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The Relationship between the Drug Delivery Properties of a Formulation of Teriparatide Microneedles and the Pharmacokinetic Evaluation of Teriparatide Administration in Rats

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Abstract

Purpose

Teriparatide is an effective drug for the treatment of osteoporosis. This study examines the relationship between the drug delivery properties of the solid formulation with teriparatide and the pharmacokinetic properties of teriparatide in vivo.

Methods

Teriparatide microneedles with different dissolution rates were prepared using sucrose and carboxymethylcellulose (CMC). There were three aspects of this study: (1) The dissolution rate of teriparatide from both formulations (sucrose and CMC) was measured in vitro. (2) After administration into porcine skin ex vivo, the diffusion rate of FITC-dextran was observed using a confocal microscope. (3) Pharmacokinetic studies were performed in rats and pharmacokinetic data compared with the release rate and the diffusion pattern.

Results

In the in vitro dissolution experiment, 80% of teriparatide was released within 30 min from the CMC MNs, whereas 80% of teriparatide was released within 10 min from the sucrose MNs. After 30 min, the fluorescence intensity on the surface of the MNs was 40% of the initial intensity for sucrose MNs and 90% for CMC MNs. In the pharmacokinetic study, the Cmax values of the CMC and sucrose MNs were 868 pg/mL and 6809 pg/mL, respectively, and the AUClast values were 6771 pg*hr/mL for the CMC MNs and 17,171 pg*hr/mL for the sucrose MNs.

Conclusions

When teriparatide is delivered into the skin using microneedles, the release rate from the solid formulation determines the drug’s pharmacokinetic properties. The diffusion pattern of fluorescence into the skin can be used to anticipate the pharmacokinetic properties of the drug.

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Abbreviations

AUClast :

The area under the plasma concentration–time curve from zero to time last

BA (F):

Bioavailability

CMC:

Carboxymethylcellulose

CMC MNs:

Microneedles using CMC as the main additive in the coating layer

Cmax :

Maximum serum concentration (Cmax)

FITC:

Fluorescein isothiocyanate

Fl-Su:

Sucrose MNs with FITC-dextran

Fl-CMC:

CMC MNs with FITC-dextran

HPLC:

High-performance liquid chromatography

MNs:

Microneedles

PK:

Pharmacokinetics

PTH:

Human recombinant parathyroid hormone

PLA:

Polylactic acid

PDMS:

Poly dimethyl siloxane

PBS:

Phosphate-buffered saline

SC:

Subcutaneous

Sucrose MNs:

Microneedles using sucrose as the main additive in the coating layer

Te-Su:

Sucrose MNs with Teriparatide

Te-CMC:

CMC MNs with teriparatide

Tmax :

Time to maximum plasma concentration

T1/2 :

Terminal half-life

Vd/F:

Apparent volume of distribution

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Funding

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT (No. NRF- 2018R1A5A2024425), Ministry of Health & Welfare, Republic of Korea (Grant No: HV20C0014) and Korea Ministry of Trade, Industry & Energy (MOTIE, 20014936 (Industrial Strategic Technology Development Program)).

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Author notes

  1. Yu-Jeong Oh and Nae-Won Kang these authors have equally contributed.

Authors and Affiliations

  1. Department of Bionano Technology and Gachon BioNano Research Institute, Gachon University, Gyeonggi-do, Republic of Korea

    Yu-Jeong Oh, Hye-Rin Jeong & Jung-Hwan Park

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea

    Nae-Won Kang, Seo-Yeon Sohn, Yae-Eun Jeon, Na-Young Yu & Dae-Duk Kim

  3. Hanlim Pharmaceutical.Co.,Ltd, Yeongmun-ro, Cheoin-gu, Yongin-si, Gyeonggi-do, Republic of Korea

    Yura Hwang & Sunkyung Kim

  4. QuadMedicine R&D Centre, QuadMedicine Co., Ltd, Seongnam, Republic of Korea

    Jung-Hwan Park

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  1. Yu-Jeong Oh
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  2. Nae-Won Kang
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Corresponding authors

Correspondence to Dae-Duk Kim or Jung-Hwan Park.

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Conflict of Interest Statement

PJH is an inventor of patents that have been licensed to companies developing microneedle-based products, is a shareholder of companies developing microneedle-based products.

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Oh, YJ., Kang, NW., Jeong, HR. et al. The Relationship between the Drug Delivery Properties of a Formulation of Teriparatide Microneedles and the Pharmacokinetic Evaluation of Teriparatide Administration in Rats. Pharm Res 39, 989–999 (2022). https://doi.org/10.1007/s11095-022-03254-6

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