Banu S. Zolnik

Minireview: Nanoparticles and the Immune System

Today nanotechnology is finding growing applications in industry, biology, and medicine. The clear benefits of using nanosized products in various biological and medical applications are often challenged by concerns about the lack of adequate data regarding their toxicity. One area of interest involves the interactions between nanoparticles and the components of the immune system. Nanoparticles can be engineered to either avoid immune system recognition or specifically inhibit or enhance the immune responses. We review herein reported observations on nanoparticle-mediated immunostimulation and immunosuppression, focusing on possible theories regarding how manipulation of particle physicochemical properties can influence their interaction with immune cells to attain desirable immunomodulation and avoid undesirable immunotoxicity.

Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs

The promise of nanoscale material containing drug products to treat complex diseases is mounting. According to the literature, in addition to the liposomes, micelles, emulsions, there are novel drug delivery systems such as dendrimers and metal colloids at different stages of pre-clinical and clinical development. With the anticipation that more nanoscale material containing drug products will be submitted to the Food and Drug Administration (FDA) for approval in the future, FDA formed a Nanotechnology Task Force in 2006 to determine the critical regulatory issues regarding nanomaterials. As a result, all centers within the FDA are considering the development of guidance documents to address nanomaterial specific issues. It is well established in the literature that physico-chemical characterization (PCC) studies are crucial for nanomaterial containing drug products. However, this paper addresses the equally important topic of Absorption, Distribution, Metabolism and Excretion (ADME) studies for nanomaterials and provides examples of how physical properties affect biodistribution (i.e. the state of agglomeration, or aggregation, surface characteristics, stability of PEG). This paper also attempts to highlight some of the ADME study design issues related to nanomaterials such as the need for conducting biodistribution studies on each moiety of the multifunctional nanoparticles, dual labeled pharmacokinetic (PK) studies, and comparative PK studies on the free versus encapsulated drugs. In addition, this paper underlines the importance of long-term biodistribution and mass balance studies to understand the nanoparticle accumulation profile which may help to assess the safety and efficacy of the nanomaterial containing drug products. This review also lists some of the pre-clinical guidance documents that may help sponsors get started in developing data for inclusion in an initial investigational new drug application package for nanoscale material containing drug products.

In Vitro and In Vivo Performance of Different Sized Spray-Dried Crystalline Itraconazole

The objectives of the present study were to formulate and optimize different sized liquid and solid nanocrystalline formulations and evaluate their in vitro and in vivo performance to determine the effect of particle size on the oral bioavailability of solid nanocrystalline formulations. Nanotechnology is a promising approach to solve the problem of poor oral bioavailability of Biopharmaceutical Classification System class II/IV compounds. However, the highly exposed surface area of nanocrystals and hence their high Gibbs free energy poses a great challenge to nanocrystalline suspension stabilization. In this study, stabilization was achieved by preparing spray-dried nanocrystalline powders. A design of experiment approach was utilized to optimize the nanocrystalline suspensions/powders. On the basis of drug solubility studies, polyvinylpyrrolidone 40 KDa and sodium lauryl sulfate were selected for wet milling processing. Mannitol was chosen as the auxiliary excipient for spray-drying processing. In vitro dissolution utilizing a United States Pharmacopeia (USP) apparatus II showed superior release profiles for both liquid and nanocrystalline powder formulations compared with coarse-sized and unmilled formulations. Significantly, the oral bioavailability of nanocrystalline formulations with particle size of 280 nm was more than 20 times that of the unmilled formulation, whereas the nanocrystalline formulation with particle size of 750 nm showed only a 2.8 times increase in bioavailability compared with the unmilled formulation.

In situ fiber optic method for long-term in vitro release testing of microspheres.

The objective of this study was to develop an in vitro release method for relatively unstable drugs in long-term modified release (MR) formulations, such as microspheres. Drug stability in the release medium can complicate in vitro release testing of such delivery systems. To overcome this problem, a method has been developed where the model drug, cefazolin, and its degradation products are monitored simultaneously, using UV fiber optic probes, to account for cumulative drug release from poly(lactic-co-glycolic) acid (PLGA) microspheres. United States Pharmacopeia (USP) Apparatus 2 and 4 were used to evaluate cefazolin release throughout the 30-day study period. Cefazolin exhibits an isosbestic point (wavelength where the drug and the degradation products have the same absorbance). Cumulative drug release was compared at the isosbestic (288 nm) point and at the UV max (270 nm). Monitoring at the isosbestic point allowed determination of total drug release with approximately 100% release by day 25. Whereas, at the UV max approximately 61% release was detected by day 25 as a result of drug degradation. Problems were encountered using USP Apparatus 2 with the in situ UV fiber optic probes as a result of microsphere accumulation at and interference with the probe detection window.

Formulation and Performance of Danazol Nano-crystalline Suspensions and Spray Dried Powders

ABSTRACTPurposeThis study focuses on the formulation optimization, in vitro and in vivo performance of differently sized nano-crystalline liquid suspensions and spray-dried powders of a poorly soluble BCS class II compound i.e. Danazol.MethodsA DoE approach was utilized to optimize stabilizer concentration and formulate danazol (BCS class II) nano-crystalline suspensions and dry powders via wet milling followed by spray drying. Solubility studies were performed to select best stabilizers. Particle size, PXRD, contact angle measurement and in vitro dissolution were utilized in characterization of the liquid and spray-dried powder formulations.ResultsThe liquid nano-crystalline suspensions followed particle size-dependent dissolution rates i.e. faster dissolution for smaller crystals. The spray-dried nano-crystal powders did not show fast dissolution profiles compared to the liquid nano-crystalline suspension. The poor dissolution of the spray-dried powder correlated to its high LogP value (i.e. LogP 4.53) and poor wetting (or polar surface-area). In vivo bioavailability studies showed superior performance of the liquid nano-crystalline suspensions compared to other milled and un-milled formulations.ConclusionWet-milling and spray-drying optimization for danazol nano-crystalline suspension was performed. This study indicates that drug candidates with high LogP values and low polar surface area may not be suitable for formulation as dry nano-crystals.

Preparation of Drug Delivery Biodegradable PLGA Nanocomposites and Foams by Supercritical COsub2 Expanded Ring Opening Polymerization and by Rapid Expansion from CHCIF2 Supercritical Solutions

Abstract : The synthesis of poly(lactic-co-glycolic acid) (PLGA) by the ring opening copolymerization of D,L-lactide and glycolide was performed at 110 deg C to 130 deg C using Sn(Oct)2 as catalyst, 1,10-decanediol as initiator in a supercritical sc-CO2 expanded medium at pressures of up to 2,500 psi. Due to the limited monomer solubility in sc-CO2 at low temperatures (70 deg C), only Mn=2,500 is typically obtained. However, molecular weight increases with both temperature and sc-CO2 pressure. Thus, Mn = 13,000 (PDI = 1.28) was obtained at 110 deg C - 130 deg C even in the absence of fluorinated surfactants. Biodegradable drug delivery nanocomposites based on dexamthasone and poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA) were prepared by the rapid expansion of the corresponding supercritical CHCIF2 solutions (110 deg C, 200-300 bar) in air (RESS) and in toluene (RESOLV). The RESS process leads to a broad particle size distribution (100-500 nm) while the RESOLV generates a narrower distribution centered around 100 nm and is accompanied by the formation of a few large particles, most likely due to aggregation.