(M1230-05-27) Dual Release of Lidocaine and Tizanidine from Coated and Monolithic Implants

Purpose: In recent years, there has been significant interest in implantable devices due to their suitability for managing chronic conditions requiring prolonged therapy.^1,2 These devices facilitate effective drug delivery and promote patient adherence by minimizing potential side effects, thereby enhancing patient quality of life. Moreover, drug delivery implant designs are often developed using biodegradable materials³, avoiding the need for implant removal upon treatment completion and ensuring compatibility with the human body.⁴ Despite these advantages, implants can induce local side effects, such as pain and discomfort at the insertion site, attributed to the implantation procedure. Lidocaine (LD), a widely used local anesthetic agent, may mitigate such pain. In the present work, we developed a combined implant containing TZ for the treatment of muscular spasticity and LD for alleviating pain at the implantation site, utilizing two different platforms.

Methods: Monolithic implants: Implants were created using a Vacuum Compression Molding (VCM) technique, combining drug and polymer in a 1:1 mass ratio. Films of TZ-PCL and LD-PCL mixture were initially made by dissolving PCL in dichloromethane (DCM). A piece of each film was then heated at 80°C for 5 minutes and cooled for 5 minutes to form cylindrical rods (2.9 x 15 mm) containing 45.81±4.9 mg of TZ and 23.21±4.4 mg of LD. Coated implants: The same VCM technique was used to make TZ-PCL implants, but LD was incorporated into an external membrane. PCL (50 kDa), PCL (550 Da), LD (in a 0.5:0.5:1 ratio), and DCM were mixed to form a solution, which was cast on a spinning metal rod (75 rpm) to create membranes with either 3 or 5 layers. In vitro release study involved placing the implants in PBS (pH: 7.4) at 37°C and 40 rpm in an incubator. Samples (1 mL) were collected at specific intervals over 30 days and analyzed using RP-HPLC.

Results: Implants successfully developed can contain two different drugs, either in the core or the membrane. Evaluation of drug release from each implant was conducted over 30 days. Nearly the entire quantity of the drug was released from all the formulations tested, implying that the developed implants have the potential to facilitate controlled and extended drug release. In the realm of pharmaceutical treatments, minimizing the number of implants is pivotal to reduce the impact of application. Possessing attributes such as compact size and the capacity for controlled and sustained drug release, these implantable devices hold considerable promise for addressing chronic conditions while concurrently providing local anesthesia post-implantation.

Conclusion: Implants were successfully developed, capable of containing two different drugs, either in the core or the membrane. The results demonstrated the potential of the developed implant to facilitate controlled and extended drug release. The results obtained for the developed system device so far seem promising for use in other chronic diseases.

References: 1. Langer, R. New methods of drug delivery. Science, 1990, 249, 1527-1533 (1979).
2. Dash, A.K. and Cudworth, G.C., Therapeutic applications of implantable drug delivery systems. J Pharmacol Toxicol Methods, 40, 1-12 (1998).
3. Magill, E.; Demartis, S.; Gavini, E.; Permana, A. D.; Thakur, R. R. S.; Adrianto, M. F.; Waite, D.; Glover, K.; Picco, C. J.; Korelidou, A.; Detamornrat, U.; Vora, L. K.; Li, L.; Anjani, Q. K.; Donnelly, R. F.; Domínguez-Robles, J. and Larrañeta, E. Solid implantable devices for sustained drug delivery. Adv Drug Deliv Rev, 199, 114950 (2023).
4. Walter, J. J.; Bohr, A.; Boetker, J.; Aho, J.; Sandler, N.; Nielsen, H. M. and Rantanen, J. Three-Dimensional printing of drug-elution implants: Preparation of an antimicrobial polylactide feedstock material. J Pharm Sci, 104, 1099-1107 (2015).


Figure 1. a) Final monolithic implant containing LD and TZ, and final coated implant b) with 3 layers and c) 5 layers (upper images). Cumulative release of both drugs over 30 days from a monolithic implant in d) percentage and g) milligrams, coated implant with 3 layers in e) percentage and h) milligrams, and 5 layers in f) percentage and i) milligrams.


Table 1. Drug amount of TZ and LD loaded in the different implant devices.