Intranasal delivery of antipsychotic drugs.

Antipsychotic drugs are used to treat psychotic disorders that afflict millions globally and cause tremendous emotional, economic and healthcare burdens. However, the potential of intranasal delivery to improve brain-specific targeting remains unrealized. In this article, we review the mechanisms and methods used for brain targeting via the intranasal (IN) route as well as the potential advantages of improving this type of delivery. We extensively review experimental studies relevant to intranasal delivery of therapeutic agents for the treatment of psychosis and mental illnesses. We also review clinical studies in which intranasal delivery of peptides, like oxytocin (7 studies) and desmopressin (1), were used as an adjuvant to antipsychotic treatment with promising results. Experimental animal studies (17) investigating intranasal delivery of mainstream antipsychotic drugs have revealed successful targeting to the brain as suggested by pharmacokinetic parameters and behavioral effects. To improve delivery to the brain, nanotechnology-based carriers like nanoparticles and nanoemulsions have been used in several studies. However, human studies assessing intranasal delivery of mainstream antipsychotic drugs are lacking, and the potential toxicity of nanoformulations used in animal studies has not been explored. A brief discussion of future directions anticipates that if limitations of low aqueous solubility of antipsychotic drugs can be overcome and non-toxic formulations used, IN delivery (particularly targeting specific tissues within the brain) will gain more importance moving forward given the inherent benefits of IN delivery in comparison to other methods.

Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain.

Memory antibody response from antigen loaded polymer particles and the effect of antigen release kinetics.

Memory antibody response is the hallmark of long lasting immunity. In this study, we report the generation of memory antibody response while immunizing with single dose of polymer particle entrapped antigens. Immunization with admixture of alum and polylactide (PLA) polymer particles (2-8 microm) entrapping antigens not only elicited long lasting primary antibody response but also very high levels of memory antibody titer upon re-exposure to very small amount of soluble antigen. In the case of tetanus toxoid (TT), the memory antibody titers from PLA particle based immunization were almost four times higher than that achieved from two doses of alum adsorbed antigen and sustained at a higher level for a longer period of time. Memory antibody response was detected even after challenging the animals after 18 months of primary immunization. Similar enhanced memory antibody response was also observed in the case of immunization with PLA particle entrapping diphtheria toxoid (DT). Memory antibody response generated from polymeric formulations was highly antigen specific. Polymer particles with different release profile of antigen were used as a model system to evaluate the role of antigen on immunological memory. The results suggest that slow and continuous release of antigen from polymer particles plays a critical role in eliciting improved memory antibody response from single point immunization.

Role of alum in improving the immunogenicity of biodegradable polymer particle entrapped antigens.

This study was aimed at understanding the role of alum in improving the immunogenicity of biodegradable polymer particle entrapped antigens. Presence of alum formed a fine network around PLA particles holding them together and promoted attachment of higher number of particles on macrophage surface for a considerable period of time. Use of alum lowered the burst release of the entrapped antigen from particles and thereafter also reduced the cumulative release of antigen from particles. Apart from this, PLA microparticles alone induced macrophages to release TNF-alpha similar to that induced by alum. However admixture of PLA particles and alum enhanced the secretion of TNF-alpha from 876pg/ml at 6h to 3500pg/ml at 24h which was higher than that induced by alum adsorbed TT. Immunization with admixture of antigen loaded polylactide (PLA) microparticles (2-8microm) and alum improved the antibody titers almost twice than that achieved from particle alone in experimental animals. Single point immunization with particle entrapped antigens and alum also elicited antibody titers comparable to two doses of alum adsorbed tetanus toxoid (TT) or diphtheria toxoid (DT). Our results suggest that presence of alum acts in multiple ways to improve the antibody titers of polymer particles entrapped antigens. Such co-operative adjuvant action of alum and polymer particles can be exploited to improve the immunogenicity of other antigens.

Making polymeric micro- and nanoparticles of complex shapes.

Polymeric micro- and nanoparticles play a central role in varied applications such as drug delivery, medical imaging, and advanced materials, as well as in fundamental studies in fields such as microfluidics and nanotechnology. Functional behavior of polymeric particles in these fields is strongly influenced by their shape. However, the availability of precisely shaped polymeric particles has been a major bottleneck in understanding and capitalizing on the role of shape in particle function. Here we report a method that directly addresses this need. Our method uses routine laboratory chemicals and equipment to make particles with >20 distinct shapes and characteristic features ranging in size from 60 nm to 30 microm. This method offers independent control over important particle properties such as size and shape, which is crucial to the development of nonspherical particles both as tools and products for a variety of fields.

Particle shape: a new design parameter for micro- and nanoscale drug delivery carriers.

Encapsulation of therapeutic agents in polymer particles has been successfully used in the development of new drug carriers. A number of design parameters that govern the functional behavior of carriers, including the choice of polymer, particle size and surface chemistry, have been tuned to optimize their performance in vivo. However, particle shape, which may also have a strong impact on carrier performance, has not been thoroughly investigated. This is perhaps due to the limited availability of techniques to produce non-spherical polymer particles. In recent years, a number of reports have emerged to directly address this bottleneck and initial studies have indeed confirmed that particle shape can significantly impact the performance of polymer drug carriers. This article provides a review of this field with respect to methods of particle preparation and the role of particle shape in drug delivery.

Influences of excipients on in vitro release and in vivo performance of tetanus toxoid loaded polymer particles.

Protein instability during microencapsulation has been one of the major hurdles of biodegradable polymer particles-based vaccine delivery systems. In the present work, effect of serum albumin, sucrose and sodium bicarbonate on surface morphology, entrapment efficiency, in vitro release and in vivo performance tetanus toxoid (TT) loaded PLA particles were investigated. Use of serum albumin as well as high concentration of protein antigen ( approximately 60mg/ml) helped in protecting the immunoreactivity of the antigen during primary emulsification step of particle formulation. Incorporation of sucrose in the internal aqueous phase led to the reduction in encapsulation efficiency of TT from 43.8+/-4.3% to 27.3+/-3.6% in PLA particles and resulted with formation of particles having irregular surface characteristics. Addition of sodium bicarbonate along with sucrose during primary emulsion led to slight improvement in encapsulation efficiency of TT (34.3+/-3.2%) but affected the in vivo performance in terms of serum anti-TT antibody titers from single point immunization. Restoration of osmotic balance by adding equivalent amount of sucrose in external aqueous phase helped in preventing multiple emulsion instability and subsequently improved the encapsulation efficiency of TT to 63.1+/-4.2%. Maximum entrapment efficiency of TT up to 69.2+/-5.1% was achieved when serum albumin, sucrose and sodium bicarbonate were used in internal aqueous phase and sucrose was used in the external aqueous phase. Polymer particles entrapping tetanus toxoid along with optimal stabilizers showed burst release of immunoreactive antigen (>40% in early period) and elicited high and sustained anti-TT antibody titers from single point intramuscular immunization. Anti-TT antibody titers were further enhanced upon immunization of admixture of PLA particles and alum. Choice and use of stabilizers during particle formulation thus need careful considerations not only to protect the immunoreactivity of the antigen, but also to produce stable, uniform particles for optimal in vivo performances.

Immunogenicity and lower dose requirement of polymer entrapped tetanus toxoid co-administered with alum.

Low adjuvanticity of microparticles based vaccine formulation necessitates the use of alum along with particles to elicit improved antibody titers from single point immunization. It was observed that antibody response from immunization with admixture of alum and polymer entrapped antigen was dependent on particle size, amount of antigen released during burst phase and dose of microencapsulated antigen. In the animals immunized with polymer entrapped tetanus toxoid (TT) very large particles (50-150 microm) did not elicited high antibody titers where as microparticles in the range 2-8 microm exhibited remarkable improvement in the antibody response. Very small size particles (<2 microm) were also not as effective as 2-8 microm size particles for generation of antibody response. Presence of alum improved the immune response by adsorbing the burst released antigen from the particle surfaces. Role of alum in potentiation of immune response from polymer entrapped TT was highly significant at lower dose regimes. Polymer entrapped TT as little as 0.1 Lf when immunized along with alum generated antibody responses superior to those elicited by 10 Lf soluble antigen. Immunization with admixture of particles and alum generated two to three times higher antibody titer than that observed from immunization with similar single doses of alum adsorbed TT. Single point immunization of admixture of particles entrapped TT and alum generated sustained long lasting antibody responses comparable to two divided doses of alum-adsorbed antigen. Superiority of single dose polymeric formulation in comparison to two divided doses of alum adsorbed TT was more evident at lower doses of TT immunization. This reflected the profound synergistic effect of both the adjuvants at lower doses. Affinity of antibodies generated from single point immunization was comparable to that achieved with two doses of alum adsorbed TT immunization. Particle alone elicited more of IgG2a type antibody where as immunization with admixture of alum and particles improved the overall antibody response and more of Th2 type response.

Influence of particle size, antigen load, dose and additional adjuvant on the immune response from antigen loaded PLA microparticles.

Polylactide (PLA) polymer particles entrapping tetanus toxoid (TT) were evaluated in terms of particle size, antigen load, dose and additional adjuvant for achieving high and sustained anti-TT antibody titer from single point intramuscular immunization. Admixture of polymer entrapped TT and alum improved the immune response in comparison to particle-based immunization. High and long lasting antibody titer was achieved upon immunization with 2-8 microm size particles. Microparticles within the size range 50-150 microm elicited very low serum antibody response. Immunization with very small particles (<2 microm) and with intermediate size range particles (10-70 microm) elicited comparable antibody response from single point immunization but lower in comparison to that achieved while immunizing with 2-8 microm size particles. Potentiation of antibody response on immunization of admixture of microparticles and alum was also dependent on particle size. These results indicate the need of optimal particle sizes in micron ranges for improved humoral response from single point immunization. Increasing antigen load on polymer particles was found to have positive influence on generation of antibody titers from particle based immunization. Maximum peak antibody titer of approximately 300 microg/mL was achieved on day 50 upon immunization with particles having highest load of antigen (94 microg/mg of polymer). Increase in dose of polymer entrapped antigen resulted in concomitant increase in peak antibody titers indicating the importance of antigen stability, particle size and load on generating reproducible immune response. Optimization of particle size, antigen load, dose and use of additional adjuvant resulted in high and sustained anti-TT antibody titers over a period of more than 250 days from single point immunization. Serum anti-TT antibody titers from single point immunization of admixrure of PLA particles and alum was comparable with immunization from two divided doses of alum adsorbed TT.

Improved immune response from biodegradable polymer particles entrapping tetanus toxoid by use of different immunization protocol and adjuvants.

Poly lactide-co-glycolide (PLGA) and polylactide (PLA) particles entrapping immunoreactive tetanus toxoid (TT) were prepared using the solvent evaporation method. The effect of different formulation parameters such as polymer hydrophobicity, particle size and use of additional adjuvants on the generation of immune responses in experimental animals was evaluated. Immune responses from hydrophobic polymer particles were better than those from hydrophilic polymer. Immunization with physical mixtures of different size particles resulted in further improvement in anti-TT antibody titers in Wistar rats. Physical mixture of nano and microparticles resulted in early as well as high antibody titers in experimental animals. Immunization with polymer particles encapsulating stabilized TT elicited anti-TT antibody titers, which persisted for more than 5 months and were higher than those obtained with saline TT. However, antibody responses generated by single point immunization of either particles or physical mixture of particles were lower than the conventional two doses of alum-adsorbed TT. Immunization with nanoparticles along with alum resulted in very high and early immune response: high anti-TT antibody titers were detected as early as 15 days post-immunization. Use of a squalene emulsion along with the particles during immunization enhanced the level of anti-TT antibody titers considerably. Single point immunization with admixtures of PLA microparticles and alum resulted in antibody response very close to that achieved by two injections of alum-adsorbed TT; the antibody titers were more than 50 microg/ml over a period of 6 months. These results indicated that the judicious choice of polymer and particles size, protecting the immunoreactivity of the entrapped antigen and the appropriate design of immunization protocol along with suitable adjuvant can lead to the generation of long lasting immune response from single dose vaccine formulation using polymer particles.