Impact of manufacturing variables on product performance of contraceptive levonorgestrel intrauterine systems.

The development of Levonorgestrel Intrauterine Systems (LNG-IUSs) stands as a formidable challenge due to their intricate design and reliance on specialized manufacturing methods. Pharmaceutical manufacturers face a labyrinth of process variables that demand precise identification and comprehension to establish a robust product design to ensure consistent performance. The current manuscript navigates through this complexity, describing a small-scale processing method for LNG-IUSs via addition and condensation curing processes, as well as investigating the influence of key manufacturing variables on LNG-IUS product performance. Different mixing speeds and time exhibited distinct impact on drug content uniformity within the IUS drug-polymer reservoirs. Surprisingly, no variation in drug release rates were observed. Curing temperature and time were the critical processing parameters of IUSs which were dependent on the polymer type (polydimethylsiloxane, PDMS) and drug loading. At lower curing temperatures, crosslinking in PDMS remained relatively unaffected, irrespective of drug loading. By contrast, elevating curing temperatures resulted in a drastic reduction in PDMS crosslinking densities at higher drug loading. This was attributed to increased drug volume fraction within the matrix, impeding optimal prepolymer chain mobility and rearrangement which is crucial for complete crosslinking. Interestingly, rapid curing led to increased PDMS crystallinity, thereby retarding drug release rates while concurrently compromising mechanical properties. PDMS curing chemistry, such as condensation cure (no filler) and addition cure (cured at room temperature), did not affect drug release rates of the LNG-IUSs. In the condensation cure-based LNG-IUS, the formulations prepared without filler had higher drug release rates than those containing silica or diatomaceous earth fillers. Overall, the present study unravels the intricate interplay between PDMS characteristics, processing variables, and product performance, offering fundamental insights into product design and manufacturing of brand and generic LNG-IUS products.

Tailoring drug release from long-acting contraceptive levonorgestrel intrauterine systems.

The wide array of polydimethylsiloxane (PDMS) variants available on the market, coupled with the intricate combination of additives in silicone polymers, and the incomplete understanding of drug release behavior make formulation development of levonorgestrel intrauterine systems (LNG-IUSs) formidable. Accordingly, the objectives of this work were to investigate the impact of excipients on formulation attributes and in vitro performance of LNG-IUSs, elucidate drug release mechanisms, and thereby improve product understanding. LNG-IUSs with a wide range of additives and fillers were prepared, and in vitro drug release testing was conducted for up to 12 months. Incorporating various additives and/or fillers (silica, silicone resins, silicone oil, PEG, etc.) altered the crystallization kinetics of the crosslinked polymer, the viscosity, and the microstructure. In addition, drug-excipient interactions can occur. Interestingly, additives which increased matrix hydrophobicity and hindered PDMS crystallization facilitated dissolution and permeation of the lipophilic LNG. The influence of additives and lubricants on the mechanical properties of LNG-IUSs were also evaluated. PDMS chemical substitution and molecular weight were deemed to be most critical polymer attributes to the in vitro performance of LNG-IUSs. Drugs with varying physicochemical characteristics were used to prepare IUSs, modeling of the release kinetics was performed, and correlations between release properties and the various physicochemical attributes of the model drugs were established. Strong correlations between first order release rate constants and both drug solubility and Log P underpin the partition and diffusion-based release mechanisms in LNG-IUSs. This is the first comprehensive report to provide a mechanistic understanding of material-property-performance relationships for IUSs. This work offers an evidence-based approach to rational excipient selection and tailoring of drug release to achieve target daily release rates in vivo. The novel insights gained through this research could be helpful for supporting development of brand and generic IUS products as well as their regulatory assessment.

Mucoadhesive drug delivery systems: a promising non-invasive approach to bioavailability enhancement. Part I: biophysical considerations.

INTRODUCTION: Mucoadhesive drug delivery systems (MDDS) are specifically designed to interact and bind to the mucosal layer for localized, prolonged, and/or targeted drug delivery. Over the past 4 decades, different sites have been explored for mucoadhesion including the nasal, oral, and vaginal cavities, the gastrointestinal tract and ocular tissues. AREAS COVERED: The present review aims to provide a comprehensive understanding of different aspects of MDDS development. Part I focuses on the anatomical and biological aspects of mucoadhesion, which include a detailed elucidation of the structure and anatomy of the mucosa, the properties of mucin, the different theories of mucoadhesion and evaluation techniques. EXPERT OPINION: The mucosal layer presents a unique opportunity for effective localization as well as systemic drug delivery via MDDS. Formulation of MDDS requires a thorough understanding of the anatomy of mucus tissue, the rate of mucus secretion and turnover, and the physicochemical properties of mucus. Further, the moisture content and the hydration of polymers are crucial for interaction with mucus. A confluence of different theories used to explain the mechanism of mucoadhesion is useful for understanding the mucoadhesion of different MDDS and their evaluation is subject to factors, such as the site of administration, type of dosage form, and duration of action. [Figure: see text].

Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations.

INTRODUCTION: Mucoadhesive drug delivery systems (MDDS) are specifically designed to interact and bind to the mucosal layer of the epithelium for localized, prolonged, and/or targeted drug delivery. Over the past 4 decades, several dosage forms have been developed for localized as well as systemic drug delivery at different anatomical sites. AREAS COVERED: The objective of this review is to provide a detailed understanding of the different aspects of MDDS. Part II describes the origin and evolution of MDDS, followed by a discussion of the properties of mucoadhesive polymers. Finally, a synopsis of the different commercial aspects of MDDS, recent advances in the development of MDDS for biologics and COVID-19 as well as future perspectives are provided. EXPERT OPINION: A review of the past reports and recent advances reveal MDDS as highly versatile, biocompatible, and noninvasive drug delivery systems. The rise in the number of approved biologics, the introduction of newer highly efficient thiomers, as well as the recent advances in the field of nanotechnology have led to several excellent applications of MDDS, which are predicted to grow significantly in the future.

Impact of drug loading on release from levonorgestrel intrauterine systems.

Levonorgestrel intrauterine systems (LNG-IUSs) are polydimethylsiloxane (PDMS) based non-biodegradable complex drug-device combination products providing efficacy for up to several years based on the strength. A large amount of LNG (e.g., 52 mg in Mirena and Liletta) must be loaded in the LNG-IUS products to maintain the long-acting effect even though LNG is a potent hormone. However, the high amount of LNG not only poses the potential risk of dose dumping, but also leads to drug waste due to incomplete drug utilization close to the end of usage. It has been unclear whether the duration of usage of these products should be extended for full drug utilization or products with lower drug loading should be developed. Therefore, it is critical to understand the impact of strength (or drug loading) on drug release from LNG-IUSs. In the current study, drug reservoirs with a broad range of drug loading (from 0.5% w/w to 50% w/w) were prepared and assembled into LNG-IUSs. Different accelerated release conditions were used to perform release testing of LNG-IUSs with different drug loading. 5% to 10% variation in excipient of the LNG-IUSs did not significantly alter the drug release profiles of the LNG-IUSs. The release rate of LNG-IUSs is inversely proportional to their drug loading at high drug loading (10% w/w, 25% w/w and 50% w/w). Drug release was incomplete for LNG-IUS with low drug loading (2.5% w/w and 1% w/w) and no drug release could be detected for the LNG-IUS with 0.5% w/w drug loading. In addition, the burst effect of the LNG-IUSs with different drug loading was investigated. This is the first research report covering ultra-long duration (more than four years) of real-time drug release from LNG-IUSs with different drug loading (0.5%-50% w/w). The amount of excipient (PDMS) used in the reservoir of LNG-IUSs was determined to be not a critical quality parameter in the formulation design since LNG-IUSs (50% w/w drug loading) with up to 10% variation in excipient did not show significant differences in their release profiles. The drug release kinetics/mechanism remained the same for LNG-IUSs with drug loading ranging from 1% to 50%. In addition, the accelerated release testing methods were confirmed to be representative of the real-time release profiles and this can give confidence in extending the duration of usage for these products provided that the device remains physically intact (no tearing or damage in the outer membrane) and the release rate is within the therapeutic window. It is recommended to perform both real-time and accelerated release testing simultaneously for LNG-IUSs to understand the burst effect as well as the complete release characteristics. Lastly, drug/polymer interaction may play a role when designing LNG-IUS formulations with low drug loading (<5% w/w) since drug/polymer interaction is significant when only a small amount of drug present.

Long-acting intrauterine systems: Recent advances, current challenges, and future opportunities.

Levonorgestrel intrauterine systems (LNG-IUSs) are complex drug-device combination products designed to release a hormonal contraceptive drug for up to 7 years. These drug delivery systems offers a great promise as a modern method of long-acting reversible contraceptives (LARCs) to improve women's health. Unfortunately, there are some scientific challenges associated with the development of these products which are among the major reasons contributing to the availability of relatively few IUS products on the market. This review summarizes the formulation considerations (drug and excipient attributes), manufacturing methods, advances in characterization and in vitro drug release testing of IUSs, as well as factors influencing drug release from IUSs. A critical discussion on the major challenges to IUS product development is presented. Specifically, insights on bioequivalence evaluation, in vitro-in vivo correlation (IVIVC) establishment, and regulatory challenges are detailed. Lastly, methodological tools to overcome some of these hurdles to product development are proposed. The knowledge furnished through this review will be helpful towards obtaining better product understanding. Such understanding will facilitate the development of these complex drug products, as well as their regulatory approval process.

Impact of polymer crosslinking on release mechanisms from long-acting levonorgestrel intrauterine systems.

Polydimethylsiloxane (PDMS) crosslinking density is a critical material attribute of levonorgestrel intrauterine systems (LNG-IUSs) that affects drug release and may have a significant influence on product performance and safety. Accordingly, the objective of the present work was to investigate the impact of PDMS crosslinking on the release mechanisms of LNG-IUSs and thereby achieve better product understanding. To investigate the effect of PDMS crosslinking, LNG-IUSs with varying prepolymer ratios and different mixing conditions were prepared. Accelerated and real-time in vitro release of the LNG-IUSs were conducted for up to 80 days and 7 months, respectively. Contrary to conventional understanding, formulations with higher crosslinking density showed faster drug release rates. To further understand this anomalous release behavior, the microstructure and molecular properties (using scanning electron microscopy, mercury intrusion porosimetry, polymer swelling studies, solid-state silicon NMR, and wide-angle X-ray diffraction) were investigated. Interestingly, it was revealed that high PDMS crosslinking forms a solid-state porous branched network with amorphous polymer domains facilitating fast solvent uptake (in organic solvents) and easy access to the drug particles leading to rapid mass transport of the drug molecules. Furthermore, formulations processed using planetary mixing showed higher crosslinking densities and faster drug release rates than those prepared using manual mixing. Model fitting of all LNG-IUSs were carried out using first order, two-phase (zero order plus Higuchi), and Korsmeyer-Peppas models. The first order model (which showed the best fitting for the full release profile) was used to establish correlations between the drug release rates and the PDMS crosslinking densities of LNG-IUSs. This is the first comprehensive report providing novel insights into crosslinking-induced microstructural changes and physicochemical properties that dictate drug release from LNG-IUSs.

Effect of crosslinking on the physicochemical properties of polydimethylsiloxane-based levonorgestrel intrauterine systems.

Polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs) such as Mirena® are long-acting drug-device combination products designed to release LNG for contraceptive purposes up to 6 years. LNG-IUSs consist of a hollow cylindrical drug-PDMS reservoir mounted with a polyethylene frame and covered by an outer PDMS membrane. PDMS is the release-controlling excipient present in both the matrix and the outer membrane. The degree of PDMS crosslinking is a key parameter in LNG-IUS manufacturing, dictating the elasticity and mechanical strength (which are critical parameters in molding and demolding of the cylindrical reservoirs). In addition, elasticity and mechanical strength are also important to prevent deformation during insertion into the uterine cavity. The objectives of this study were to investigate the impact of PDMS crosslinking on the physicochemical properties of LNG-IUSs and to develop appropriate testing methods for characterization of their mechanical strength. Formulations with different degrees of crosslinking were prepared by varying the ratio of the PDMS elastomer base and the crosslinking agent. A novel solvent swelling and extraction method was developed to determine the degree of PDMS crosslinking. The extent of crosslinking was also characterized via FTIR, Raman, 1H NMR, DSC, TGA and dynamic mechanical analysis. As expected, formulations with higher degrees of crosslinking showed lower crystallinity. Interestingly, the less crystalline formulations showed higher Tg values and storage moduli compared to the high crystalline formulations, implying that crosslinking is the predominant parameter governing the physicochemical and mechanical properties in LNG-IUSs. Correlations were established between PDMS crosslinking and the physicochemical properties of LNG-IUSs which will be useful for quality control purposes during formulation screening and development. A better understanding of the physicochemical characteristics of these complex products will facilitate drug product development.