possible to ascertain the physical integrity of the lipoid liquid film immobilized by capillary action in the inner microporous structure of the membrane during the test. This condition is essential to maintain a balance between the parameters regulating the diffusion process between the different compartments of the system. The use of a lipoid-soaked membrane makes it possible to avoid interactions between the ointment sample and an aqueous acceptor phase, such as hydrosoluble bases. Since the diffusion across a lipoid film immobilised within a porous membrane depends on the drug release rate from the ointment base, the test allows a contextual evaluation of the release kinetics as well as an indication of the drug absorption possibilities through an in vitro model of the cutaneous compartment.

Effect of drug solubility on in vitro availability rate from suppositories with polyethylene glycol excipients.

Factors involved in the availability mechanism of different drugs from suppositories with polyethylene glycol (PEG) excipients were studied using an in vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. Different from lipophilic excipients, the drug is released as a consequence of the progressive dissolution of PEG into the intrarectal aqueous phase. Drug concentration in this small intrarectal phase produces the gradient against the large volume of the plasmatic phase, which regulates the diffusion rate through the barrier. As with lipophilic excipients, drug solubility in water was found to be an important factor influencing suppository release rate. Nevertheless, PEG influenced in vitro drug availability considerably, by increasing both drug solubility and dissolution rate. The osmotic effect of PEG in the intrarectal compartment influenced the increase in volume of the aqueous phase. The results, compared with those obtained from suppositories with a lipophilic excipient, show a higher dissolution rate from PEG excipient, but a higher diffusion rate across the barrier did not always correspond. Drugs less soluble in water showed a greater availability from PEG suppositories. On the contrary the more soluble drugs were less available.

Effect of gelling conditions and mechanical treatment on drug availability from a lipogel.

This study has been conducted to determine whether the rheological differences depending on gelling and treatment conditions could have an influence on drug availability. Lipogels with constant composition were obtained by gelling olive oil with monodiglycerides at rest, under stirring, and milled after gelling. The considerable differences in rheological characteristics produced significant differences on in vitro drug release tests, whereas a lesser influence was observed on in vitro simulated absorption test. The rheological differences appeared not to influence in vivo drug availability. Also, rheological differences owing to the concentration of the gelling agent showed no significant influence on in vivo availability.

Effect of drug solubility on the in vitro availability rate from suppositories with lipophilic excipients.

The factors involved in mechanisms of availability of different drugs from suppositories with lipophilic excipients were studied by using an in vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. The solubility in water of drugs was found to be the fundamental factor influencing the release rate from suppositories. In fact, following the melting of the suppository at body temperature the drug particles can migrate to the interface with the small volume of rectal secretion where they dissolve. Drug molecules can so diffuse until they come into contact with the rectal barrier through which the drug is absorbed. Drug concentration in the intrarectal aqueous phase produces the gradient against the large volume of the plasma phase. This gradient regulates the diffusion rate through the barrier. A drug with a low water solubility saturates the intrarectal phase at low concentration hindering the subsequent dissolution of the drug particles remaining in the melted excipient. This fact maintains the viscosity of the melted suppository at a ligh level, which slows the migration of the particles. On the other hand, a drug with high water solubility quickly leaves the excipient, producing a high concentration in the intrarectal phase which supports a high diffusion rate across the barrier. The results obtained indicate that drugs with low solubility in water result in low availability, while drugs with good solubility can give an intense and rapid drug supply for a rapid and intense therapeutic response with the dose administered almost completely utilised.

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

Possibilities of conveying a cationic drug in Carbomer hydrogels.

A drug with cationic characteristics such as procaine can be conveyed in a Carbomer hydrogel in two different ways: (i) in the form of salt in solution in the aqueous phase, and (ii) in the base form salified with the same polymer. Introduction of the drug into the hydrogel with different concentrations of polymer produced, in both cases, a reduction in viscosity in relation to drug concentration. The gels with procaine salified with the polymer showed greater viscosity. The drug release rate, in general, diminished with the increase in polymer concentration. Nevertheless, when this concentration was maintained, there was no variation in release rate when the viscosity produced as a consequence of drug concentration was changed. Gels with procaine salified with the carboxyvinylic polymer had a faster release rate than those with procaine in the hydrochloride form dissolved in the aqueous phase. These results have also been confirmed by a simulated absorption test.

Kinetics of release and simulated absorption of methyl nicotinate from different ointment formulations: in vitro-in vivo correlations.

The influence of the vehicle on release and simulated absorption of methyl nicotinate (MN) was evaluated using in vitro systems in order to find a correlation with data previously obtained in vivo. Simulation of drug absorption was carried out using a porous polymer membrane soaked with lipophilic phases such as n-dodecanol and isopropyl myristate. Ointment composition influenced differently both release and absorption of MN independent of drug concentration. The degree of skin redness induced by MN was found to be significantly correlated to in vitro simulated drug absorption but not to in vitro drug release.

Influence of ointment formulation on skin erythema induced by nicotinate esters.

The influence of the chemico-physical nature of the vehicle on the skin penetration of topically applied drugs was evaluated in vivo. Five different ointment formulations containing nicotinate esters as model penetrants were tested on human skin. The degree of drug penetration allowed by the various formulations was revealed by means of the erythema induced by the drug, detected by a X-Rite tristimulus reflection colorimeter. The excipient influenced the penetration of the nicotinate esters used to various extents. The concentrations of the tested drugs were found to be an important factor influencing drug penetration and persistence of erythema.

Technological testing of calcium carbonate tablets for use in the treatment of renal osteodystrophy.

Samples of calcium carbonate tablets produced by different manufacturers were subjected to various tests in order to evaluate tablet quality parameters, mostly indicative for calcium availability. Indications about tablet suitability for treatment of renal osteodystrophy in uremic patients were also tested. The disintegration test turned out to be the most useful in evaluating calcium carbonate availability from tablets. Samples from several manufacturers varied in their behaviour to disaggregation. The availability of calcium dissolved in gastric fluid and the extent of phosphorus binding appeared to depend on disintegration behaviour.

Effects of two different kinds of silicium dioxide on release of drugs from suppositories: benzydamine hydrochloride.

Silica gel confirmed its function as viscosity agent for lipophylic excipients for suppositories, ensuring homogeneous drug distribution in the suppository mass. The influence on release rate of a water-soluble drug (benzydamine hydrochloride) was clearly different according to type of silica gel. With Aerosil 200 (hydrophylic), after a progressive decrease in release rate at the lowest concentrations, an increase was observed at the highest concentrations, until it reached that of the suppositories without silica gel. With Aerosil R972, release rate decreased progressively with increased silica gel concentration, until release was practically inhibited even at low concentrations.