Baclofen-loaded microspheres in gel suspensions for intrathecal drug delivery: in vitro and in vivo evaluation.

Severe spasticity is a very disabling disorder treated by continuous baclofen intrathecal infusion which unfortunately remains an expensive and uncomfortable treatment. In order to address these issues, new sustained release formulations designed for intrathecal baclofen delivery were sought with the aim of minimising the burst effect of baclofen which can lead to toxicity. Baclofen was encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres which were then dispersed in chitosan thermosensitive gels, Pluronic PF-127 gels, carboxymethylcellulose solutions or Ringer lactate solution. The release rate was assessed in vitro using continuous flow cells and in vivo after intrathecal injection in goats: baclofen was quantified in cerebrospinal fluid (CSF) and plasma, and the associated pharmacological effect was evaluated. The results showed that the burst effect was reduced by at least a factor of 2 in vitro, after microsphere dispersion in viscous media. In vivo, PF-127 gel was found to be the best vehicle to reduce the burst effect by a factor of 10 in CSF, and by a factor of 2 in plasma. The toxic effect of baclofen due to the burst effect was reduced by the dispersion in PF127 gels. Therapeutic levels of baclofen in CSF were maintained during at least 1 month.

Biopharmaceutics of intrathecal baclofen-loaded microparticles in a goat model.

The goal of this study was to develop a goat model allowing reliable pharmacokinetic (PK) studies of intrathecal baclofen (ITB) sustained release dosage forms using an implanted silicone catheter. ITB PK parameters (clearance, volume of distribution) following intrathecal bolus injection were determined for doses ranging from 100 to 560 microg and a comparison to human data was made. Baclofen-loaded microparticles were then implanted in the intrathecal space of goats and the resulting baclofen levels were determined during 28 days. Finally, PK parameters were used to predict cerebrospinal fluid (CSF) baclofen rates from in vitro release profiles of baclofen-loaded microspheres. The catheter was well tolerated and did not interfere with behavioral testings. Baclofen CSF clearance (mean = 8.59+/-2.43 ml/h) and volume of distribution (21.06+/-13.32 ml) were not significantly affected by the increase of the dose (p > 0.05). In vivo, the baclofen levels in CSF were stabilized at 200 microg/l after a period of 3 days. The predictive value of the in vitro release studies was good since the theoretical levels ranged between 128 and 257 microg/l. In conclusion, a large animal model was developed and allowed the biopharmaceutic evaluation of baclofen microparticles injected via intrathecal route.

Baclofen-loaded microspheres: preparation and efficacy testing in a new rabbit model.

Intrathecal baclofen is the reference treatment for severe spasticity. This drug has to be injected chronically in the intrathecal space by implanted pumps which are very expensive, uncomfortable and sometimes lead to side effects. Previous work has been performed by our group to assess the feasibility of encapsulating baclofen into poly(lactide-co-glycolide) (PLGA) microspheres and injecting these preparations in the intrathecal space of rabbits. The aims of the present study were to improve the encapsulation process for industrial application (scale-up), and to set up an animal model to assess the duration of effect of the new formulations. Modifications included the replacement of methylene chloride by a less toxic solvent, ethyl acetate, and the use of high molecular weight polymers to extend the release rate of the drug. The temperature and organic solvent extraction rate were fully controlled during the whole manufacturing process. All these modifications resulted in high quality microsphere batches with a CV inferior to 5% for encapsulation efficiency and drug loading. Encapsulation efficiency and release patterns were dependent on the drug payload and the polymer used. A formulation displaying a sustained release of baclofen over 174 days and a moderate burst effect of 16% in the first day in vitro was evaluated in a new reliable model of baclofen activity based on electrophysiological measurement of H-reflex in the rabbit. The activity of a very low dose of baclofen microspheres in vivo was sustained over 35 days. Furthermore, the preparation was well tolerated. These newly developed preparations are a very promising approach for enhancing the efficacy and comfort of patients undergoing spasticity treatment.

Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma: a randomized phase II trial.

OBJECTIVE: This study was a randomized, multicenter Phase II trial comparing the effect of perioperative implantation of 5-fluorouracil-releasing microspheres followed by early radiotherapy (Arm A) and early radiotherapy alone (Arm B) in patients with gross total resection of high-grade glioma. METHODS: Patients were randomized on clinical and radiological assumption of supratentorial high-grade glioma. All patients underwent surgery, and after resection and histological confirmation, patients randomized to Arm A received multiple injections of microsphere suspension (130 mg of 5-fluorouracil). Conventional fractionated radiotherapy (59.4 Gy) was initiated between the second and the seventh day after surgery for both arms. RESULTS: A total of 95 patients were randomized. Seventy-seven patients were treated and analyzed in intention to treat for efficacy and safety. Overall survival was 15.2 months in Arm A and 13.5 months in Arm B. In the subpopulation of patients with complete resection, overall survival was 15.2 months in Arm A versus 12.3 months in Arm B. However, these differences were not significant. Safety was acceptable with prophylactic high doses of corticosteroids. CONCLUSION: It may be hypothesized that the implantation of 5-fluorouracil-loaded microspheres in the wall of the cavity resection did increase the overall survival, but the present study was not designed and sufficiently powered to demonstrate this.

Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma.

BACKGROUND: The authors developed a new method of drug delivery into the brain using implantable, biodegradable microspheres. The strategy was evaluated initially to provide localized and sustained delivery of the radiosensitizer 5-fluorouracil (5-FU) after patients underwent surgical resection of malignant glioma. In this study, the microspheres were implanted by stereotaxy into deeply situated and inoperable brain tumors. METHODS: Ten patients with newly diagnosed, inoperable, malignant gliomas were included in the study, and 1 dose of 5-FU was studied (132 mg). After histologic confirmation, a suspension of poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres was implanted by stereotaxy into the tumor in one or several trajectories with one to seven deposits per trajectory. External beam radiation (59.4 grays) was started before postoperative Day 7. Patients were followed by clinical examination, computed tomography scanning, magnetic resonance imaging, and 5-FU assays in blood and cerebrospinal fluid (CSF). RESULTS: The number of trajectories was adapted to the size and shape of the tumor. Microsphere implantation was tolerated well, except in four patients who received a single trajectory and experienced a transitory worsening of preexisting neurologic symptoms. There were no episodes of edema or hematologic complications. 5-FU was detected in CSF and blood in some patients at very low concentrations. The median overall survival was 40 weeks, with 2 patients who had longer survival (71 weeks and 89 weeks, respectively). CONCLUSIONS: In this study, the authors demonstrated that biodegradable microspheres could be implanted by stereotaxy and were efficient systems for drug delivery into brain tumors. This method may have future applications in the treatment of patients other malignancies.

Release kinetics of 5-fluorouracil-loaded microspheres on an experimental rat glioma.

BACKGROUND: Biodegradable loaded systems are promising devices for controlled and sustained release of anticancer drugs to brain tumours. We investigated the influence of drug-release profiles of 5-fluorouracil-loaded microspheres designed for the treatment of malignant gliomas. MATERIALS AND METHODS: 2.5 mg 5-FU delivered by either fast. (1 formulation) or slow-(2 formulations) 5-FU release microspheres (MS) were tested in C6-glioma rat brains. Tumor response was assessed by T2-weighted MRI. RESULTS: All treated animals, whatever the release profile considered, displayed a comparable 50% increase in life span versus controls. Delays in C6-glioma development appeared to correspond to the in vitro release periods of MS. In terms of curative prospect, complete remission was only observed in 11% of 5-FU-treated animals (4 out of 38). CONCLUSION: Formulation was unambiguously implicated in the response observed after local delivery of 5-FU to glioma.

A new mathematical model quantifying drug release from bioerodible microparticles using Monte Carlo simulations.

PURPOSE: The major objectives of this study were to 1) develop a new mathematical model describing all phases of drug release from bioerodible microparticles; 2) evaluate the validity of the theory with experimental data; and 3) use the model to elucidate the release mechanisms in poly(lactide-co-glycolide acid)-based microspheres. METHODS; 5-Fluorouracil-loaded microparticles were prepared with an oil-in-water solvent extraction technique and characterized in vitro. Monte Carlo simulations and sets of partial differential equations were used to describe the occurring chemical reactions and physical mass transport phenomena during drug release. RESULTS: The new mathematical model considers drug dissolution, diffusion with nonconstant diffusivities and moving boundary conditions, polymer degradation/erosion, time-dependent system porosities, and the three-dimensional geometry of the devices. In contrast with previous theories, this model is able to describe the observed drug release kinetics accurately over the entire period of time, including 1) initial "burst" effects; 2) subsequent, approximately zero-order drug release phases; and 3) second rapid drug release phases. Important information, such as the evolution of the drug concentration profiles within the microparticles, can be calculated. CONCLUSIONS; A new, mechanistic mathematical model was developed that allows further insight into the release mechanisms in bioerodible microparticles.