Controlling the in vitro release profiles for a system of haloperidol-loaded PLGA nanoparticles.

We have used a systematic methodology to tailor the in vitro drug release profiles for a system of PLGA/PLA nanoparticles encapsulating a hydrophobic drug, haloperidol. We applied our previously developed sonication and homogenization methods to produce haloperidol-loaded PLGA/PLA nanoparticles with 200-1000 nm diameters and 0.2-2.5% drug content. The three important properties affecting release behavior were identified as: polymer hydrophobicity, particle size and particle coating. Increasing the polymer hydrophobicity reduces the initial burst and extends the period of release. Increasing the particle size reduces the initial burst and increases the rate of release. It was also shown that coating the particles with chitosan significantly reduces the initial burst without affecting other parts of the release profile. Various combinations of the above three properties were used to achieve in vitro release of drug over a period of 8, 25 and >40 days, with initial burst <25% and a steady release rate over the entire period of release. Polymer molecular weight and particle drug content were inconsequential for drug release in this system. Experimental in vitro drug release data were fitted with available mathematical models in literature to establish that the mechanism of drug release is predominantly diffusion controlled. The average value of drug diffusivities for PLGA and PLA nanoparticles was calculated and its variation with particle size was established.

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits.

RATIONALE: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. OBJECTIVES: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. MATERIALS AND METHODS: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. RESULTS: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. CONCLUSIONS: The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.

Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content.

We have produced haloperidol-loaded PLGA/PLA nanoparticles by using two emulsification-solvent evaporation methods: homogenization and sonication. We have established how five independent processing parameters and two materials characteristics control the particle size and drug content. The interdependencies between processing and materials parameters and the subsequent nanoparticle characteristics are discussed in terms of underlying scientific principles that are broadly applicable to the production of drug-loaded polymer nanoparticles. This level of understanding should quicken the pace of designing protocols for making new drug-PLGA nanoparticles. It was determined that the particle size of haloperidol-loaded PLGA/PLA nanoparticles is effectively controlled by the amount of shear stress transferred from the energy source to the organic phase, which is strongly correlated to the following parameters: type of applied energy, aqueous phase volume, and polymer concentration in the organic solvent. The drug content of these nanoparticles is controlled by reducing the diffusion of the drug from the organic to the aqueous phase during the solvent evaporation stage of the preparation and by increasing the drug-polymer interactions. The following significantly inhibit drug diffusion: large particle size, higher polymer concentration and polymer molecular weight, and reducing the drug solubility in the aqueous phase by adjusting the pH. Specific drug-polymer interactions are engineered by optimizing the lactide to glycolide ratio (L:G ratio) and including specific polymer end groups. When optimized, the drug-loaded PLGA/PLA nanoparticles contain as much as 2.5% haloperidol.

Nanoscale Aggregation in Acid- and Ion-Containing Polymers.

In this review we summarize recent efforts in understanding nano-aggregation in acid- and ion-containing polymer systems. The acid and ionic groups have specific interactions that drive aggregation and alter polymer behavior at the nano-, micro-, and bulk length scales. Advancements in synthetic methods, characterization techniques, and computer simulations have enabled researchers to better understand the morphologies and dynamics, particularly at the nanoscale. This overview of recent advancements in nano-aggregated polymer systems highlights the current understanding of the field and presents promising directions for future investigations and new applications.

Effect of drug type on the degradation rate of PLGA matrices.

We compare the rate of drug release through the degradation of 50:50 polylactic-co-glycolic acid polymer pellets, for six different drugs: Thiothixene, Haloperidol, Hydrochlorothiozide, Corticosterone, Ibuprofen, and Aspirin. Despite using the same polymer matrix and drug loading (20% by weight), we find that the rate of polymer degradation and the drug release profile differ significantly between the drugs. We conclude that the design of biodegradable polymeric drug carriers with high drug loadings must account for the effect of the drug on the polymer degradation and drug release rate.

Surgically implantable long-term antipsychotic delivery systems for the treatment of schizophrenia.

Non-adherence with medication remains a major correctable cause for poor outcome in schizophrenia. We describe a surgically implantable preparation of haloperidol with the aim that patients will have superior outcomes with improved medication adherence from implants. In contrast to depot formulations, implantable pellets could last many months, providing symptomatic improvement for periods of time never before possible. Additionally, in the event of unacceptable side effects, implants could be removed, offering a degree of reversibility not available with depot formulations. A surgically-implantable formulation of haloperidol has been created using biodegradable polymers. Implants have been characterized for in-vitro kinetics, as well as in-vivo bioactivity in rodents. Haloperidol implants demonstrate steady release of drug for 5 months. Animals treated with haloperidol implants display increased striatal D2 receptor expression as well as increased apomorphine stimulated locomotion. Surgically-implantable formulations are a viable approach to provide long-term delivery of antipsychotic medications to patients with psychotic disorders.

Reversible stimuli-responsive nanostructures assembled from amphiphilic block copolymers.

We present a novel route to assemble perpendicular cylinders by converting an asymmetric diblock copolymer from poly(styrene-b-tert-butyl acrylate) (PS-b-PtBA) to poly(styrene-b-acrylic acid) (PS-b-PAA) using an autocatalytic reaction. Upon exposure of the films of PS-b-PAA to water, PAA cylinders constrained by the continuous, glassy PS phase protrude 10 nm above the surface and swell laterally to form mushroom caps, rendering the entire surface hydrophilic. Upon annealing, the original nanostructures re-form demonstrating reversibility of swelling. Because of their stimuli-responsive behavior, these nanoscale materials are excellent candidates for sensors and microfluidic applications.

Production of haloperidol-loaded PLGA nanoparticles for extended controlled drug release of haloperidol.

This study developed an emulsion-solvent evaporation method for producing haloperidol-loaded PLGA nanoparticles with up to 2% (wt/wt. of polymer) drug content, in vitro release duration of over 13 days and less than 20% burst release. The free haloperidol is removed from the nanoparticle suspension using a novel solid phase extraction technique. This leads to a more accurate determination of drug incorporation efficiency than the typical washing methods. It was discovered that PLGA end groups have a strong influence on haloperidol incorporation efficiency and its release from PLGA nanoparticles. The hydroxyl-terminated PLGA (uncapped) nanoparticles have a drug incorporation efficiency of more than 30% as compared to only 10% with methyl-terminated PLGA (capped) nanoparticles. The in vitro release profile of nanoparticles with uncapped PLGA has a longer release period and a lower initial burst as compared to capped PLGA. By varying other processing and materials parameters, the size, haloperidol incorporation and haloperidol release of the haloperidol-loaded PLGA nanoparticles were controlled.

Nanoparticle networks reduce the flammability of polymer nanocomposites.

Synthetic polymeric materials are rapidly replacing more traditional inorganic materials, such as metals, and natural polymeric materials, such as wood. As these synthetic materials are flammable, they require modifications to decrease their flammability through the addition of flame-retardant compounds. Environmental regulation has restricted the use of some halogenated flame-retardant additives, initiating a search for alternative flame-retardant additives. Nanoparticle fillers are highly attractive for this purpose, because they can simultaneously improve both the physical and flammability properties of the polymer nanocomposite. We show that carbon nanotubes can surpass nanoclays as effective flame-retardant additives if they form a jammed network structure in the polymer matrix, such that the material as a whole behaves rheologically like a gel. We find this kind of network formation for a variety of highly extended carbon-based nanoparticles: single- and multiwalled nanotubes, as well as carbon nanofibres.