Tumor targeted nanoparticles for cancer therapy

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O-9Development of modified release multiple unit dosage forms

I. Antal a, N. Kallai a, N. Angyal a,b, E. Balogh a, J. Dredan a,A. Devay c, I. Klebovich a

a Semmelweis University Department, of Pharmaceutics, Hungaryb Sanofi Aventis, Chinoin Co. Ltd., Hungaryc University of Pecs, Institute of Pharmaceutical Technology andBiopharmacy, Hungary

E-mail address: antist@hogyes.sote.hu (I. Antal).

Objective: The basic concept of multiple-unit systems is thatthe dose of the active ingredient is released by individual sub-units, and the functionality of the entire dose depends onthe quality of the subunits. The objective of this study wasto investigate the effect of formulation factors in the develop-ment of two types of multiple unit dosage forms such as pelletsand minitablets. Modified release from the dosage forms wasensured by coating as well as applying matrix formers in theformulation.

Method: Sodium diclofenac, ibuprofen, and theophyllinewere used as model drugs for pellets and minitablets. Drugswere layered on neutral pellets based on saccharose, micro-crystalline cellulose, and isomalt. Minitablets with 3 mmdiameter were prepared with direct compression. Pellets andminitablet cores were coated using fluid-bed bottom spraymethod. The dissolution from the dosage forms was inves-tigated in three different media (pH = 1, pH = 4.5, pH = 6.8) instandard dissolution test apparatus. Morphology and struc-ture of the multiparticulates were analyzed with imageanalysis, near-infrared spectroscopy and pharmacopoeialmethods considering physical properties. Wetting character-istics were studied using Sigma KSV 70 contact angle meter.

Result: Beside type and amount of coating polymers, thedissolution profile from pellets was influenced by the type ofneutral spheres, too. Modulation of the dissolution rate wasrelated to wetting and water adsorption characteristics of themultiparticulates. In the case of minitablets, the desired pro-longed dissolution profile was ensured applying one part ofthe film-forming polymer as matrix former in the minitabletcores. The drug release profiles were evaluated with modeldependent methods to collect information on subunits andpredict the resultant dissolution profile mathematically.

Conclusion: The critical formulation factors offer severalapproaches ensuring modified release for coated pellets andminitablets. Mathematical modelling allows to construct an

doi:10.1016/j.ejps.2007.05.020

a l s c i e n c e s 3 2 S ( 2 0 0 7 ) S6–S21

O-10Tumor targeted nanoparticles for cancer therapy

E. Bilensoy

Hacettepe University, Faculty of Pharmacy, Department of Pharma-ceutical Technology, 06100 Ankara, Turkey

E-mail address: eremino@hacettepe.edu.tr.

Cancer chemotherapy is associated with various challengessuch as; toxicity and severe side effects arising from param-eters like formulation factors (solubilizers), pharmacokineticvariability of anticancer agents and non-selective cytotoxicity,poor drug solubility and stability, drug resistance and lack oforal chemotherapy.

Nanoparticles are submicron colloidal carriers with matrixor membrane type structure generally made out of polymersor polysaccharides of different nature. Nanoparticles possessthe advantage of accumulation in tumor tissues due to theleaky and abnormal vasculature of the cancer site resultingfrom the small particle size of these carrier systems (less than400 nm). As well as the enhanced permeation through tumorvasculature, a molecule entering the tumor site is not regularlydrained due to the lack of a functioning lymphatic drainage.This is the so-called EPR (enhanced permeation and retention)effect and the major passive targeting pathway for nanopar-ticles. Different nanoparticles in the form of nanospheres ornanocapsules have been studied using various polymers andmacromolecules. Passive targeting, however, is limited to RESuptake after injection of nanoparticles which limits the effec-tive delivery of anticancer drug-loaded nanoparticles to cancercells.

For this reason, many active targeting strategies have beenapplied to nanoparticles including size reduction and sur-face modification with hydrophilic polymers such as PEGor PEO or specific antigens. Surface coating or modificationwith hydrophilic polymers help repel proteins and pre-vent opsonization allowing prolonged circulation of injectednanoparticles which result in higher accumulation tumor site.

To achieve specific targeting to the tumor, some antigenswith specific affinity to substrates overexpressed on tumorcell surface such as folate or transferrin can be grafted to thepolymer which forms the nanoparticle to improve the activetargeting to tumor. Active targeting can also be achieved byusing pH-sensitive or thermosensitive polymers adjusted toreact to slightly acidic tumor pH or hyperthermia induced dur-ing chemotherapy. Magnetic fields may be used to orient thenanoparticles towards the magnetic field created at tumor site.Nanoparticles are also reported to overcome multidrug resis-tance acquired during chemotherapy. They are also used forimaging and diagnosis of tumors due to their affinity to cancer

doi:10.1016/j.ejps.2007.05.021