Encapsulation of poorly water-soluble drugs into yeast glucan particles by spray drying: Improvement of dispersion and dissolution properties

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F19%3A43919292" target="_blank" >RIV/60461373:22340/19:43919292 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Encapsulation of poorly water-soluble drugs into yeast glucan particles by spray drying: Improvement of dispersion and dissolution properties

Popis výsledku v původním jazyce

Yeasts are single-celled microorganisms belonging to the fungus kindom. They are more commonly known for their use in food products and, in the biomedical field, they have been of great interest for drug delivery. The so-called yeast glucan particles (GP) are obtained after removing all the internal organelles and cell wall componets, other than β-glucans, from Saccharomyces cerevisiae (baker’s yeast). The result are hollow and porous shells which are suitable for drug encapsulation. Since they are obtained from microorganisms, they activate pattern recognition receptors of host immune cells, triggering immune responses [1]. For this reason, most of the studies have been focused on the use of GP for the encapsulation and macrophage-targeted delivery of drugs. Peptides [2], liposomes [3], siRNA [4], DNA [5], among others water-soluble payloads, have been successfully encapsulated into GP for macrophage-targeted delivery. Publications on the encapsulation of poorly-water soluble drugs, on the other hand, are scarse, constituting an area of study yet to explore. Low water-soluble resveratrol, for instance, was encapsulated in living yeast [6], and curcumin, also insoluble in water, was loaded in 1,3-β-glucan isolated from mushrooms [7]. Given that GP are mainly composed of amorphous polysaccharides (&gt;85% β-glucans), they are suitable candidate materials for the development of amorphous solid dispersions (ASDs). To the best of our knowledge, no studies are found either regarding the encapsulation of low-water soluble drugs in beta-glucan particles by spray drying, or regarding the use of beta-glucan particles for the amorphization of low water-soluble drugs. In this work, low water-soluble drug models, such as ibuprofen (IBU) and curcumin (CC), were loading into GP using spray drying. Microparticles with different IBU-to-GP mass ratios were prepared and characterized. Samples with low IBU content (20% or less) exhibited amorphous state, but crystallinity peaks appeared and increased with drug content. The presence of IBU crystals outside the GP was observed in the case of the samples with higher IBU/GP mass ratio (&gt;20% IBU). This was evident also in the XRD results. Different sets of spray-drying parameters were tested to evaluate the influence of droplet size and initial solid content on encapsulation efficiency (EE). It was determined that both, droplet size and initial solid content, have an influence on EE, but the effect of droplet size seems to be more significant; larger droplet sizes lead to higher encapsulation efficiencies. For instance, approximately 100% encapsulation efficiency was obtained for a CC/GP sample produced using an ultrasonic nozzle (USN), whereas a drug content of 61.5 % was obtained for the CC/GP sample prepared with the 2-fluid nozzle (2FN). With the USN, much larger droplets are produced than with the 2FN under the conditions used. Therefore, the difference in EE is attributed to losses of curcumin that precipitated outside of the glucan particles in the case of the 2FN-sample due to a smaller droplet size (see Fig. 1). Such curcumin particles are very small; therefore, there is a high possibility that they were not collected in the cyclone, causing the losses along the spray dryer. Figure 1. Confocal microscopy images of YGP/CC produced with 2-fluid nozzle (left side), and ultrasonic nozzle (right side). Lastly, dissolution kinetics were evaluated for IBU/GP composites produced using the USN, and physical mixtures of the composites with crude crystalline ibuprofen. Progressively faster dissolution profiles (see Fig. 2) were obtained with increasing mass fraction of the composites, until the solubility limit was reached. In fact, the fast release of the IBU/GP composites lead to supersaturation, a typical characteristic of ASD. This is an important characteristic because, if the supersaturated state is maintained for sufficient time, the in-vivo drug absorption may increase, resulting in an overall improved oral bioavailability [8-10]. Finally, besides fast dissolution, these IBU/GP composites exhibited outstanding wettability and dispersion properties. Figure 3. Dissolution kinetics of crude ibuprofen, IBU/GP composites prepared with ultrasonic nozzle, and physical mixtures of them (e.g. mixture 75/25 = 75 wt.% of IBU/GP composites and 25 wt.% of crude ibuprofen). Acknowledgements. Authors acknowledge financial support by the European Structural and Investment Funds, OP RDE-funded project &apos;CHEMFELLS4UCTP&apos; (No. CZ.02.2.69/0.0/0.0/17_050/0008485), and by the Agency for Healthcare research, project no. 16-27522A. References [1] A.B.C. Samuelsen, J. Schrezenmeir, S.H. Knutsen, Effects of orally administered yeast-derived beta-glucans: A review, Molecular Nutrition &amp; Food Research, 58 (2014) 183-193. [2] X. Zhang, Y. Zhao, Y. Xu, Y. Pan, F. Chen, A. Kumar, G. Zou, X.-J. Liang, In situ self-assembly of peptides in glucan particles for macrophage-targeted oral delivery, Journal of Materials Chemistry B, 2 (2014) 5882-5890. [3] F. Garello, R. Stefania, S. Aime, E. Terreno, D. Delli Castelli, Successful Entrapping of Liposomes in Glucan Particles: An Innovative Micron-Sized Carrier to Deliver Water-Soluble Molecules, Molecular Pharmaceutics, 11 (2014) 3760-3765. [4] M. Aouadi, G.J. Tesz, S.M. Nicoloro, M. Wang, M. Chouinard, E. Soto, G.R. Ostroff, M.P. Czech, Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation, Nature, 458 (2009) 1180-1184. [5] E.R. Soto, G.R. Ostroff, Characterization of Multilayered Nanoparticles Encapsulated in Yeast Cell Wall Particles for DNA Delivery, Bioconjugate Chemistry, 19 (2008) 840-848. [6] G. Shi, L. Rao, H. Yu, H. Xiang, H. Yang, R. Ji, Stabilization and encapsulation of photosensitive resveratrol within yeast cell, Int J Pharm, 349 (2008) 83-93. [7] H.L. Mai, T.H. Phuong, T.N.T. Bich, H.T.T. Hong, T.H.T. Minh, T.M. Thu, H.T.T. Nhu, N.D. Huu, P.N. Xuan, Q.D. Tuan, Preparation and Antitumor-promoting Activity of Curcumin Encapsulated by 1,3-β-Glucan Isolated from Vietnam Medicinal Mushroom Hericium erinaceum, Chemistry Letters, 40 (2011) 846-848. [8] A. Dahan, A. Beig, D. Lindley, J.M. Miller, The solubility–permeability interplay and oral drug formulation design: Two heads are better than one, Advanced Drug Delivery Reviews, 101 (2016) 99-107. [9] S.P. Chaudhari, A. Gupte, Mesoporous Silica as a Carrier for Amorphous Solid Dispersion, arXiv preprint arXiv:1707.00036, (2017). [10] J. Brouwers, M.E. Brewster, P. Augustijns, Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?, Journal of Pharmaceutical Sciences, 98 (2009) 2549-2572.

Název v anglickém jazyce

Encapsulation of poorly water-soluble drugs into yeast glucan particles by spray drying: Improvement of dispersion and dissolution properties

Popis výsledku anglicky

Yeasts are single-celled microorganisms belonging to the fungus kindom. They are more commonly known for their use in food products and, in the biomedical field, they have been of great interest for drug delivery. The so-called yeast glucan particles (GP) are obtained after removing all the internal organelles and cell wall componets, other than β-glucans, from Saccharomyces cerevisiae (baker’s yeast). The result are hollow and porous shells which are suitable for drug encapsulation. Since they are obtained from microorganisms, they activate pattern recognition receptors of host immune cells, triggering immune responses [1]. For this reason, most of the studies have been focused on the use of GP for the encapsulation and macrophage-targeted delivery of drugs. Peptides [2], liposomes [3], siRNA [4], DNA [5], among others water-soluble payloads, have been successfully encapsulated into GP for macrophage-targeted delivery. Publications on the encapsulation of poorly-water soluble drugs, on the other hand, are scarse, constituting an area of study yet to explore. Low water-soluble resveratrol, for instance, was encapsulated in living yeast [6], and curcumin, also insoluble in water, was loaded in 1,3-β-glucan isolated from mushrooms [7]. Given that GP are mainly composed of amorphous polysaccharides (&gt;85% β-glucans), they are suitable candidate materials for the development of amorphous solid dispersions (ASDs). To the best of our knowledge, no studies are found either regarding the encapsulation of low-water soluble drugs in beta-glucan particles by spray drying, or regarding the use of beta-glucan particles for the amorphization of low water-soluble drugs. In this work, low water-soluble drug models, such as ibuprofen (IBU) and curcumin (CC), were loading into GP using spray drying. Microparticles with different IBU-to-GP mass ratios were prepared and characterized. Samples with low IBU content (20% or less) exhibited amorphous state, but crystallinity peaks appeared and increased with drug content. The presence of IBU crystals outside the GP was observed in the case of the samples with higher IBU/GP mass ratio (&gt;20% IBU). This was evident also in the XRD results. Different sets of spray-drying parameters were tested to evaluate the influence of droplet size and initial solid content on encapsulation efficiency (EE). It was determined that both, droplet size and initial solid content, have an influence on EE, but the effect of droplet size seems to be more significant; larger droplet sizes lead to higher encapsulation efficiencies. For instance, approximately 100% encapsulation efficiency was obtained for a CC/GP sample produced using an ultrasonic nozzle (USN), whereas a drug content of 61.5 % was obtained for the CC/GP sample prepared with the 2-fluid nozzle (2FN). With the USN, much larger droplets are produced than with the 2FN under the conditions used. Therefore, the difference in EE is attributed to losses of curcumin that precipitated outside of the glucan particles in the case of the 2FN-sample due to a smaller droplet size (see Fig. 1). Such curcumin particles are very small; therefore, there is a high possibility that they were not collected in the cyclone, causing the losses along the spray dryer. Figure 1. Confocal microscopy images of YGP/CC produced with 2-fluid nozzle (left side), and ultrasonic nozzle (right side). Lastly, dissolution kinetics were evaluated for IBU/GP composites produced using the USN, and physical mixtures of the composites with crude crystalline ibuprofen. Progressively faster dissolution profiles (see Fig. 2) were obtained with increasing mass fraction of the composites, until the solubility limit was reached. In fact, the fast release of the IBU/GP composites lead to supersaturation, a typical characteristic of ASD. This is an important characteristic because, if the supersaturated state is maintained for sufficient time, the in-vivo drug absorption may increase, resulting in an overall improved oral bioavailability [8-10]. Finally, besides fast dissolution, these IBU/GP composites exhibited outstanding wettability and dispersion properties. Figure 3. Dissolution kinetics of crude ibuprofen, IBU/GP composites prepared with ultrasonic nozzle, and physical mixtures of them (e.g. mixture 75/25 = 75 wt.% of IBU/GP composites and 25 wt.% of crude ibuprofen). Acknowledgements. Authors acknowledge financial support by the European Structural and Investment Funds, OP RDE-funded project &apos;CHEMFELLS4UCTP&apos; (No. CZ.02.2.69/0.0/0.0/17_050/0008485), and by the Agency for Healthcare research, project no. 16-27522A. References [1] A.B.C. Samuelsen, J. Schrezenmeir, S.H. Knutsen, Effects of orally administered yeast-derived beta-glucans: A review, Molecular Nutrition &amp; Food Research, 58 (2014) 183-193. [2] X. Zhang, Y. Zhao, Y. Xu, Y. Pan, F. Chen, A. Kumar, G. Zou, X.-J. Liang, In situ self-assembly of peptides in glucan particles for macrophage-targeted oral delivery, Journal of Materials Chemistry B, 2 (2014) 5882-5890. [3] F. Garello, R. Stefania, S. Aime, E. Terreno, D. Delli Castelli, Successful Entrapping of Liposomes in Glucan Particles: An Innovative Micron-Sized Carrier to Deliver Water-Soluble Molecules, Molecular Pharmaceutics, 11 (2014) 3760-3765. [4] M. Aouadi, G.J. Tesz, S.M. Nicoloro, M. Wang, M. Chouinard, E. Soto, G.R. Ostroff, M.P. Czech, Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation, Nature, 458 (2009) 1180-1184. [5] E.R. Soto, G.R. Ostroff, Characterization of Multilayered Nanoparticles Encapsulated in Yeast Cell Wall Particles for DNA Delivery, Bioconjugate Chemistry, 19 (2008) 840-848. [6] G. Shi, L. Rao, H. Yu, H. Xiang, H. Yang, R. Ji, Stabilization and encapsulation of photosensitive resveratrol within yeast cell, Int J Pharm, 349 (2008) 83-93. [7] H.L. Mai, T.H. Phuong, T.N.T. Bich, H.T.T. Hong, T.H.T. Minh, T.M. Thu, H.T.T. Nhu, N.D. Huu, P.N. Xuan, Q.D. Tuan, Preparation and Antitumor-promoting Activity of Curcumin Encapsulated by 1,3-β-Glucan Isolated from Vietnam Medicinal Mushroom Hericium erinaceum, Chemistry Letters, 40 (2011) 846-848. [8] A. Dahan, A. Beig, D. Lindley, J.M. Miller, The solubility–permeability interplay and oral drug formulation design: Two heads are better than one, Advanced Drug Delivery Reviews, 101 (2016) 99-107. [9] S.P. Chaudhari, A. Gupte, Mesoporous Silica as a Carrier for Amorphous Solid Dispersion, arXiv preprint arXiv:1707.00036, (2017). [10] J. Brouwers, M.E. Brewster, P. Augustijns, Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?, Journal of Pharmaceutical Sciences, 98 (2009) 2549-2572.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

20401 - Chemical engineering (plants, products)

Projekt

<a href="/cs/project/NV16-27522A" target="_blank" >NV16-27522A: Přírodní bioaktivní látky enkapsulované v glukanových mikročásticích jako biomateriál vhodný pro léčbu střevních zánětlivých onemocnění</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů