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Encapsulation and release of hydrocortisone from proliposomes govern vaginal delivery

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Abstract

Topical preparations of hydrocortisone can be used for the anti-inflammatory treatment of the female genital area. Although the drug is a low-strength corticosteroid, systemic absorption and distribution of the drug are the most common safety risks associated with this therapy. In the current investigation, we elucidate the physicochemical properties of lipid-based drug carrier systems that govern the local bioavailability of hydrocortisone for intravaginal administration. For this purpose, we compared various proliposome formulations with a commercial cream. Depending on the availability of physiological acceptors, encapsulation and drug release from the lipid phase were found to be the most important drivers of drug bioavailability. The high permeability of hydrocortisone leads to rapid transport of the drug across the mucosal cell layer as indicated by experiments using HEC-1-A and CaSki cell monolayer models. Under sink conditions, differences in the release from the liposomes as determined in the Dispersion Releaser were almost negligible. However, under non-sink conditions, the drug release plateaued at levels corresponding to the encapsulation efficiency. After redispersion, all liposomal formulations performed better than the commercial drug product indicating that the encapsulation into the lipid phase is the main driver sustaining the release.

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Materials are commercially available; data will be made available on request.

Abbreviations

ANOVA:

Analysis of variance

β-CD:

Methyl-β-cyclodextrin

C:

Cholesterol

Caco-2:

Carcinoma colon

CaSki:

Human cervical carcinoma

CC50 :

Half-maximal cytotoxic concentration

CE:

Cellulose ester

DLS:

Dynamic light scattering

DSC:

Differential scanning calorimetry

EE%:

Encapsulation efficiency

EPC:

Egg phosphatidylcholine

f1:

Difference factor

f2:

Similarity factor

HBSS:

Hank’s Balanced Salt solution

HEC-1-A:

Human endometrial adenocarcinoma

HPLC-UV:

High-performance liquid chromatography with ultraviolet detection

LOD:

Limit of detection

LOQ:

Limit of quantitation

MWCO:

Molecular weight cutoff

Papp :

Apparent permeability coefficients

PDI:

Polydispersity index

PER:

Permeability enhancement ratio

PTDR:

Pharma Test Dispersion Releaser

PTFE:

Polytetrafluoroethylene

SPC:

Soy phosphatidylcholine

sVSF:

Simplified vaginal simulant fluid

SE:

Standard error

SD:

Standard deviation

TEER:

Transepithelial electrical resistance

TEM:

Transmission electron microscopy

US-FDA:

United States Food and Drug Administration

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Acknowledgements

Marc-Phillip Mast acknowledges the State of Hessen for financial contributions to the LOEWE research center for Translational Medicine and Pharmacology (Frankfurt, Germany). Matthias G. Wacker acknowledges the Singaporean Ministry of Education (A-0004627-00-00) and the Resilience & Growth Fund of the National Research Foundation (A-0000065-09-00) for financial support. José das Neves acknowledges financing by Portuguese funds through FCT – Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” (UID/BIM/04293/2019). This work was supported by the Ministry of Science and Higher Education of the Russian Federation (grant No. 075-15-2020-792, Unique identifier RF-190220X0031).

Funding

All funding sources have been declared under Acknowledgements.

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Authors and Affiliations

  1. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany

    Marc-Phillip Mast

  2. Goethe University, Max-Von-Laue-Straße 9, 60438, Frankfurt/Main, Germany

    Marc-Phillip Mast

  3. i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal

    Letícia Mesquita & José das Neves

  4. INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal

    Letícia Mesquita & José das Neves

  5. IUCS—Instituto Universitário de Ciências da Saúde, Universidade do Porto, 4585-116, Gandra, Portugal

    José das Neves

  6. Department of Pharmacy, Faculty of Science, National University of Singapore, 4 Science Drive 2, 117544, Singapore, Singapore

    Kennard Gan & Matthias G. Wacker

  7. D. Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, 125047, Moscow, Russia

    Svetlana Gelperina

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  1. Marc-Phillip Mast
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  2. Letícia Mesquita
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  3. Kennard Gan
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  4. Svetlana Gelperina
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  5. José das Neves
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  6. Matthias G. Wacker
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Contributions

Conceptualization: MPM, MGW; investigation: MPM, LM; writing—original draft preparation: MPM; writing—review and editing: MPM, KG, JdN, MGW, S.G.; funding acquisition: JdN, MGW; supervision: JdN, MGW, SG. All authors have read and agreed to the published version of the manuscript.

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Correspondence to José das Neves or Matthias G. Wacker.

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Mast, MP., Mesquita, L., Gan, K. et al. Encapsulation and release of hydrocortisone from proliposomes govern vaginal delivery. Drug Deliv. and Transl. Res. 13, 1022–1034 (2023). https://doi.org/10.1007/s13346-022-01263-x

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