Preparation, characterisation, and testing of reservoir-based implantable devices loaded with tizanidine and lidocaine

Abstract

Multiple sclerosis is a chronic neuroimmunological disorder that causes progressive disability, primarily in young adults. It places a significant burden on healthcare systems due to high medication costs and long-term care needs. Implantable devices offer a promising alternative for delivering sustained drug doses in the treatment of chronic conditions. This study introduces a novel long-acting subcutaneous implant for dual-drug delivery: tizanidine (TZ) for spasticity management and lidocaine (LD) for post-insertion pain relief. Reservoir-type implants were developed with TZ in the core and LD in the shell. Two fabrication methods—direct compression and vacuum compression moulding (VCM)—were evaluated for TZ-loaded pellets (3 mm diameter, ~ 10 mm length) using TZ base and TZ hydrochloride. Pellets were encapsulated inside a biodegradable polycaprolactone (PCL) tubular membrane to control drug release. Direct compression pellets, made with poly(vinyl pyrrolidone) and hydroxypropyl-β-cyclodextrin, disintegrated quickly, releasing TZ over 20 days. VCM pellets, formulated with PCL or PCL/poly(ethylene glycol) (PEG), offered prolonged release: up to 200 days for TZ base and 80 days for TZ hydrochloride. Adding PEG accelerated TZ release, reducing duration to 20 days (TZ base) and 125 days (TZ hydrochloride). LD was incorporated into the PCL membrane, providing up to three days of sustained release. Physicochemical analysis confirmed formulation homogeneity and no covalent interactions. These findings highlight the potential of this implant system for MS-related spasticity management, supporting further research into long-acting implants to improve treatment adherence and patient outcomes.

Introduction

Multiple sclerosis (MS) is the most prominent neuroimmunology disorder [1, 2]. The disease is defined by lengthy survival and progressive disability over time, occurring in young adults most of the cases [1]. Multiple sclerosis is placing a growing burden on health-care resources because of the high cost of medication, the necessity of ongoing care, and the requirement for rehabilitation in the latter stages of the disease [2]. Spasticity is the main symptom of MS, characterised by increased muscular tone, resistance to movement, and reduced reflex function, leading to symptoms such as muscle stiffness, involuntary contractions, fibrosis, and atrophy. Spasticity causes pain and reduces movement and mobility, making it difficult to perform daily activities like walking, sitting, and standing, while also raising the risk of falls and fractures [3,4,5]. In children spasticity can be followed by disability, growth problems, and deformed joints [6]. Over 12 million people worldwide suffer with spasticity, including over 80% of those who have multiple sclerosis and cerebral palsy [2, 6]. Spasticity is one of the most prevalent, potentially disabling, and annoying symptoms of spinal cord injury (SCL). Approximately 70% of people with SCL are spastic one year after injury, and roughly half of them receive antispastic medication [7]. Every year, roughly 110,000 people in England suffer a stroke, with spasticity affecting 19–38% of them (up to 41,800 people) [3]. The range of disability caused by spasticity is minimal to extreme. Additionally, there could be variations in spasticity throughout the day, which tend to be more noticeable in those with cervical SCL. Furthermore, 40% of patients who report spasticity may not respond to movement provocation during a physical examination [7].

Associated with the burden of the disease itself chronic conditions deal with the burden of management and treatment of the disease. This is largely due to the ongoing need for treatments intending to ameliorate symptoms or altering the progression of the disease [8,9,10]. Treatment burden is a significant clinical concern as it can lead to decreased adherence to prescribed treatments and self-care practices, which is strongly associated with adverse clinical outcomes. These outcomes include increased hospitalizations, higher mortality rates, and reduced health-related quality of life [11,12,13,14,15,16]. In the management of spasticity, treatments are diverse and often used in combination. These may include physical therapy, exercise, medication, surgery, and psychological therapy. Nevertheless, the use of medication has been described as one of the most common treatment forms, with the volume of medications dispensed to the community steadily rising [17]. Despite the availability if these treatments, ensuring adherence to treatment in these patients remains an important challenge in health care where more intensive research is required. Many patients with chronic conditions often need to take medications over extended periods, causing discomfort i.e., “pill fatigue”, side effects and the inconsistent therapeutic effects caused by pharmacokinetic fluctuations. These factors often contribute to higher relapse rates, increased hospitalization, poorer quality of life and higher levels of residual symptoms [18]. From a healthcare systems perspective, patients with chronic conditions represent about 50% of all general practitioner (GP) appointments, over 70% of all inpatient bed days and 64% of all outpatient appointments [19]. Moreover, the expenditures of handling the consequences of poor medication adherence in UK are exorbitant, estimated to be more than $100 billion per year [19]. The global cost of chronic disease was predicted to reach $47 trillion by 2030 [20]. In this scenario, the development of long-acting drug delivery systems presents a promising alternative for the management of chronic conditions, offering the potential to improve treatment adherence and reduce the overall burden on both patients and healthcare system.

Implantable devices have been widely investigated to improve the treatment of multiple diseases, especially for chronic diseases, which need treatment for long periods (more than one month) [21,22,23,24]. Even with low drug loadings, these devices can achieve effective delivery and increase patient compliance by minimising potential side-effects [25], consequently enhancing the quality of life of the patients. In chronic conditions this aspect is extremely important because the disease and the treatment are often lifelong [26]. Implantable devices have been investigated for different sites of administration such as subcutaneous, intravaginal, intranasal, intratumoral, intracranial, and intravesical [23, 27]. Despite all the advantages they can produce pain and discomfort at the insertion site [28]. This is due to the process of inserting the implant inside the body. A widely used local anaesthetic agent can be used to reduce pain [29,30,31]. In the present work, we developed a combined implant containing tizanidine (TZ), for the treatment of muscular spasticity, and LD to reduce the pain at the insertion site [31]. We look ahead to alleviate the burden of chronic diseases and we foresee ongoing innovation. With an implant device, we encourage the patient better adherence to treatment medication with a simple technology that not only will provide a long drug release of tizanidine, but also a local anaesthesia after implant insertion provided by lidocaine.

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Materials

Tizanidine base form (TZB) was purchased from Cangzhou Enke Pharma-Tech Co. Ltd. (Cangzhou, China). Tizanidine Hydrochloride (TZHCL) powder was sourced from Tokyo Chemical Industry (The Oxford Science Park, Oxford, United Kingdom). Lidocaine hydrochloride (LD) powder was provided by Fagron UK Ltd. (Newcastle, UK). Poly(vinylpyrrolidone) (PVP) (Plasdone™ K29-32) and hydroxypropyl-β-cyclodextrin (HPBCD) were kindly donated by Ashland (Kidderminster, UK). PCL CAPA™ 6505 (MW = 50 kDa) and PCL (MW = 550 Da) were obtained from Ingevity (North Charleston, South Carolina, U.S.A). Dichloromethane (DCM), methanol (MeOH), trifluoracetic (TFA) and poly(ethylene)glycol PEG (MW = 3,000 Da) were provided by Sigma-Aldrich (Gillingham, Dorset, UK).

Drug containing pellet preparation

To find the best formulation, pellets containing TZHCL and different excipients were formulated with a mass ratio of 1:1. The excipients evaluated were PVP, Hydroxypropyl-β HPBCD, and PCL. Each powdered blend was uniformly mixed and compressed using a hydraulic press at 1 tonne pressure for 30 s. The composition of the pellets can be seen in Table 1. Melt-processed pellets containing TZHCL-PCL, TZB-PCL, TZHCL-PCL-PEG, and TZB-PCL-PEG, in a mass ratio of 1:1, were also prepared using the Vacuum Compression Moulding (VCM) technique (MeltPrep®, Graz, Austria). To ensure a homogeneous distribution of the drug in the pellet, films containing 50% of the drug and 50% of the polymer were prepared by dissolving the mixture with 4 ml of DCM. The formulation was left for one day in a petri dish to allow the evaporation of the organic solvent, and once the film was dried, a piece of it was introduced into the chamber at 80 °C for 5 min. The chamber was then kept closed for another 5 min to cool down. Table 1 shows the composition of the pellets prepared using VCM.

Picco, C.J., Bhalerao, M.S., Fandino, O.E. et al. Preparation, characterisation, and testing of reservoir-based implantable devices loaded with tizanidine and lidocaine. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01855-3

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MeltPrep – Rapid and Lossless Screening of Hot-melt Extruded Formulations