
	Mesoporous silicon (PSi) has lately been the focus of interest as a potential new orally dosed drug carrier in a steeply increasing number of papers, where the strengths of PSi in such applications has been shown. Perhaps most importantly, drugs will remain in an amorphous form instead of crystallizing while loaded into the pores of PSi. The advantage of this is greatly increased solubility and dissolution rate of the drug. In the present work, we investigate the possibility of enhancing the drug carrier functionality of PSi micro- and nanoparticles by encapsulating the drug loaded PSi particles in a suitable polymer capsule structure by the method of collision of oppositely charged, electrosprayed droplets. Embed-ding the PSi particles in such polymer structure of micrometer scale will not only vastly im-prove the workability of PSi nanoparticles and the smallest of microparticles, but with suit-able material choices will also potentially enable targeted release of the drug loaded PSi par-ticles to a desired part of the gastrointestinal (GI) tract. This would help towards eliminating the intestinal first-pass effect of an orally dosed drug, which together with the already advan-tageous properties of PSi would result in an increased bioavailability of the drug. The gained advantage would be significant, since it has been estimated that more than 95% of new drug candidates suffer from poor pharmacokinetic properties, resulting in poor bioavailability.</p

Jarno Salonen

Jorma Roine

Matti Murtomaa

UTUPub

Proc. ESA Annual Meeting on Electrostatics 2010, Paper I2Electroencapsulation of Mesoporous Silicon Particles for Controlled Oral Drug Delivery Jorma Roine1,2,*, Matti Murtomaa1 and Jarno Salonen11Laboratory of Industrial Physics, Department of Physics and Astronomy University of Turku, FI-20014 Turku, Finland 2Graduate School of Materials Research, Turku, Finland *e-mail: jorma.roine@utu.fi Abstract—Mesoporous silicon (PSi) has lately been the focus of interest as a potential new orally dosed drug carrier in a steeply increasing number of papers, where the strengths of PSi in such applications has been shown. Perhaps most importantly, drugs will remain in an amorphous form instead of crystallizing while loaded into the pores of PSi. The advantage of this is greatly increased solubility and dissolution rate of the drug. In the present work, we investigate the possibility of enhancing the drug carrier functionality of PSi micro- and nanoparticles by encapsulating the drug loaded PSi particles in a suitable polymer capsule structure by the method of collision of oppositely charged, electrosprayed droplets. Embed-ding the PSi particles in such polymer structure of micrometer scale will not only vastly im-prove the workability of PSi nanoparticles and the smallest of microparticles, but with suit-able material choices will also potentially enable targeted release of the drug loaded PSi par-ticles to a desired part of the gastrointestinal (GI) tract. This would help towards eliminating the intestinal first-pass effect of an orally dosed drug, which together with the already advan-tageous properties of PSi would result in an increased bioavailability of the drug. The gained advantage would be significant, since it has been estimated that more than 95% of new drug candidates suffer from poor pharmacokinetic properties, resulting in poor bioavailability. I. INTRODUCTION Where possible, the oral route is often preferred for drug adm inistration due t o comfort of usage and a wel l cont rolled drug rel ease rate. However, m any pot ential drug mole-cules possess poor pharmacokinetic properties, such as poor solubility, dissolution of the drug in the intestinal lumen, poor permeation in the gast rointestinal (GI) t ract, or hi gh intestinal or hepatic first p ass metabolism. Hence the bioavailability of the drug will b e inadequate when administered orally, resulting in poor efficiency [1]-[4]. During the past decade, the strengths of mesoporous silicon  (PSi) as a potential drug carrier medium have been shown. Drugs confined to the pores of PSi will not form crys-tal lattices as easily as free drug molecules, but instead remain to some extent in its amor-Proc. ESA Annual Meeting on Electrostatics 2010 2 phous form. This has a significant effect on th e solubility and the dissolution rate of the drug in the intestinal lumen. The drug release rate is easily adjustable by changing pore properties. Drugs can be l oaded t o t he pores of PSi  part icles i n room temperature sol-vents, enabling the usage of temperature sensitive drugs such as p eptides and hormones [1], [5]-[7]. This presentation discusses the electroencapsulation of drug loaded PSi particles in or-der to enhance t he oral drug del ivery process. Such composite capsule particles possess the shielding properties of the selected capsule material and good workability of the drug due to the achieved greater size scale of the processed unit. After the capsule shell layer dissolution in the GI tract, the d rug release rate will b e co mpletely d etermined b y th e properties of the released drug loaded PSi particles. The structure potentially enables safe delivery and controlled release of drug l oaded PSi particles in a sel ected part  of t he GI tract when dosed orally [8], [9]. II. MATERIALS AND METHOD A. Electroencapsulation setup The PSi particles are encapsulated by the means of electrospraying. The used setup is shown schematically in Fig. 1. Two streams of micro-size droplets consisting of two mu-tually immiscible but wettable liquids, a shell liquid and a core l iquid, are electrosprayed in cone-jet mode from two nozzles kept at oppositely signed electric potentials. As a re-sult, the droplets in each str eam become charged in opposite signs and connect inside the electrospraying chamber due to Coulomb attraction. By adjusting the volume flow rate, applied voltage and inner diam eter of each nozzle according to the m aterial choices, the process can be st abilized whi le bri nging t he m ean dropl et si ze and charge per droplet ratio of the two electrosprays sufficiently close to each other to enable formation of com-plete m icrocapsules that are electrically neut ral. A cap sule is fo rmed as a sh ell liq uid droplet (of a lower surface tension than that of  the core liquid droplet s) envelope a core liquid droplet upon impact. The shel l sol vent t hen evaporat es, l eaving behi nd a sol id shell layer. Neu tralized capsules are easily co llectable as th ey fall to  the bottom of the chamber. The tem perature and pressure of the electrospraying cham ber can be adjusted to optimize the evaporation rate o f the used solvents so  that the evaporation will occur only after droplet com bination, but before the form ed capsules reach the bottom  of the electrospraying chamber. The setup consists of two conductive capillaries angled 30 degrees with respect to each other, which are run through an i nsulating air-tight lid into a heat able vacuum chamber (inner diameter 110 mm, inner height 840 mm). The electric potential of each capillary is oppositely signed and i ndependently adjustable. The vacuum chamber walls and ground plates suspended from the capillary constructs are grounded. The nozzle tips are change-able to enable the usage of different nozzle inner diameters (ranging from 0.10 m m up-ward). The position of the nozzle tip relative to the capillary construct lower (high volt-age) surface and to the freely m ovable ground plate are adjustable. Volum e flow rates through each nozzle are program mable, and sprayed particles can be collected in a dry Petri dish or in a gelatinizing path to enhance the capsule shell hardening, in case normal pressure i s used. A LED l ighting sy stem and t wo specially constructed windows (not Proc. ESA Annual Meeting on Electrostatics 2010 3 visible in Fig. 1.) are posi tioned below the lowest level of the ground plates’ freedom of action to provide a possibility to observe the electrospraying process visually.  Fig. 1. A schem atic diagram  of the used electrospra ying set-up. The illustrated electrospraying chamber is greatly flattened for clarity of the diagram.  B. Materials For the demonstrative capsules presented in  th is paper, Eudragit® E 100 pol ymer shell was used. The electrosprayed shell liquid wa s com posed of t he pol ymer di ssolved i n chloroform, with concentrations ranging from 200 to 300 mg/ml. Less than 10 mg/ml of talc was added to reduce adhesion o f cap sules to  th e b ottom o f th e p article co llection dish. The capsule core l iquid was a suspensi on of PSi  microparticles in glycerol, doped with about 0.03 M of NaI t o improve conductivity and l ess than 1 mg/ml of fl uorescein to facilitate detection of cap sule leakage. The PSi particles were therm ally carbonized, and sieved using a 25 µm sieve. Concentration of PSi in glycerol was 10 mg/ml. C. Microcapsule production by collision of two oppositely charged electrosprays The experimental microcapsules produced for t his paper were el ectrosprayed in normal air pressure. The interior of the electrospra ying chamber was held at a tem perature of 35 °C. The shell liquid was kept at 25 °C immediately before feeding the liquid through the electrospraying chamber lid, while the glycerol based core l iquid was heat ed to 42 °C. Proc. ESA Annual Meeting on Electrostatics 2010 4 The slightly increased tem perature decreases the viscosity of  glycerol considerably, and this together with the increased conductivity due to NaI-doping and reduced volume flow rate (discussed later) helped to stabilize the atomization process of glycerol and decrease the attained dropl et si ze. On t he ot her hand, excessi ve heat ing woul d have resul ted i n premature evaporation of chloroform from the atomized shell liquid droplets. For both nozzle system s, the distance between  the circular lower surface of the capil-lary construct and the suspended parallel circular ground plate, both 32 mm in diameter, was 9.0 m m. Diam eter of the center holes in the capillary construct and ground plate were 5.0 m m and 12.0 m m, respectively. The nozzl e emerged out of the center hole of the upper plate surface, with the tip lying close to the center of the volum e between the parallel plates. With t he used t emperatures and geom etry, nozzl e vol tages of -2.9 kV and +5.3 kV were used t o i nduce t he cone-jet  m odes fo r shel l and core l iquid at omization, respec-tively. Volume flow rates of 2.50 ml/h and 0.75 ml/h were used, respectively, to even out the attained mean droplet size. The inner diameter of the used nozzles affects the stability of the electrospraying proc-ess, and possibly contributes slightly the observed mean droplet size. While fine nozzles are preferable to achieve a st able process and the sm allest possible droplet size, the elec-trosprayed liquids and the used conditions dictate the minimum limit for the inner diame-ter of the nozzles used. Narrow capillaries w ill quickly get clogged by precipitations of the spray ed pol ymer sol utions i f t he evaporat ion rat e of the used solvent becomes too high because of raised tem perature of hi gh voltage. W hile using PSi suspensions, ag-glomerates of PSi p articles will q uickly form to  the capillaries if the maximum particle size is to o clo se to  th e in ner d iameter o f th e u sed cap illary. To o wide capillaries may cause problems in stability, as the volume of the induced Taylor cone increases within an intense, inhomogeneous electric field. In t he present work, nozzles of inner diameter of 0.41mm were used. Using the defined parameters, a stable encapsulation process was achieved and a sam-ple of capsules was collected at the bottom of the electrospraying chamber on a dry Petri dish. III. RESULTS AND DISCUSSION Encapsulation of PSi  part icles by  t he m ethod of dual nozzle electrospraying seems successful, based on vi sual observat ion. M icroscope i mages of som e of t he col lected capsules after ten days of storage in a temperature of 22 °C and relative humidity of 23 % are shown i n Fig. 2. The l argest PSi  part icles can be spot ted as dark areas through the partially invisible capsule shell layers. Th e capsules are easily de tachable from the col-lection dish, and can be m oved around without glycerol l eakages. Pressure durability measurements are necessary to investigate the feasibility of the capsules for tablet press-ing.   The produced capsul es are cl ose t o m onodisperse, wi th a m ean size of about 30-40 µm. The observed mean size is a good bal ance for fast  dissolution of t he capsule shel l layer in triggering conditions and, on the other hand, easy workability of the capsules. By earlier experiments we can conclude that using PSi particles smaller than 25 µm of mean size (e.g. nanopart icles) i n t he core l iquid does not  al ter t he st ructure of t he produced Proc. ESA Annual Meeting on Electrostatics 2010 5 capsules in any significant way. However, us age o f larg er th an 2 5 µm  PSi p articles quickly leads to structural problem s, as in su ch a scenario the PSi pa rticles can be larger than the mean size of an electrosprayed core liquid droplet.  Fig. 2. Microscope image of produced Eudragit® E 100-glycerol-Psi capsules. The next step in our work is manufacturing capsules of an enteric polymer shell, filled with drug loaded PSi micro- or nanopart icles to enable controlled drug release in the se-lected part of the GI tract. This will involve encapsulation expe riments using new sol-vents and base liquids for the capsule core suspension, followed by in vitro drug dissolu-tion measurements and tabletization experiments. Should the electroencapsulation m ethod prove useful for ultim ately helping im prove the bioavailability of poorly soluble drugs in  oral dosing, a scale-up in capsule produc-tion rate will be required for industrial applica tions. For scientific experim ents, the yield of a single dual nozzle electrospraying system is adequate.  IV. ACKNOWLEDGMENTS Evonik Industries is acknowledged for providing the Eudragit® E 100 polymer. Graduate School of Materials Research is acknowledged for financial support. REFERENCES [1] J. Salonen, A. M. Kaukonen, J. Hirvonen, V.-P. Lehto, “ Mesoporous Silicon in Drug Delivery  Applica-tions,” J. Pharm. Sci., vol. 97, pp. 632-653, Feb. 2008. [2] M. Koulu, J. Tuomisto, Farmakologia ja Toksikologia, 6th edition , Medicina Oy, Kuopio, Finland, 2001, pp. 81-84. [3] S. S. Davis, L. Illum, “Drug Delivery Systems for Challenging Molecules,” Int. J. Pharm., vol. 176, pp. 1-8, Dec. 1998. [4] D. J. Brayden, “Controlled Release Technologies for Drug Delivery,” Drug Disc. Today, vol. 8, pp. 976-978, Nov. 2003. Proc. ESA Annual Meeting on Electrostatics 2010 6 [5] J. Anglin, L. Cheng, W. R. Freem an, M. J. Sailor,  “Porous Silicon in Drug Delivery Devices and Materi-als,” Adv. Drug. Del. Rev., vol. 60, pp. 1266-1277, Aug. 2008. [6] P. Horcajada, A. Ramila, J. Perez-Pariente, M. Valle t-Regi, “Influence of Pore Size of MCM-41 Matrices on Drug Delivery Rate,” Micropor. Mesopor. Mater., vol. 68, pp. 105-109, Mar. 2004. [7] M. Vallet-Regi, “Ordered Mesoporous Materials in the Context of Dr ug Delivery Systems and Bone T is-sue Engineering,” Chem. Eur. J., vol. 12, pp. 5934-5943, Jul. 2006. [8] A. Jaworek, A. T. Sobczyk, “Electrospraying Route to Nanotechnology: An Overview,” J. Electrost., vol. 66, pp. 197-219, Mar. 2008. [9] A. Jaworek, “Micro- and Nanoparticle Production by Electrospraying,” Powder Tech., vol. 176, pp. 18-35 Jul. 2007. 

Electroencapsulation of Mesoporous Silicon Particles for Controlled Oral Drug Delivery

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Electroencapsulation of Mesoporous Silicon Particles for Controlled Oral Drug Delivery

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