Organic solvents as vehicles for precipitating liquid embolics: a comparative angiotoxicity study with superselective injections of swine rete mirabile.

BACKGROUND AND PURPOSE: The organic solvent dimethyl-sulfoxide (DMSO), as a commonly used vehicle for nonadhesive liquid embolics, is not devoid of local angiotoxic effects. We compared microvascular toxicities of superselective infusions of DMSO with potentially more compatible solvents in swine rete mirabile. METHODS: Fourteen swine underwent angiography for superselective catheterization of 28 arteries of the rete while electrocardiography and intra-arterial pressure were continuously monitored. The investigated solvents were DMSO, dimethyl isosorbide (DMI), ethyl lactate, glycofurol 75, N-methyl pyrrolidone (NMP), and solketal. Control infusion of saline ruled out catheter induced vasospasm in all cases. Each artery of the rete was infused only once with 0.8 mL of one of the solvents over 60 seconds. Acute angiographic and hemodynamic consequences were evaluated. Blood samples were assessed for signs of intravascular hemolysis. Brains and retia were harvested for gross and histopathologic investigation. RESULTS: On the basis of the angiographic data, DMSO induced the most pronounced vasospasm with the longest recovery period of all solvents investigated. Ethyl lactate, glycofurol 75, and solketal elicited less severe vasospasms and accordingly resolved much more quickly. DMI and NMP induced only minimal vasospasms with comparably short duration. No solvent caused significant hemodynamic alterations or hemolysis. Gross inspection of brains showed no abnormalities, whereas histopathologic examination revealed mostly nonspecific findings. One rete exposed to solketal displayed possible causal histotoxic changes. CONCLUSION: DMI and NMP produced far less vasospasm than DMSO. No changes in hemodynamic or hemolytic parameters and no histopathologic findings were observed with infusion of these solvents.

Embolization of experimental wide-necked aneurysms with iodine-containing polyvinyl alcohol solubilized in a low-angiotoxicity solvent.

BACKGROUND AND PURPOSE: To evaluate the ready-to-use iodine-containing polyvinyl alcohol (I-PVA) dissolved in the low angiotoxic solvent N-methyl pyrrolidone (NMP) for embolization of porcine wide-necked aneurysms. METHODS: Fourteen broad-based carotid sidewall aneurysms were surgically constructed in 7 swine. I-PVA (40%) in NMP was injected under temporary balloon occlusion bridging the aneurysm neck. After 4 weeks, follow-up angiography, multisection CT angiography (MSCTA), and 3T MR imaging including MR angiography (MRA) sequences were performed. Afterward, harvested aneurysms were investigated histopathologically. RESULTS: The liquid embolic was well visible under fluoroscopy and displayed a favorable precipitation pattern, allowing for controlled polymer delivery. Ten aneurysms (71%) were initially completely occluded, whereas in 1 aneurysm, a minimal polymer leakage was observed. The other 4 aneurysms (29%) were almost completely occluded. One animal suffered a lethal rebleeding from the anastomosis after uneventful embolization. Aneurysms embolized with I-PVA could be discriminated well from the parent artery without beam-hardening artifacts on MSCTA, and no susceptibility artifacts were encountered on MR imaging. Histologic examination revealed all aneurysms covered with a membrane of fibroblasts and an endothelial cell layer while a moderate intraaneurysmal inflammatory response to the polymer was observed. CONCLUSION: I-PVA dissolved in NMP has proved its effectiveness for the embolization of experimental wide-necked aneurysms. This precipitating liquid embolic offers several interesting features in that it needs no preparation before use and no radiopaque admixtures, the latter allowing for artifact-free evaluation of treated aneurysms with MSCTA and MRA. Moreover, it uses NMP as a solvent, which has only a low angiotoxicity.

Radiopaque polymeric materials for medical applications. Current aspects of biomaterial research.

The aim of this review is to give an overview and some insight into different radiopaque polymeric materials that are currently used as medical implants or inserts. The advantages and limitations of each radiopaque polymeric material are summarized. The main method used to make medical implants radiologically visible is based on blending polymers with conventional radiopaque agents, blends which usually are a physical mixture of acrylic derivatives and inorganic salts. Other methods reported involve either the formation of single-phase radiopaque polymer salt complexes somehow preventing the release of the radiopacifying element by entrapment of the complex in a crosslinked network, or radiopaque polymerized monomers characterized by a radiopacifying element associated with the monomer unit prior to polymerization. In the near future, research will certainly concentrate on biocompatible radiopaque polymers with covalently bound opaque elements leading to stable polymers with properties equivalent to the nonopaque, parent polymer.

Modelling of sustained release of water-soluble drugs from porous, hydrophobic polymers.

The release behaviour of water-soluble drugs from hydrophobic, porous polymeric matrices is complicated by the dissolution of the drug in the water-filled pores under quiescent conditions. Mathematical models are presented for drug release above and below the solubility limit of the drug in the dissolution medium, for constant void fraction (porosity). Experimental studies of KCl release from the porous ethyl cellulose tablets in water at 37 degrees C are explained in terms of dissolution-controlled and diffusion-controlled steps of the release mechanism.

In vitro assessment of new embolic liquids prepared from preformed polymers and water-miscible solvents for aneurysm treatment.

Treatment of cerebral aneurysms by embolic liquids has been proposed as an alternative strategy to coil or balloon techniques. In order to assess the feasibility of this approach, a general screening of preformed polymers dissolved in biocompatible, water-miscible solvents has been carried out. The solubilizing capacity of the solvents has been evaluated by the solubility parameters approach. The viscosity of the solutions has been determined and the precipitation characteristics of the embolic liquids have been investigated in phosphate buffer solution pH 7.4 at 37 degrees C to mimic physiological conditions. The radiopaque agent bismuth (III) oxide was added to solutions having appropriate precipitation characteristics and the angiographic assessment, in an in vitro aneurysm model, were consistent with the precipitation properties and confirmed that only hard and coherent masses allowed satisfactory embolization. However, the solubilizing prediction using the calculation of the solubility parameters was only partially successful owing to the highly hydrophilic functional groups of the chosen solvents. This failing justifies the experimental screening that was carried out. This study pointed out that the frequently used solvent dimethyl sulfoxide could be replaced by more biocompatible solvents offering the possibility of using other preformed polymers. In conclusion, nine solutions of the selected polymer-solvent combinations could be used as embolic liquids for the treatment of cerebral aneurysms with respect to their satisfactory precipitation properties and viscosity.

Long-term histopathological study of new polypeptidic biomaterials.

The long-term histopathological evaluation of a new class of synthetic polypeptides, the poly(tert-butyloxycarbonylmethyl glutamates), as implantable drug delivery systems is addressed. This evaluation was performed in rat muscles over one year. The histological analysis included the measurement of many parameters, such as the type and thickness of the collagen capsule. The influence of the presence of progesterone, the selected active drug, could also be monitored over time.

Iodine-containing cellulose mixed esters as radiopaque polymers for direct embolization of cerebral aneurysms and arteriovenous malformations.

The present study deals with the synthesis and characterization of radiopaque polymers which could, when solubilized in an appropriate water-miscible solvent, be useful embolic materials for the treatment of cerebral aneurysms and arteriovenous malformations. For this purpose cellulose (both microcrystalline and powdered) and partially substituted cellulose acetate (two different viscosity grades) were selected as starting materials to prepare iodine-containing polymers through various synthetic routes. The materials obtained were characterized by IR and NMR spectroscopy, molecular weight, iodine content, radiopacity and solubility in selected injectable organic solvents. The embolic liquids were evaluated for their precipitation behavior in a phosphate buffer solution (pH 7.4) mimicking physiological conditions using an in vitro aneurysm model. A sheep model was also used to assess in vivo the radiopacity and precipitation properties of a highly concentrated solution of a cellulose acetate 2,3,4-triiodobenzoate mixed ester. All materials with 4-iodo- and 2,3,5-triiodobenzoyl groups gave sufficient radiopacity to be regarded as possible embolization materials, whereas iododeoxycellulose and iododeoxycellulose acetate were not radiopaque because of their low iodine content. Esters synthesized using cellulose as starting material were not soluble in the selected organic solvents due to the presence of many residual hydroxyl groups, but could be used for other biomedical applications where insoluble radiopaque materials are used. In contrast, solubility of the materials as well as satisfactory precipitation properties were ensured using cellulose acetate as the starting material. In conclusion, cellulose acetate iodobenzoate mixed esters dissolved in diglyme or dimethyl isosorbide (dimethyl sulfoxide is probably less appropriate because of its toxicity and hemolytic properties) could be useful embolic liquids for the treatment of cerebral aneurysms or arteriovenous malformations.

Influence of the microencapsulation method and peptide loading on poly(lactic acid) and poly(lactic-co-glycolic acid) degradation during in vitro testing.

Three methods were used, namely spray drying, w/o/w solvent evaporation and the aerosol solvent extraction system (ASES), for the preparation of microparticles having the same size range, to study the influence of the preparation method on polymer degradation in vitro (PBS, 37 degrees C, one month). The following five polymers of the biodegradable poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) group were selected: L-PLA, MW 81 200; DL-PLGA 75:25, MW 64-300; DL-PLGA 50:50 MW 52 600; DL-PLGA 50:50 MW 14 500, AND DL-PLGA 50:50, MW 3400, to prepare drug-free and drug-loaded microparticles. Tetracosactide was selected as model peptide. When microparticles were prepared by solvent evaporation, the mean diameter and, more markedly, the drug encapsulation efficiency tended to decrease when decreasing the molecular weight and increasing the proportion of glycolic acid in the polymer. In contrast, no direct influence of the polymer nature on these parameters was observed in spray dried microparticles. Polymer degradation was heterogenous in L-PLA and DL-PLGA 75:25 microparticles and was not influenced by the presence of the drug at a nominal loading of 1% (w/w), when prepared by the three methods (note that with ASES, only L-PLA could be used for microencapsulation). In batches made of DL-PLGA 50:50 MW 52 600, the degradation rate decreased slightly when increasing the drug loading. Only in the case of DL-PLGA 50:50 MW 14 500, the polymer degradation rate for spray dried microparticles was higher compared to that for microparticles prepared by the w/o/w solvent evaporation method. Generally, the degradation rates of the different microparticles followed the expected order: L-PLA

Modified drug release from inert matrix tablets prepared from formulations of identical composition but different organisations.

This paper develops for the first time a concept to modify the release rate of a fixed formulation by changing only the organisation of the mix used to prepare the tablets (ordered mixing). To estimate the influence of the organisation of binary mixes, several mixes of ethylcellulose and niflumic acid of the same composition but different organisation were compacted. The tablet surfaces were examined by energy dispersive X-ray microanalysis before the release experiments. Finally, the cross-sections of the remaining matrix were examined by scanning electronic microscopy. Excipient-excipient and excipient-drug interactions are the major factors influencing the drug release rate from the tablets. In the case of interacting materials, the initial release behaviour depends on the tablet surface presented to the dissolution media. The dissolution properties of the tablets are governed by the percolating material. When the inert excipient is percolating, the release rate increases linearly with the excipient/drug size ratio, whereas when the drug is the only material percolating through the system, its release rate is independent of the size ratio. When both materials are percolating through the system, the release rate is independent of the component particle sizes.

Oral bioavailability of a poorly water soluble HIV-1 protease inhibitor incorporated into pH-sensitive particles: effect of the particle size and nutritional state.

The new chemical entity CGP 70726, a very poorly water-soluble HIV-1 protease inhibitor, was incorporated into pH-sensitive nanoparticles and microparticles made of the poly(methacrylic acid-co-ethylacrylate) copolymer Eudragit((R)) L100-55. The particles were characterized in terms of morphology, size distribution, drug loading, production yield and dispersion state of the drug inside the polymeric matrices. Aqueous dispersions of the particles were administered orally to Beagle dogs against a suspension of free drug (control formulation) all at a dose of 100 mg/kg. Oral administration was conducted in the absence and presence of food. Plasma concentrations and pharmacokinetic parameters were determined within 8 h post-dose. While no measurable absorption of the drug resulted after administration of the control formulation, substantial systemic exposure to the compound was obtained with both kinds of pH-sensitive formulations. The selective release of CGP 70726 in a highly dispersed/amorphous state and creation of high concentrations close to its absorption site was thought to account for this positive result. The largest areas under the plasma concentration-time curve (AUC) were obtained in the fasted state, with slightly better performance of the microparticles over the nanoparticles, in both nutritional states (7.8+/-1.5 versus 5.8+/-0. 8 micromol.h/l in the fasted state; 4.4+/-1.4 versus 2.00+/-0.5 micromol.h/l in the fed state). With these results, the potential of pH-sensitive particles for the oral delivery of HIV-1 protease inhibitors with low water solubility was confirmed.

An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D,L-lactic acid) nanoparticles by human monocytes.

We demonstrate here that polyethylene glycol (PEG) 6,000 protects biodegradable poly(D,L-lactic acid) nanoparticles (PLA NP) from extensive uptake by monocytes in plasma. These results are in agreement with those previously obtained with PEG 20,000 which reduced the uptake of PLA NP by human monocytes in phosphate buffered saline and plasma, and prolonged the NP circulation time in vivo. The coating efficiency of PEG 6,000 and 20,000 was substantially decreased in serum. The difference between the uptake of plain and coated NP clearly reappeared for PEG 20,000-coated NP in heat inactivated serum and in IgG-depleted serum. We suggest that typical plasma proteins, heat labile serum proteins (e.g. complement components) and IgG are involved in the opsonization of plain and coated PLA NP. Other proteins previously found to adsorb onto these NP, namely albumin and apolipoprotein E, did not appear to directly influence the uptake process.

A case study of preservation of semi-solid preparations using the European Pharmacopoeia test: comparative efficacy of antimicrobial agents in zinc gelatin.

The present study was undertaken with the aim of finding an alternative preservative system to methyl parahydroxybenzoate in zinc gelatin, which was described in the monographs of the Swiss Pharmacopoeia (until Ph. Helv. 8) and in previous editions of the German Pharmacopoeia (until DAB 7). This antimicrobial agent has now been withdrawn in the DAB, because of its potential allergy risks. As for the USP and DAB-DDR zinc gelatin preparations, they have always been devoid of any preservative agent, probably relying on the mild antimicrobial activity of zinc. A literature survey did not reveal if such an aqueous preparation containing the water-insoluble zinc oxide shows efficacious antimicrobial activity by itself. Thus, a comparative evaluation of differently preserved zinc gelatin preparations was performed using a test for the efficacy of antimicrobial preservation that has been modified with regard to the European Pharmacopoeia (EP) test to take into account the solid state of the preparations and the bactericidal effect of the zinc. Three zinc gelatin preparations were checked, either: (i), without any agent; or (ii), with 0.1% methyl parahydroxybenzoate; or (iii), with 0.5% phenoxyethanol, a broad-spectrum antimicrobial agent almost devoid of allergy risks. The three preparations behave quite differently, in particular with respect to fungi. All three preparations passed the modified EP test as far as bacteria are concerned. Even zinc gelatin without preservative is very effective, not only because of the mild antimicrobial activity of zinc (the soluble fraction of zinc oxide in the liquid phase of zinc gelatin was determined to be 13 microg/ml), but most probably because of the low water activity of the preparation (measured as around 0.81), as shown by the absence of growth of a zinc-resistant strain of Pseudomonas aeruginosa. Zinc gelatin preserved with methyl parahydroxybenzoate has a weak, although satisfactory, activity against Staphylococcus aureus. Regarding fungi, gelatin without an antimicrobial agent and that preserved with methyl parahydroxybenzoate meet the requirements for efficacy against Candida albicans, but are only bacteriostatic against Aspergillus niger. As for zinc gelatin preserved with phenoxyethanol, it displays the best activity against C. albicans and, above all, appears to be the only formulation exhibiting fungicidal activity against A. niger. It is therefore recommended to preserve zinc gelatin with this antimicrobial agent, as recently adopted in Supplement 2000 of the Swiss Pharmacopoeia.

Cellular uptake of PEO surface-modified nanoparticles: evaluation of nanoparticles made of PLA:PEO diblock and triblock copolymers.

Nanoparticles with either physically adsorbed or covalently bound poly(ethylene oxide) (PEO) coatings were produced from various combinations of poly(lactic acid) (PLA) and diblock or triblock copolymers of PLA and PEO. The particles were produced by the salting-out process and purified by the cross-flow filtration technique. The amount of PEO at the nanoparticle surface, as well as the residual amount of emulsifier poly(vinyl alcohol) were assessed, with a good correlation with expected values. Stability of the nanoparticulate suspensions was studied at 4 degrees C and after freezing under various conditions for up to 6 months. The nanoparticle redispersibility after storage was related to the thermal behavior of the PEO coatings. The in vitro cellular uptake of the different types of nanoparticles was compared by flow cytometry after incubation with human monocytes in serum and in plasma. The influence of the PEO molecular weight and surface density on the particle uptake was especially marked for the diblock and triblock copolymer formulations, with a decrease in uptake of up to 65% with one of the diblock copolymer formulations. Nanoparticles made of triblock copolymer with short PEO chains at their surface in the postulated "loop conformation" proved to be as resistant to cellular uptake as nanoparticles made of diblock copolymers with PEO chains in the "brush conformation".

Osmotic water transport through cellulose acetate membranes produced from a latex system.

The advisability of a progressive curtailment of organic solvent film coating offers an incentive to develop latex systems. Here, the use of aqueous colloidal dispersions of cellulose acetate, plasticized with water-soluble additives, is proposed as an alternative way to obtain cellulose acetate membranes either by casting or spraying. The osmotic water permeability of both kinds of films was measured, as well as their loss of leachable materials and degree of swelling in a saturated solution of potassium chloride. The permeabilities varied over a wide range depending on the physicochemical properties of the plasticizer and its initial concentration in the latex, and on the conditions for coating (temperature, rate of spraying, and drying duration). High boiling point plasticizers gave more permeable films. Films prepared by casting were found to be sensitive to their sodium dodecyl sulfate content.

Pharmacokinetics of a novel HIV-1 protease inhibitor incorporated into biodegradable or enteric nanoparticles following intravenous and oral administration to mice.

CGP 57813 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease. This lipophilic compound was successfully entrapped into poly(D,L-lactic acid) (PLA) and pH sensitive methacrylic acid copolymers nanoparticle. The intravenous administration to mice of PLA nanoparticles loaded with CGP 57813 resulted in a 2-fold increase of the area under the plasma concentration-time curve, compared to a control solution. An increase in the elimination half-life (from 13 to 61 min) and in the apparent volume of distribution (1.7-3.6 L/kg) was observed for the nanoparticle incorporated compound vs control solution. Following oral administration, only nanoparticles made of the methacrylic acid copolymer soluble at low pH provided sufficient plasma levels of CGP 57813. In vitro, these nanoparticles dissolved completely within 5 min at pH 5.8. PLA nanoparticles, which are insoluble in the gastrointestinal tract, did not provide significant plasma concentrations of CGP 57813. From these observations, one can conclude that the passage of intact PLA nanoparticles across the gastrointestinal mucosa appears to be very low.

Mechanisms of potassium chloride release from compressed, hydrophilic, polymeric matrices: effect of entrapped air.

The release of potassium chloride from hydroxypropyl methylcellulose matrices was investigated for tablets prepared with several different compression forces. It was determined that the release kinetics for these systems deviates significantly from the classical t1/2 dependence. This behavior was attributed to air entrapped in the matrix during preparation. Removal of the air prior to release restored the traditional t1/2 behavior.

Pseudolatex preparation using a novel emulsion-diffusion process involving direct displacement of partially water-miscible solvents by distillation.

Pseudolatexes were obtained by a new process based on an emulsification-diffusion technique involving partially water-miscible solvents. The preparation method consisted of emulsifying an organic solution of polymer (saturated with water) in an aqueous solution of a stabilizing agent (saturated with solvent) using conventional stirrers, followed by direct solvent distillation. The technique relies on the rapid displacement of the solvent from the internal into the external phase which thereby provokes polymer aggregation. Nanoparticle formation is believed to occur because rapid solvent diffusion produces regions of local supersaturation near the interface, and nanoparticles are formed due to the ensuing interfacial phase transformations and polymer aggregation that occur in these interfacial domains. Using this method, it was possible to prepare pseudolatexes of biodegradable and non-biodegradable polymers such as poly(D,L-lactic acid) and poly(epsilon-caprolactone), Eudragit E, cellulose acetate phthalate, cellulose acetate trimellitate using ethyl acetate or 2-butanone as partially water-miscible solvents and poly(vinyl alcohol) or poloxamer 407 as stabilizing agent. A transition from nano- to microparticles was observed at high polymer concentrations. At concentrations above 30% w/v of Eudragit E in ethyl acetate or cellulose acetate phthalate in 2-butanone only microparticles were obtained. This behaviour was attributed to decreased transport of polymer molecules into the aqueous phase.

Mechanically strong films produced from cellulose acetate latexes.

Mechanically strong films, comparable with those obtained from organic solutions, can be produced from cellulose acetate latexes, a new type of dispersion, both by casting and spraying. The prerequisite conditions for high strength, which include choice of water-soluble plasticizers possessing some degree of volatility, are discussed.

The expanded Hansen approach to solubility parameters. Paracetamol and citric acid in individual solvents.

In this study two solubility-parameter models have been compared using as dependent variables the logarithm of the mole fraction solubility, lnX2e, and ln(alpha)/U (originally used in the extended Hansen method), where alpha is the activity coefficient and U is a function of the molar volume of the solute and the volume fraction of the solvent. The results show for the first time the proton-donor and -acceptor hydrogen-bonding capacities of paracetamol, as measured by the acidic and basic partial-solubility parameters. The influence of solvents on the differential scanning calorimetry (DSC) pattern of the solid phases was also studied in relation to the solubility models tested. Citric acid was chosen as a test substance because of its high acidity and its proton donor capacity to form hydrogen bonds with basic solvents. The partial acidic and basic solubility parameters obtained from multiple regression were consistent with this property, validating the model chosen. The results show that the more direct lnX2e variable was more suitable for fitting both models, and the four-parameter model seemed better for describing the interactions between solvent and solute.

Methodology for a better evaluation of the relation between mechanical strength of solids and polymorphic form.

In order to evaluate the role played by polymorphism in the mechanical strength of solid dosage forms (e.g. compressed tablets) and minimize the influence of other factors (such as compaction force, porosity, particle size, and possibly crystal habit), a melted disc technology was developed. With this technique, tablet-shaped discs of zero porosity were prepared by melting powder and subsequent crystallization in the desired modifications. Taking phenobarbitone as a model drug, different methods were used to get discs of forms I, II and III and the amorphous form. Mechanical properties of the discs were assessed, primarily through their bending strength. The Vickers hardness number was also determined for some specimen discs and monocrystals. Results showed that the amorphous form and form III of phenobarbitone gave the toughest discs and would therefore the most suitable materials to manufacture coherent tablets. Moreover, the various preparation methods used resulted in discs of different internal structures. Both crystal size and crystal habit significantly affected the physical properties of the tested materials.