An isocratic RP-HPLC-UV method for simultaneous quantification of tizanidine and lidocaine: application to <i>in vitro</i> release studies of a subcutaneous implant

Implantable devices have been widely investigated to improve the treatment of multiple diseases. Even with low drug loadings, these devices can achieve effective delivery and increase patient compliance by minimizing potential side effects, consequently enhancing the quality of life of the patients. Moreover, multi-drug products are emerging in the pharmaceutical field, capable of treating more than one ailment concurrently. Therefore, a simple analytical method is essential for detecting and quantifying different analytes used in formulation development and evaluation. Here, we present, for the first time, an isocratic method for tizanidine hydrochloride (TZ) and lidocaine (LD) loaded into a subcutaneous implant, utilizing reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with a UV detector. These implants have the potential to treat muscular spasticity while providing pain relief for several days after implantation. Chromatographic separation of the two drugs was accomplished using a C18 column, with a mobile phase consisting of 0.1% TFA in water and MeOH in a 58 : 42 ratio, flowing at 0.7 ml min−1. The method exhibited specificity and robustness, providing accurate and precise results. It displayed linearity within the range of 0.79 to 100 μg ml−1, with an R2 value of 1 for the simultaneous analysis of TZ and LD. The developed method demonstrated selectivity, offering limits of detection and quantification of 0.16 and 0.49 μg ml−1 for TZ, and 0.30 and 0.93 μg ml−1 for LD, respectively. Furthermore, the solution containing both TZ and LD proved stable under various storage conditions. While this study applied the method to assess an implant device, it has broader applicability for analysing and quantifying the in vitro drug release of TZ and LD from diverse dosage forms in preclinical settings.<br/

3D-printed implantable devices with biodegradable rate-controlling membrane for sustained delivery of hydrophobic drugs

Implantable drug delivery systems offer an alternative for the treatments of long-term conditions (i.e. schizophrenia, HIV, or Parkinson’s disease among many others). The objective of the present work was to formulate implantable devices loaded with the model hydrophobic drug olanzapine (OLZ) using robocasting 3D-printing combined with a pre-formed rate controlling membrane. OLZ was selected as a model molecule due to its hydrophobic nature and because is a good example of a molecule used to treat a chronic condition schizophrenia. The resulting implants consisted of a poly(ethylene oxide) (PEO) implant coated with a poly(caprolactone) (PCL)-based membrane. The implants were loaded with 50 and 80% (w/w) of OLZ. They were prepared using an extrusion-based 3D-printer from aqueous pastes containing 36–38% (w/w) of water. The printing process was carried out at room temperature. The resulting implants were characterized by using infrared spectroscopy, scanning electron microscopy, thermal analysis, and X-ray diffraction. Crystals of OLZ were present in the implant after the printing process. In vitro release studies showed that implants containing 50% and 80% (w/w) of OLZ were capable of providing drug release for up to 190 days. On the other hand, implants containing 80% (w/w) of OLZ presented a slower release kinetics. After 190 days, total drug release was ca. 77% and ca. 64% for implants containing 50% and 80% (w/w) of OLZ, respectively. The higher PEO content within implants containing 50% (w/w) of OLZ allows a faster release as this polymer acts as a co-solvent of the drug

Additive manufacturing methods for pharmaceutical and medical applications

Three-dimensional (3D) printing has been geared up to become a highly revolutionary technology within the manufacturing industry, especially within the pharmaceutical and medical fields. Three-dimensional printing utilizes computer-aided design (CAD) software to manufacture objects of any size and shape. Due to the potential capabilities, many industries are now making use of this manufacturing technique, from rapid prototyping in engineering to the production of personalized medicine within the medical and pharmaceutical industries. It has the potential to cause a paradigm shift and revolutionize the way medicines and medical devices are designed, manufactured, and used. This chapter provides an overview of the field of 3D printing, current medical applications, 3D-printed dosage forms, and drug delivery systems as well as the benefits and limitations of this technique. It focuses on the potential and motivations of this method of additive manufacturing, including the challenges and future possibilities it could bring to the field of medicine and pharmaceuticals.<br/

Development of 3D-printed vaginal devices containing metronidazole for alternative bacterial vaginosis treatment

Bacterial vaginosis (BV) is an abnormal condition caused by the change of microbiota in the vagina. One of the most common bacteria found in the case of BV is Gardnerella vaginalis, which is categorised as anaerobic facultative bacteria. Currently, the available treatment for BV is the use of antibiotics, such as metronidazole (MTZ), in topical and oral dosage forms. The limitation of the currently available treatment is that multiple administration is required and thus, the patient needs to apply the drug frequently to maintain the drug efficacy. To address these limitations, this research proposed prolonged delivery of MTZ in the form of intravaginal devices made from biodegradable and biocompatible polymers. Semi-solid extrusion (SSE) 3D printing was used to prepare the intravaginal devices. The ratio of high and low molecular weight poly(caprolactone) (PCL) was varied to evaluate the effect of polymer composition on the drug release. The versatility of SSE 3D printer was used to print the intravaginal devices into two different shapes (meshes and discs) and containing two different polymer layers made from PCL and a copolymer of methyl vinyl ether and maleic anhydride (Gantrez™-AN119), which provided mucoadhesive properties. Indeed, this layer made from Gantrez™-AN119 increased ca. 5 times the mucoadhesive properties of the final 3D-printed devices (from 0.52 to 2.57 N). Furthermore, MTZ was homogenously dispersed within the polymer matrix as evidenced by scanning electron microscopy analysis. Additionally, in vitro drug release, and antibacterial activity of the MTZ-loaded intravaginal devices were evaluated. Disc formulations were able to sustain the release of MTZ for 72 h for formulations containing 70/30 and 60/40 ratio of high molecular weight/low molecular weight PCL. On the other hand, the discs containing a 50/50 ratio of high molecular weight/low molecular weight PCL showed up to 9 days of release. However, no significant differences in the MTZ release from the MTZ-loaded meshes (60/40 and 50/50 ratio of high molecular weight/low molecular weight PCL) were found after 24 h. The results showed that the different ratios of high and low molecular weight PCL did not significantly affect the MTZ release. However, the shape of the devices did influence the release of MTZ, showing that larger surface area of the meshes provided a faster MTZ release. Moreover, MTZ loaded 3D-printed discs (5% w/w) were capable of inhibiting the growth of Gardnerella vaginalis. These materials showed clear antimicrobial properties, exhibiting a zone of inhibition of 19.0 ± 1.3 mm. Based on these findings, the manufactured represent a valuable alternative approach to the current available treatment, as they were able to provide sustained release of MTZ, reducing the frequency of administration and thus improving patient compliance

Systemic delivery of tenofovir alafenamide using dissolving and implantable microneedle patches

The human immunodeficiency virus (HIV) remains a global health concern, with 37.7 million people currently living with the infection and 1.5 million new cases every year. Current antiretroviral (ARV) therapies are administered through the oral route daily, often in lifelong treatments, leading to pill fatigue and poor treatment adherence. Therefore, the development of novel formulations for the administration ARV drugs using alternative routes is actively sought out. In this sense, microneedle array patches (MAPs) offer a unique user-centric platform that can be painlessly self-applied to the skin and deliver drugs to the systemic circulation. In this work, dissolving and implantable MAPs loaded with the tenofovir alafenamide (TAF) were developed with the aim of releasing the drug systemically. Both MAPs were sufficiently strong to pierce excised neonatal full-thickness porcine skin and form drug depots. In vitro release experiments performed in dialysis membrane models, demonstrated a relatively fast delivery of the drug in all cases. Franz cells experiments revealed that dissolving and implantable MAPs deposited 47.87 ​± ​16.33 ​μg and 1208.04 ​± ​417.9 ​μg of TAF in the skin after 24 ​h. Pharmacokinetic experiments in rats demonstrated a fast metabolization of TAF into tenofovir, with a rapid elimination of the metabolite from the plasma. The MAPs described in this work could be used as an alternative to current oral treatments for HIV management

Use of 3D Printing for the Development of Biodegradable Antiplatelet Materials for Cardiovascular Applications

Small-diameter synthetic vascular grafts are required for surgical bypass grafting when there is a lack of suitable autologous vessels due to different reasons, such as previous operations. Thrombosis is the main cause of failure of small-diameter synthetic vascular grafts when used for this revascularization technique. Therefore, the development of biodegradable vascular grafts capable of providing a localized and sustained antithrombotic drug release mark a major step forward in the fight against cardiovascular diseases, which are the leading cause of death globally. The present paper describes the use of an extrusion-based 3D printing technology for the production of biodegradable antiplatelet tubular grafts for cardiovascular applications. For this purpose, acetylsalicylic acid (ASA) was chosen as a model molecule due to its antiplatelet activity. Poly(caprolactone) and ASA were combined for the fabrication and characterization of ASA-loaded tubular grafts. Moreover, rifampicin (RIF) was added to the formulation containing the higher ASA loading, as a model molecule that can be used to prevent vascular prosthesis infections. The produced tubular grafts were fully characterized through multiple techniques and the last step was to evaluate their drug release, antiplatelet and antimicrobial activity and cytocompatibility. The results suggested that these materials were capable of providing a sustained ASA release for periods of up to 2 weeks. Tubular grafts containing 10% (w/w) of ASA showed lower platelet adhesion onto the surface than the blank and grafts containing 5% (w/w) of ASA. Moreover, tubular grafts scaffolds containing 1% (w/w) of RIF were capable of inhibiting the growth of Staphylococcus aureus. Finally, the evaluation of the cytocompatibility of the scaffold samples revealed that the incorporation of ASA or RIF into the composition did not compromise cell viability and proliferation at short incubation periods (24 h)

Reservoir-type intranasal implants for sustained release of risperidone: a potential alternative for long-term treatment of schizophrenia

To overcome the challenges of the blood-brain barrier for drug delivery to the central nervous system (CNS), intranasal implants were developed to improve the management of CNS conditions, such as schizophrenia. In the present work, we developed and characterised a drug-containing implant consisting of two parts: a core layer made from risperidone (RIS) and water-soluble polymers, including poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) (PEG), and a coating layer made of poly(caprolactone) (PCL) membrane. The obtained implants, where the core layer contained 75% w/w risperidone, were characterised using several techniques: scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR). Moreover, the in vitro release profile of RIS was studied, showing that the PCL membrane could extend the release of RIS from 2 days up to 100 days. The in vitro release profile of the PCL-coated implant exhibited a linear release over the first 10 days, followed by a slower release rate that reached another linear phase up to 40 days. Subsequently, the drug release rates progressively slowed down. Finally, the results of in vitro biocompatibility studies indicated that the intranasal implants were biocompatible and non-cytotoxic. These findings suggest that the implants prepared in this work have the potential to provide long-acting drug delivery for targeting the brain.<br/