Tuesday, May 26, 2009

Polymer Implants for Intratumoral Drug Delivery

Polymer Implants for Intratumoral Drug Delivery

A simplified scheme of drug transport from an implant centrally placed in a liver tumor. Transport of the drug into the tumor tissue is governed by the diffusion constant of drug in tumor (D tumor), and two simultaneous modes of elimination: metabolism to inactive forms in tumor cells (? tumor metabolism) or transport into nearby blood vessels which wash drug out of the region (? tumor perfusion). Once drug reaches the surrounding normal tissue, it continues to diffuse outward into liver tissue (D liver), where it has different rates of elimination by metabolism (? liver metabolism) or perfusion (? liver perfusion).

To address the need for minimally invasive treatment of unresectable tumors, we have developed intratumoral polymer implants designed to release a variety of chemotherapeutic agents for locoregional cancer therapy. These implants, also called polymer millirods, are designed to provide optimal drug release kinetics to improve drug delivery efficiency and antitumor efficacy in the treatment of unresectable tumors.

Modeling drug transport properties in different tissue environments provided theoretical insights into rational implant design, and several imaging techniques have been established to monitor the local drug concentrations surrounding these implants both ex vivo and in vivo. Preliminary antitumor efficacy and drug distribution studies in a rabbit liver tumor model showed that these implants can restrict tumor growth in small animal tumors (diameter <1>

In the future, new approaches, such as 3-D drug distribution modeling and the use of multiple drug-releasing implants, will be used to extend the efficacy of these implants in larger tumors that are similar to intractable human tumors.

Weinberg BD, Blanco E, Gao J. Polymer implants for intratumoral drug delivery and cancer therapy. J Pharm Sci. 2007;97(5):1681-1702. Correspondence to Jinming Gao, PhD, Simmons Comprehensive Cancer Center, Dallas, at

The Hexose Transporter and Improved Intestinal Membrane Permeability

Structures of the sugar-modified quinolones synthesized in this study and anti-malarial drugs.

Intestinal membrane permeability is an important factor that affects the bioavailability of drugs. Membrane transporters offer a useful strategy for improving membrane permeability, because essential nutrients are absorbed efficiently via specific transporters.

There are reports that intestinal hexose transporters might be used as a tool to improve permeability; however, there was no direct evidence that the transporter protein, sodium/glucose cotransporter 1 (SGLT1), is involved in the transport of hexose analogs. Accordingly, we examined specifically whether the intestinal membrane permeability of hexose analogs could be improved by utilizing SGLT1. We synthesized three hexose-quinoline derivatives and evaluated their interactions with SGLT1.

Among the three derivatives, the glucose-quinoline molecule exhibited an inhibitory effect on D-glucose uptake by both rat intestinal brush border membrane vesicles and Xenopus oocytes expressing SGLT1. In addition, using both an electro-physiological assay and direct measurement of the uptake of the compound, we observed significant uptake of the glucosequinoline derivative by Xenopus oocytes expressing SGLT1; the galactose-quinoline derivative did not show significant uptake via SGLT1. Thus, we demonstrated that SGLT1 could be used as a tool for the improvement of intestinal membrane permeability of drugs by modification to the glucose analogs.

Otake K, Suzuki H, Higashi R, et al. Improved intestinal membrane permeability of hexose-quinoline derivatives via the hexose transporter, SGLT1. J Pharm Sci. 2007;97(5):1821-1830. Correspondence to Ikumi Tamai, Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science,


Sumatriptan succinate transdermal delivery system with methyl cellulose primer.

We have successfully obtained sumatriptan transdermal systems with different polymer compositions: methyl cellulose (MC), polyvinylpyrrolidone (PVP), and a polyvinylpyrroli-done (PVP)-polyvinyl alcohol (PVA) mixture. The systems contained 1,2-propilenglycol (MC) or sorbitol as a plasticizer (PVP and PVP-PVA), methacrylate copolymer as an adhesive agent, and an occlusive liner. Azone (5% weight-to-weight ration) was incorporated into all the systems as a percutaneous enhancer. Transdermal systems are thin, transparent, and non-adhesive in a dry state.

We studied the permeation of sumatriptan succinate across pig ear skin using the prepared systems. The formulation with MC polymer produced a statistically significant increment with respect to the PVP and PVP-PVA formulations (p<0.05).>

Balaguer-Fernandez C, Femenia-Font A, Del Rio-Sancho S, et al. Sumatriptan succinate transdermal delivery systems for the treatment of migraine. J Pharm Sci. 2007;97(5):2102-2109. Correspondence to A. L�pez-Castellano, Departament de Farm�cia i Tecnologia Farmac�utica, Facultat de Farm�cia,

A) Transmission electron microscope (TEM) micrograph of lyophilized PBCA-Tp5-NP (30,000X), (B) TEM micrograph of PBCA-Tp5-NP colloid stored at room temperature for three months (30,000X); and, (C) TEM micrograph of lyophilized PBCA-Tp5-NP keeping at room temperature for three months (20,000X).

We loaded thymopentin (Tp5) into poly-butylcyanoacrylate (PBCA) nanoparticles (NP) in order to enhance the oral bioavailability of Tp5. We prepared PBCA-Tp5-NP using nanoprecipitation methods. We employed the dialyzing membrane method to examine the in vitro release of PBCA-Tp5-NP in PBS; Tp5 samples in the release medium were detected by HPLC. We conducted the cell proliferation test (3H-thymidine) to verify the PBCA-Tp5-NP bioactivity in vitro. We performed the pharmacodynamical studies on preimmunoinhibited rats and in flow cytometer.

The size and the entrapment efficiency of PBCATp5-NP were 178 � 39 nm and 92.21 � 1.08%, respectively. In vitro release data show that less than 60% Tp5 was released from lyophilized PBCA-Tp5-N, while 80% Tp5 was released from the colloidal PBCA-Tp5-NPs in 48 hours. The proliferation test showed that PBCA-Tp5-NP had a similar effect to that of Tp5. The in vivo data showed that oral PBCA-Tp5-NPs functioned in a similar fashion to intravenous Tp5. The oral bioavailability of Tp5 could be enhanced by PBCA nanoparticles. PBCA-Tp5-NP had the property of sustained release, and the efficacy of Tp5 was not changed after formulation.

He W, Jiang X, Zhang ZR. Preparation and evaluation of poly-butylcyanoacrylate nanoparticles for oral delivery of thymopentin. J Pharm Sci. 2007;97(6):2250-2259. Correspondence to Zhi-Rong Zhang, Education Ministry Key Laboratory of Drug Targeting and Drug Delivery Systems, National Key Laboratory of Biotherapy, West-China School of Pharmacy, Sichuan University,


Schematic diagram of an automated flow injection spectrophotometer: Pump A (reservoir of selenium [IV]); Pump B (reservoirs of 4-AAP); Pump C (reservoir of NEDA); Pump D (reservoir of acids dilute HCL). LR3 is the reaction coil.

We have developed an automated flow injection spectrophoto-metric method for the rapid, simple, selective, and sensitive determination of selenium (IV) from various pharmaceutical multi-vitamin and mineral formulations. The method was based on the oxidation of 4-aminoantipyrine (4-amino-1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazole-3-one; 4-AAP) by selenium in presence of acidic medium and the coupling with N-(naphthalen-1-yl)ethane-1,2-diamine dihydrochloride (NEDA) to give a violet color derivative. We used a Gilson P2 mini pulse peristaltic pump for introducing the selenium (IV), dilute HCl, 4-AAP, and NEDA solutions into a reaction coil by an automatic system. We measured the absorbance of the 4-AAP-NEDA color derivative at 563 nm after a reaction time of 3 minutes in stop flow of 4-AAP-NEDA.

Beer'S law was obeyed for selenium in the concentration range 0.05-5.0 �g mL-1, and we found Sandell'S sensitivity to be 0.00286 �g cm2. We compared the performance of the present method with the official method in terms of Student'S F- and t-tests and observed no significant difference. We found this method suitable for estimating the selenium (IV) concentration in various pharmaceutical multivitamin and mineral formulations such as tablets and capsules.

Kumar KS, Suvardhan K, Kang SH. Facile and sensitive determination of selenium (IV) in pharmaceutical formulations by flow injection spectrophotometry. J Pharm Sci. 2007;97(5):1927-1933. Correspondence to Seong Ho Kang, Department of Chemistry and Basic Science Research Institute, Chonbuk National University,

Monoclonal Antibody Aggregation During Freeze-Thawing

Effect of initial protein concentration and salt (KCl) on freeze-thawing-induced aggregation. Samples were frozen and thawed once. The symbols represent the mean (n=3) � standard deviation. In cases where error bars are not seen, the bars are smaller than the symbols.

Freeze-thawing is a potentially damaging stressor to which therapeutic proteins can be exposed, both deliberately during storage of bulk drug substance and accidentally because of mishandling of commercial product during shipping and/or storage. The primary route of degradation induced by freeze-thawing is protein aggregation.

We studied the effects of freeze-thawing on aggregation of an IgG2 monoclonal antibody, examining solution conditions (pH and the presence or absence of 150 mM KCl), protein concentration, cooling and warming rates, and container type and material. In addition, we determined the effects of pH and KCl on protein tertiary structure and thermal stability using second derivative UV spectroscopy.

In general, aggregation of the antibody during freeze-thawing increased with decreasing pH, which correlated well with Tm values. Aggregation was most prevalent at pH 3 and 4, with potential mechanisms involving both the formation of aggregation-prone conformational states and adsorption to and denaturation at various interfaces.

Although all parameters examined demonstrated some effect on the formation of soluble aggregates, the effect of container material was especially pronounced. Samples stressed in plastic or glass containers contained low amounts of aggregate. Storage in Teflon or commercial freezing containers, however, led to significantly higher levels of aggregate formation.

Kueltzo LA, Wang W, Randolph TW, et al. Effects of solution conditions, processing parameters, and container materials on aggregation of a monoclonal antibody during freeze-thawing. J Pharm Sci. 2007;97(5):1801-1812. Correspondence to John F. Carpenter, Center for Pharmaceutical Biotechnology,

ndrimer Drug Delivery System

The release of doxorubicin from doxorubicin-polyamidoamine complex in N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid at 37oC during a 24-hour period. Each point represents the mean of three independent experiments.

The ability of polyamidoamine (PAMAM) dendrimers to permeate across intestinal epithelial barriers suggests their potential as oral drug carriers. In this study, we developed a drug-PAMAM complex for oral administration. We studied the loading of a model drug-doxorubicin-into PAMAM, the cellular uptake, and the pharmacokinetics of the doxorubicin-PAMAM complex.

The results showed that the cellular uptake of doxorubicin in Caco-2 cells treated with the doxorubicin-PAMAM complex was increased significantly, with a corresponding increase in concentration and time, as compared to those treated with free doxorubicin. Additionally, the transport efficiency of the doxorubicin-PAMAM complex from the mucosal side to the serosal side was four to seven times higher than that of free doxorubicin in different segments of the small intestines of rats. The doxorubicin-PAMAM complex supplied a bioavailability more than 200-fold higher than that of free doxorubicin after oral administration. These results indicate that PAMAM dendrimer is a promising novel carrier with the ability to enhance the oral bioavailability of drugs, especially for the P-glycoprotein substrates.

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