Transdermal Delivery of Salmon Calcitonin Using a Dissolving Microneedle Array: Characterization, Stability, and In vivo
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Research Article Transdermal Delivery of Salmon Calcitonin Using a Dissolving Microneedle Array: Characterization, Stability, and In vivo Pharmacodynamics Lu Zhang,1 Yingying Li,1 Fang Wei,1 Hang Liu,1 Yushuai Wang,1 Weiman Zhao,1 Zhiyong Dong,1 Tao Ma,1 and Qingqing Wang1,2
Received 13 September 2020; accepted 24 October 2020 Abstract. Salmon calcitonin (sCT) is a polypeptide drug, possessing the ability to inhibit osteoclast-mediated bone resorption. Just like other bioactive macromolecules, sCT is generally administered to the patients by either injection for poor compliance or through nasal spray for low bioavailability, which limits its use as therapeutic drugs. In the present study, to overcome the limitations of the conventional routes, two new dissolving microneedle arrays (DMNAs) based on transdermal sCT delivery systems were developed, namely sCT-DMNA-1 (sCT/Dex/K90E) and sCT-DMNA-2 (sCT/Dex-Tre/K90E) with the same dimension, meeting the requirements of suitable mechanical properties. An accurate and reliable method was established to determine the needle drug loading proportion in sCTDMNAs. The stability study exhibited that the addition of trehalose could improve the stability of sCT in DMNA under high temperature and humidity. Further, in vivo pharmacodynamic study revealed that DMNA patch could significantly enhanced relative bioavailability to approximately 70%, and the addition of trehalose was found to be beneficial for sCT transdermal delivery. Therefore, sCT-DMNA is expected to replace traditional dosage form, providing a secure, efficient, and low-pain therapeutic strategy for bone disorders. KEY WORDS: salmon calcitonin; dissolving microneedle array (DMNA); transdermal delivery; relative bioavailability; trehalose.
INTRODUCTION Peptides and proteins have the advantages of high specificity and safety as therapeutic agents for different diseases (1). Unfortunately, their clinical applications are limited by the existing delivery methods. One such agent is salmon calcitonin (sCT) (2), an FDA-approved polypeptide drug, primarily used for treating Paget’s disease, osteoporosis (3), malignant hypercalcemia (4), and the pain of bone metastasis (5). sCT can regulate the metabolism of calcium and phosphorus and reduce the activity of osteoclast (6). Moreover, it can minimize the loss of bone calcium and stimulate the proliferation and differentiation of osteoblasts. Additionally, it also possesses significant analgesic effect (2). As a highly bioactive polypeptide molecule, sCT has a large molecular weight with complex spatial configuration, and it is prone to denaturation under the influence of temperature as well as acids/bases. The activity of sCT mainly depends on its spatial structure and amino acid sequence (7), a common Lu Zhang and Yingying Li contributed equally to this work. 1
School of Pharmacy, Bengbu Medical College, No. 2600, Donghai Avenue, Bengbu, 233000, Anhui, China. 2 To whom correspondence should be addressed. (e–mail: [email protected])
characteristic of most biotechnological dr
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