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Formulation and optimization of pH-sensitive nanocrystals for improved oral delivery

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Abstract

The challenge of low water solubility in pharmaceutical science profoundly impacts drug absorption and therapeutic effectiveness. Nanocrystals (NC), consisting of drug molecules and stabilizing agents, offer a promising solution to enhance solubility and control release rates. In the pharmaceutical industry, top-down techniques are favored for their flexibility and cost-effectiveness. However, increased solubility can lead to premature drug dissolution in the stomach, which is problematic due to the acidic pH or enzymes. Researchers are exploring encapsulating agents that facilitate drug release at customized pH levels as a valuable strategy to address this. This study employed wet milling and spray drying techniques to create encapsulated NC for delivering the drug to the intestinal tract using the model drug ivermectin (IVM). Nanosuspensions (NS) were efficiently produced within 2 h using NanoDisp®, with a particle size of 198.4 ± 0.6 nm and a low polydispersity index (PDI) of 0.184, ensuring uniformity. Stability tests over 100 days at 4 °C and 25 °C demonstrated practical viability, with no precipitation or significant changes observed. Cytotoxicity evaluations indicated less harm to Caco-2 cells compared to the pure drug. Furthermore, the solubility of the NC increased by 47-fold in water and 4.8-fold in simulated intestinal fluid compared to the pure active compound. Finally, dissolution tests showed less than 10% release in acidic conditions and significant improvement in simulated intestinal conditions, promising enhanced drug solubility and bioavailability. This addresses a long-standing pharmaceutical challenge in a cost-effective and scalable manner.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

AE:

Acryl-EZE® (Eudragit L100-55)

BCS:

Biopharmaceutical classification system

DLS:

Dynamic light scattering

DSC:

Differential scanning colorimetry

FTIR:

Fourier-transform infrared spectra

HPMC:

Hydroxypropylmethylcellulose

IVM:

Ivermectin

NC:

Nanocrystals

NC-AE 10%:

Ivermectin nanocrystals with 10% Acryl-EZE®

NC-AE 25%:

Ivermectin nanocrystals with 25% Acryl-EZE®

NC-AE 40%:

Ivermectin nanocrystals with 40% Acryl-EZE®

NS:

Nanosuspension

NS-IVM P188 1:2:

Ivermectin nanosuspension with poloxamer 188 in a ratio 1:2

P188:

Poloxamer 188

PDI:

Polydispersity index

PM:

Physical mixture

PVP:

Polyvinylpyrrolidone

SEM:

Scanning electron microscopy

SLS:

Sodium lauryl sulfate

T80:

Tween 80

TGA:

Thermogravimetric analysis

XR:

Powder X-ray diffraction

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Acknowledgements

Daniel Real thanks FONCYT (Argentina) for a postdoctoral fellowship.

Funding

This research was funded by “Fondo para la Investigación Científica y Tecnológica (FONCyT), funding number PICT 2020-SERIEA-02037,” and Consejo Nacional de Investigación Científicas y Técnicas (CONICET), funding number PIP 11220200100580CO. The authors gratefully acknowledge the Universidad Nacional de Córdoba (Argentina) and CONICET (Argentina) for financial support.

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Authors and Affiliations

  1. Faculty of Chemical Sciences, National University of Córdoba (FCQ-UNC), Haya de la torre y Medina Allende, X5000XHUA, Córdoba, Argentina

    Lucía Lopez-Vidal, Pedro Parodi, Maribel Romanela Actis, Nahuel Camacho, Daniel Andrés Real, Fernando José Irazoqui, Juan Pablo Real & Santiago Daniel Palma

  2. Pharmaceutical Technology Research and Development Unit (UNITEFA) - CONICET, Córdoba, Argentina

    Lucía Lopez-Vidal, Nahuel Camacho, Daniel Andrés Real, Juan Pablo Real & Santiago Daniel Palma

  3. Center for Research in Biological Chemistry of Cordoba (CIQUIBIC) - CONICET, Córdoba, Argentina

    Pedro Parodi & Fernando José Irazoqui

  4. School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    Alejandro J. Paredes

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  1. Lucía Lopez-Vidal
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Contributions

Lucía Lopez-Vidal: investigation, methodology, formal analysis, validation, writing—original draft, conceptualization. Pedro Parodi: investigation, methodology. Maribel Actis: investigation and methodology. Nahuel Camacho: investigation, methodology. Daniel Andrés Real: methodology, writing—review and editing. Fernando Irazoqui: resources, conceptualization, writing—review and editing. Alejandro J. Paredes: conceptualization, writing—review and editing. Juan Pablo Real: conceptualization, supervision, formal analysis, writing—review and editing. Santiago Daniel Palma: resources, writing—review and editing, supervision, funding acquisition.

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Correspondence to Santiago Daniel Palma.

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Lopez-Vidal, L., Parodi, P., Actis, M.R. et al. Formulation and optimization of pH-sensitive nanocrystals for improved oral delivery. Drug Deliv. and Transl. Res. 14, 1301–1318 (2024). https://doi.org/10.1007/s13346-023-01463-z

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