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.

Development of Mechanistic In Vitro-In Vivo Extrapolation to Support Bioequivalence Assessment of Long-Acting Injectables.

Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI-physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera® and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs.

Hyper-spectra imaging analysis of PLGA microspheres via machine learning enhanced Raman spectroscopy.

Long-acting injectables (LAI) offer a cost-effective and patient-centric approach by reducing pill burden and improving compliance, leading to better treatment outcomes. Among various types of long-acting injectables, poly (lactic-co-glycolic acid) (PLGA) microspheres have been extensively investigated and reported in the literature. However, microsphere formulation development is still challenging due to the complexity of PLGA polymer, formulation screening, and processing, as well as time-consuming and cumbersome physicochemical characterization. A further challenge is the limited availability of drug substances in early formulation development. Therefore, there is a need to develop novel and advanced tools that can accelerate the early formulation development. In this manuscript, a novel comprehensive physicochemical characterization approach was developed by integrating Raman microscopy and the machine learning process. The physicochemical properties such as drug loading, particle size and size distribution, content uniformity/heterogeneity, and drug polymorphism of the microspheres can be obtained in a single run, without requiring separate methods for each attribute (e.g., liquid chromatography, particle size analyzer, thermal analysis, X-ray powder diffraction). This approach is non-destructive and can significantly reduce material consumption, sample preparation, labor work, and analysis time/cost, which will greatly facilitate the formulation development of PLGA microsphere products. In addition, the approach will potentially be beneficial in enabling automated high throughput screening of microsphere formulations.

In situ forming risperidone implants: Effect of PLGA attributes on product performance.

Despite the unique advantages of injectable, long-acting in situ forming implant formulations based on poly(lactide-co-glycolide) (PLGA) and N-Methyl-2-Pyrrolidone (NMP), only six products are commercially available. A better understanding of PLGA will aid in the development of more in situ forming implant innovator and generic products. This article investigates the impact of slight changes in PLGA attributes, i.e., molecular weight (MW), lactide:glycolide (L/G) ratio, blockiness, and end group, on the in vitro and in vivo performance of PLGA-based in situ forming implant formulations. Perseris (risperidone) for extended-release injectable suspension was selected as the reference listed drug (RLD). A previously developed adapter-based USP 2 method was used for the in vitro release testing of various risperidone implant formulations. A rabbit model was used to determine the in vivo pharmacokinetic profiles of the formulations (subcutaneous administration) and deconvolution (Loo-Riegelman method) was conducted to obtain the in vivo release profiles. The results showed that a 5 KDa difference in the MW (19.2, 24.2, 29.2 KDa), a 5% variation in the L/G ratio (85/15, 80/20, 75/25) and the end-cap (acid vs ester) all significantly impacted the formulation behavior both in vitro and in vivo. Higher MW, higher L/G ratio and ester end-cap PLGA all resulted in longer release durations. The formulations prepared with polymers with different blockiness values (within the blockiness range tested) did not show differences in in vitro and in vivo release. An in vitro-in vivo correlation (IVIVC) was not developed due to the different in vitro and in vivo phase separation rates, swelling tendencies and consequent significantly different release profiles. This is the first report evaluating the impact of PLGA property variation (over a narrow range) on the performance of in situ forming implants. The knowledge gained will provide a better understanding of the mechanisms underlying risperidone in situ forming implant performance and will aid the development of future products.

In vivo characterization of Perseris and compositionally equivalent formulations.

Perseris is asubcutaneous extended-release risperidone in situ forming implant (suspension) indicated for the treatment of adult schizophrenia. Owing to the release rate controlling polymer poly(lactide-co-glycolide) (PLGA), one injection of Perseris can deliver risperidone for one month, which significantly reduces the administration frequency and improves patient compliance. The PLGA and drug used in Perseris was previously identified through reverse engineering and two compositionally equivalent formulations (F-1 and F-2) showing similar in vitro drug release were developed. The current work focuses on in vivo exploration of Perseris and the developed compositionally equivalent formulations using a rabbit model and further evaluate the sameness of the developed formulations compared to Perseris. The in vivo pharmacokinetic (PK) profiles, drug absorption rate, phase separation rate, macro appearance, weight loss as well as the water uptake of the solidified drug depots at different time points were investigated and compared with the in vitro release data as well as with dog and human in vivo data available in literature. Results show that the rabbit PK profile of Perseris was relevant with those obtained from both the dog model and the clinical data, indicating that the rabbit model is appropriate for investigation of the in vivo performance of risperidone implants. Consistent with their similar in vitro drug release, the two compositionally equivalent formulations demonstrated similar PK profiles, drug absorption rates, weight loss and swelling in vivo compared to Perseris. Although the erosion mechanism appeared to be similar between in vitro and in vivo, there were in vitro-in vivo differences concerning the drug release kinetics, phase separation rates and swelling behavior. This work provides a comprehensive in vitro/in vivo understanding of Perseris and the developed compositionally equivalent formulations, which will be beneficial for future development of generic as well as novel PLGA in situ forming implant products.

Investigating structural attributes of drug encapsulated microspheres with quantitative X-ray imaging.

The intra-sphere and inter-sphere structural attributes of controlled release microsphere drug products can greatly impact their release profile and clinical performance. In developing a robust and efficient method to characterize the structure of microsphere drug products, this paper proposes X-ray microscopy (XRM) combined with artificial intelligence (AI)-based image analytics. Eight minocycline loaded poly(lactic-co-glycolic acid) (PLGA) microsphere batches were produced with controlled variations in manufacturing parameters, leading to differences in their underlying microstructures and their final release performances. A representative number of microspheres samples from each batch were imaged using high resolution, non-invasive XRM. Reconstructed images and AI-assisted segmentation were used to determine the size distribution, XRM signal intensity, and intensity variation of thousands of microspheres per sample. The signal intensity within the eight batches was nearly constant over the range of microsphere diameters, indicating high structural similarity of spheres within the same batch. Observed differences in the variation of signal intensity between different batches suggests inter-batch non-uniformity arising from differences in the underlying microstructures associated with different manufacturing parameters. These intensity variations were correlated with the structures observed from higher resolution focused ion beam scanning electron microscopy (FIB-SEM) and the in vitro release performance for the batches. The potential for this method for rapid at-line and offline product quality assessment, quality control, and quality assurance is discussed.

Long-acting PLGA microspheres: Advances in excipient and product analysis toward improved product understanding.

Poly(lactic-co-glycolic acid) (PLGA) microspheres are a sustained-release drug delivery system with several successful commercial products used for the treatment of a variety of diseases. By utilizing PLGA polymers with different compositions, therapeutic agents can be released over durations varying from several weeks to several months. However, precise quality control of PLGA polymers and a fundamental understanding of all the factors associated with the performance of PLGA microsphere formulations remains challenging. This knowledge gap can hinder product development of both innovator and generic products. In this review, variability of the key release controlling excipient (PLGA), as well as advanced physicochemical characterization techniques for the PLGA polymer and PLGA microspheres are discussed. The relative merits and challenges of different in vitro release testing methods, in vivo pharmacokinetic studies, and in vitro-in vivo correlation development are also summarized. This review is intended to provide an in-depth understanding of long-acting microsphere products and consequently facilitate the development of these complex products.

Reverse engineering of Perseris and development of compositionally equivalent formulations.

Six injectable, long-acting in situ forming implant drug products based on poly(lactide-co-glycolide) (PLGA) and N-Methyl-2-Pyrrolidone (NMP) are available on the market. However, generic products, which would likely be more affordable for patients, are not yet available. This is partially due to the unique complexity of these formulations as well as the inherent heterogeneity of PLGA and the challenges in the manufacture and characterization of this polymer. This article focuses on a comprehensive characterization of Perseris (risperidone) in situ forming implant drug product, and the development of compositionally equivalent formulations. The molecular weight (MW), lactide/glycolide (L/G) ratio, end group, blockiness and glass transition temperature (Tg) of PLGA, as well as the crystal form and particle size of risperidone powder used in Perseris were identified through reverse engineering. The dissolved/suspended drug ratio in the final implant suspension for administration, as well as the real-time drug solid state in the solidified Perseris drug depot were investigated. Two compositionally equivalent formulations prepared using customized PLGA polymers with similar properties to the Perseris PLGA showed similar in vitro release and swelling behavior to Perseris as demonstrated using a novel adapter-based dissolution method. The novelty of this dissolution method lies in its ability to control implant shape, generate reproducible data, distinguish different release phases, as well as identify formulation changes. The knowledge gained in this work and the methodology established for characterization of the implant formulations are important for implant formulation development.

Long-Acting Injectable Aqueous Suspensions-Summary From an AAPS Workshop.

Through many years of clinical application of long-acting injectables, there is clear proof that this type of formulation does not just provide the patient with convenience, but more importantly a more effective treatment of the medication provided. The formulation approach therefore contains huge untapped potential to improve the quality of life of many patients with a variety of different diseases. This review provides a summary of some of the central talks provided at the workshop with focus on aqueous suspensions and their use as a long-acting injectable. Elements as formulation, manufacturing, in vitro dissolution methods, in vitro and in vivo correlation, in silico modelling provide an insight into some of the current understandings, learnings, and not least gaps in the field.

Development of in vitro-in vivo correlations for long-acting injectable suspensions.

Long-acting injectable (LAI) aqueous suspensions achieve extended drug release over a duration of weeks to months via slow dissolution of drug crystals with low solubility. There have been around ten LAI aqueous suspensions approved by the FDA to date and there are no generic equivalents for most of them. This may be largely due to the complex formulation development as well as the challenges in establishment of in vitro-in vivo correlation (IVIVC) for these products. Level A IVIVCs, using animal models, have been proven feasible for complex long-acting microsphere formulations with multiphasic release characteristics. Accordingly, it may be possible to develop IVIVCs for LAI aqueous drug suspensions since their release characteristics are relatively simple with only a drug dissolution phase. To establish IVIVCs for LAI drug suspensions, four compositionally equivalent medroxyprogesterone acetate LAIs with differences in processing and formulation factors (drug particle size and excipient source) were prepared using Depo-SubQ Provera 104 as the reference listed drug (RLD). Two in vitro release testing methods, modified based on USP apparatus 2 (with enhancer cells) and USP apparatus 4 (with semisolid adapters), were used. The in vivo release was investigated using a rabbit model. Level A IVIVCs were successfully established using the in vitro release profiles obtained with the USP apparatus 4. This is the first report of an IVIVC for LAI aqueous suspensions.

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.

Characterization and in vitro release of minocycline hydrochloride microspheres prepared via coacervation.

Coacervation is a commonly used method for protein and peptide drug microencapsulation using biodegradable or bioresorbable polymers. However, there is a lack of literature focused on microencapsulation of small molecule drugs using coacervation techniques. In addition, the apparatus used for this microencapsulation method has not been well-described. The objectives of the present work were to: (1) establish a reliable apparatus for coacervation microencapsulation; (2) investigate the impact of the viscosity of the silicone oil used in processing on microsphere performance; and (3) develop a reproducible in vitro release testing method for minocycline hydrochloride microspheres. Minocycline hydrochloride was chosen as the model drug and two compositionally equivalent microsphere formulations were prepared via coacervation using an in-house designed glass vessel assembly with a novel in-house customized paddle to achieve a relatively homogeneous particle size distribution. The critical physicochemical properties including drug loading, particle size, and morphology of the prepared microspheres and the commercial microspheres product (Arestin) were determined. In vitro release testing of the prepared microspheres as well as of Arestin was performed using a sample-and-separate method. The method showed good reproducibility and discriminatory ability. The physicochemical properties (such as particle size) as well as the in vitro release characteristics of the prepared microspheres were determined to be sensitive to the viscosity of the silicone oil used in coacervation processing. The silicone oil with higher viscosity (1000 cSt) used during the coacervation process resulted in smaller particle sized microspheres and consequently caused a higher initial burst release. Whereas, the silicone oil with lower viscosity resulted in larger sized microspheres with low burst release and a slower drug release rate.

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.

Assessing microstructural critical quality attributes in PLGA microspheres by FIB-SEM analytics.

The distribution of the active pharmaceutical ingredient (API) within polymer-based controlled release drug products is a critical quality attribute (CQA). It is crucial for the development of such products, to be able to accurately characterize phase distributions in these products to evaluate performance and microstructure (Q3) equivalence. In this study, polymer, API, and porosity distributions in poly(lactic-co-glycolic acid) (PLGA) microspheres were characterized using a combination of focused ion beam scanning electron microscopy (FIB-SEM) and quantitative artificial intelligence (AI) image analytics. Through in-depth investigations of nine different microsphere formulations, microstructural CQAs were identified including the abundance, domain size, and distribution of the API, the polymer, and the microporosity. 3D models, digitally transformed from the FIB-SEM images, were reconstructed to predict controlled drug release numerically. Agreement between the in vitro release experiments and the predictions validated the image-based release modelling method. Sensitivity analysis revealed the dependence of release on the distribution and size of the API particles and the porosity within the polymeric microspheres, as captured through FIB-SEM imaging. To our knowledge, this is the first report showing that microstructural CQAs in PLGA microspheres derived from imaging can be quantitatively and predictively correlated with formulation and manufacturing parameters.

Polymer source affects in vitro-in vivo correlation of leuprolide acetate PLGA microspheres.

Poly(lactic-co-glycolic acid) PLGA (release controlling excipient) plays a dominant role on the performance of PLGA based long-acting parenterals. These types of drug products typically exhibit complex multi-phasic in vitro/in vivo release/absorption characteristics. In particular, owing to their large size, charged state, and hydrophilicity, peptide loaded microspheres can exhibit more complex release mechanisms. Accordingly, it is challenging to develop Level A in vitro-in vivo correlations (IVIVCs) for such complex long-acting parenterals. With the objective of gaining a better understanding of how to achieve IVIVCs for peptide loaded PLGA microspheres, formulations with similar as well as different release characteristics were prepared with PLGAs from different sources. Leuprolide acetate was selected as the model drug. Owning to the different physicochemical properties of the PLGAs (such as inherent viscosity, molecular weight and blockiness), the formulations exhibited significant differences in their critical quality attributes (such as particle size, porosity and pore size) and consequently had different in vitro and in vivo performance. Affirmative conventional IVIVCs were developed that were able to predict the in vivo performance using the corresponding in vitro release profiles. In addition, the developed conventional IVIVCs were able to discriminate between formulations with comparable in vitro/in vivo performance and those that had dissimilar in vitro/in vivo performance. The present work provides a comprehensive understanding of the influence of PLGA source variations on IVIVC development and predictability for peptide loaded PLGA microspheres.

In vitro release testing method development for long-acting injectable suspensions.

Long-acting injectable (LAI) suspensions are complex parenterals intended to control drug release over a duration of weeks to months. Any unpredictive drug release behavior may cause serious side effects. Therefore, it is important to understand the in vitro and in vivo performance, as well as the in vitro-in vivo correlation (IVIVC) of these products. There are some US FDA recommended in vitro release testing methods for LAI suspensions. However, the release duration of all the recommended methods is less than two days which may not be appropriate for the establishment of IVIVCs for LAIs considering that their in vivo efficacies range from weeks to months. To develop in vitro release testing methods that may better correlate with in vivo release with longer durations, three compositionally equivalent medroxyprogesterone acetate suspensions were prepared with different particle size, using Depo-SubQ Provera 104® as the reference listed drug (RLD). Four different methods based on USP apparatus 2 (with dialysis sacs, enhancer cells or in-house designed devices) and USP apparatus 4 (with semisolid adapters) were utilized. USP apparatus 2 with enhancer cells and USP apparatus 4 with semisolid adapters showed the best discriminatory ability and reproducibility for the LAI suspensions investigated.

In vitro-in vivo correlation of PLGA microspheres: Effect of polymer source variation and temperature.

Development of Level A in vitro-in vivo correlations (IVIVCs) remains challenging for complex long-acting parenterals, such as poly(lactic-co-glycolic acid) PLGA microspheres. The nature of the PLGA polymer excipient has a dominant influence on the performance of PLGA microspheres. These microsphere systems typically exhibit multiphasic in vitro/in vivo release/absorption characteristics and may also show interspecies differences (animal model versus human data). These issues contribute to the difficulties in the development of IVIVCs for PLGA microsphere systems. To gain a better understanding of how to achieve IVIVCs for PLGA microspheres, microsphere formulations with similar as well as different release characteristics were prepared using PLGAs from different sources. Efforts were then made to establish IVIVCs for these formulations using in vitro release profiles obtained at both 37°C (human body temperature) and 39°C (rabbit body temperature) with in vivo data obtained from an animal model (rabbit). Risperidone was selected as the model drug; microsphere formulations were prepared under the same processing methods using apparently similar PLGAs from different sources. Owning to the different physicochemical properties of the PLGAs (such as inherent viscosity, monomer ratio (L/G ratio) and blockiness), the formulations exhibited significant differences in critical quality attributes (such as particle size, particle size distribution, porosity and pore size) and consequently had different in vitro and in vivo performance. IVIVCs were developed and it was shown that model predictability improved when IVIVCs were established using those formulations with comparable release characteristics. In addition, IVIVCs were established with Tscaling factors close to 1 using in vitro release profiles acquired at 39°C, emphasizing the importance of considering the body temperature in understanding interspecies differences. The present work provides a comprehensive understanding of the impact of the PLGA source variation on IVIVC development and predictability for complex long-acting parenterals such as PLGA microspheres.

Novel adapter method for in vitro release testing of in situ forming implants.

In situ forming implants are injectable liquid formulations which form solid or semisolid depots following injection. This allows for minimally invasive administration, localized drug delivery, and extended drug release. Unfortunately, this drug delivery strategy lacks standardized in vitro dissolution methods due to the difficulties in recreating implant formation in vitro that is biomimicry and with reproducible and controllable shape and dimensions. In the present study, an innovative, adapter-based in vitro release testing method was developed to solve this problem. Two distinctively different in situ forming implants (a risperidone formulation (suspension) consisting of PLGA dissolved in N-methyl pyrrolidone (NMP), where risperidone powder was suspended to form a drug suspension, and a naproxen formulation (solution) consisting of PLGA dissolved in NMP, where naproxen was completely dissolved to form a solution), were used as model in situ-forming implants. The results revealed that the implants formed in the custom-designed adapter with a water-dissolvable polyvinyl alcohol (PVA) film were bio-mimicking and reproducible in both shape and burst release of drug according to rabbit data. For both the suspension and solution formulations, this adapter-based in vitro release testing method resulted in consistent release data. Compared with a direct injection in vitro release testing method, the release profiles generated using the adapter-based method were capable of distinguishing the different release phases (initial release within 24 h, diffusion-facilitated release, and degradation-controlled release). In addition, the adapter-based method could discriminate formulation and dissolution apparatus changes and could be utilized to develop accelerated release testing methods. This adapter-based method has the promise of wide use in release testing of in situ forming implant formulations and has the potential to be used in the development of in vivo-predictive in vitro release methods.

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.