Novel pH-Responsive Structural Rearrangement of Myristic Acid-Conjugated Quetiapine Nanosuspension for Enhanced Long-Acting Delivery Performance.

Quetiapine myristate (QM), an ester-bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self-assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200-nm-sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide-co-glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg-1 QTP), QMN undergoes pH-responsive nanoaggregation to form the lipophilic prodrug, providing esterase-oriented sustained release for five weeks compared with the two-week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long-acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long-acting injectable to improve patient compliance and dosing frequency.

Novel dissolution methods for drug release testing of Long-Acting injectables.

Long-acting parenteral drug products are a popular choice for therapeutic areas requiring long term treatment. These products range from dispersed systems such as drug suspensions and polymeric microspheres to in situ forming polymeric implants. The lack of reliable drug release testing methods for these drug products not only impedes the development of new drug products but also affects generic drug development. Current release methods suffer from a range of problems such as high variability, poor reproducibility, poor discriminatory ability, lack of depot-like structure formation (that could mimic the in vivo situation). Moreover, shorter duration (less than a week) of release renders them unsuitable for in vitro-in vivo correlations (IVIVCs). To overcome these issues, novel adapters were developed for both USP-type-II & IV apparatus. These adapters were validated and assessed using the long-acting injectable (LAI) suspension drug product Depo Provera 150® as well as its Q1/Q2 equivalents. For USP-type-IV apparatus, two open adapter designs (conical and ellipsoidal shaped cavity with volume capacities of 50 µl and 1 ml, respectively) were developed. A closed conical adapter design with a volume capacity of 0.05 ml was developed for USP apparatus type-II. All three novel adapter designs effectively retained the suspensions, achieved release durations of 3-6 weeks with good reproducibility, minimal variability (RSD≤5%) and had good discriminatory ability. Based on this, the adapter-based dissolution methods were deemed suitable for IVIVC development of long-acting injectables. A successful Level A IVIVC was developed for Depo SubQ Provera 104® and its Q1Q2 equivalents using USP apparatus type IV with a conical adapter design. The closed adapter design for apparatus type-II was also investigated for suitability with risperidone in situ forming implants. The adapter was able to securely retain and maintain the shape of the in situ forming implants and resulted in release profiles of up to one month with good discriminatory ability and low standard error (RSD≤5%). These novel adapters hold promise of wide use for in vitro release testing of different long-acting parenteral drug products.

Patient-Centric Long-Acting Injectable and Implantable Platforms─An Industrial Perspective.

The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients' unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient's provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations. In this work, a comprehensive analysis of marketed LAIs across therapeutic classes and technologies is conducted. The analysis demonstrated an increasing number of new LAIs being brought to the market, recently most as aqueous suspensions and one as a solution, but many other technology platforms were applied as well, in particular, polymeric microspheres and in situ forming gels. The analysis across the technologies provided an insight into to the physicochemical properties the compounds had per technology class as well as knowledge of the excipients typically used within the individual formulation technology. The principle behind the formulation technologies was discussed with respect to the release mechanism, manufacturing approaches, and the possibility of defining predictive in vitro release methods to obtain in vitro in vivo correlations with an industrial angle. The gaps in the field are still numerous, including better systematic formulation and manufacturing investigations to get a better understanding of potential innovations, but also development of new polymers could facilitate the development of additional compounds. The biggest and most important gaps, however, seem to be the development of predictive in vitro dissolution methods utilizing pharmacopoeia described equipment to enable their use for product development and later in the product cycle for quality-based purposes.

Implementation of long-acting cabotegravir and rilpivirine: primary results from the perspective of staff study participants in the Cabotegravir And Rilpivirine Implementation Study in European Locations.

INTRODUCTION: Cabotegravir plus rilpivirine (CAB + RPV) is the first complete long-acting (LA) regimen recommended for maintaining HIV-1 virological suppression. Cabotegravir And Rilpivirine Implementation Study in European Locations (CARISEL) is an implementation-effectiveness study examining the implementation of CAB+RPV LA administered every 2 months (Q2M) in European HIV centres. We present staff study participant (SSP) perspectives on the administration of CAB+RPV LA over 12 months. METHODS: Eighteen clinics were randomized to one of two implementation support packages: standard arm (Arm-S) or enhanced arm (Arm-E). Arm-S included video injection training and provider/patient toolkits. Additionally, Arm-E included skilled wrap-around team meetings, face-to-face injection training and continuous quality improvement (CQI) calls. SSPs completed surveys on the acceptability, appropriateness and feasibility of CAB+RPV LA as an intervention and its implementation into their clinics, as well as barriers and facilitators to implementation. All surveys were completed at Month (M)1 (baseline), M5 and M12; data collection was completed by February 2022. Qualitative data were obtained from semi-structured interviews at M1, M5 and M12. The primary objective was assessed via formal statistical comparisons between study arms of the Acceptability of Implementation Measure, Implementation Appropriateness Measure and Feasibility of Implementation Measure surveys (1-5 Likert scale ranging from 1 = "completely disagree" to 5 = "completely agree"). Equivalent measures anchored to CAB+RPV LA as a therapy were also assessed. RESULTS: Seventy SSPs completed surveys and interviews at M1, 68 at M5 and 62 at M12. Mean acceptability/appropriateness/feasibility scores were ≥3.8 (out of 5) at M12 for implementation- and intervention-based measures. An analysis of covariance showed no significant differences between study arms for these outcomes. Although barriers were noted, most SSPs were not overly concerned that these would impact implementation; concern about these anticipated barriers also decreased over time. At M12, 90.3% (n = 56/62) of SSPs held a positive opinion about CAB+RPV LA implementation. Qualitative interviews and CQI calls highlighted three top practices that supported implementation: implementation planning; education about CAB+RPV LA clinical efficacy; and education around administering injections and managing pain/discomfort after injections. CONCLUSIONS: CARISEL demonstrated that CAB+RPV LA dosed Q2M was successfully implemented across a range of European locations, with SSPs finding implementation highly acceptable, appropriate and feasible. GOV NUMBER: NCT04399551.

Long-Acting Injectable Antipsychotics in the Geriatric Population: A longitudinal Study.

OBJECTIVE: This study compares demographic, clinical characteristics, and outcomes in older adults on long-acting injectable antipsychotics (LAI-AP) vs. oral antipsychotics (PO-AP). DESIGN: This observational study with a retrospective cohort utilized the electronic medical record's search engine to review charts of geriatric patients on LAI-AP for a two-year period. A convenience sample on PO-AP formed the comparison group. LAI-AP patients were subcategorized into discontinuation and continuation groups. SETTING: Conducted at an urban, psychiatric outpatient clinic, using charts from October 2020 to 2022. PARTICIPANTS: Patients at least 60 years-old with psychotic or mood disorders on antipsychotics for at least 3-months during the study period. MEASUREMENTS: Demographic and clinical variables, including diagnosis, medication type, side effects, medical comorbidities, neurocognitive status, and secondary medications, were collected for both PO-AP and LAI-AP groups. Outcome variables included missed appointments, psychiatric and medical hospitalizations, and emergency room visits. Correlates of discontinuation of LAI-AP were also assessed. RESULTS: LAI-AP had a higher proportion than PO-AP of primary psychotic disorders (87.8% vs. 64.3%). During the study, PO-AP had higher rates of missed appointments (median 18% vs. 13% for LAI-AP) and psychiatric admissions (mean 0.019/month vs. 0.006/month for LAI-AP;); Female sex was a risk factor for discontinuation of LAI-AP (86.7% of discontinuation group vs. 55.2% of continuation group). CONCLUSIONS: The LAI-AP group showed reduced hospitalizations, better treatment engagement, and comparable tolerability to PO-AP. Preliminary data suggests gender may influence LAI-AP discontinuation rates. This study adds to the sparse literature investigating the efficacy and tolerability of LAI-AP in geriatric patients.

Engagement in Care, Awareness, and Interest in Long-Acting Injectable Anti-Retroviral Therapy.

Long Acting Injectable (LAI) therapy to treat HIV is an alternative to daily oral medications. The success of early roll-out of LAI to eligible patients requires a better understanding of patients' awareness and interest in this novel therapy. We administered an electronic survey to patients attending an urban HIV clinic in the US South. Eligible participants were 18 + years old with a most recent HIV-1 viral load < 200 copies/ml, without any evidence of genotypic resistance to LAI components or chronic hepatitis B. Survey recipients were asked about current treatment, engagement in care, and knowledge of LAI. Between January-April 2023, 480 patients were screened; 319 were eligible, and 155 (49%) completed the survey. The majority (119, 77%) were aware of, and 87 (56%) were interested in LAI. In regression analysis, only age was associated with interest in LAI (OR 0.95, 95% CI 0.92,0.99). Among proposed benefits of injectables, ease of travel without pills, lack of daily pill-taking, and fewer medication interactions were most appealing. Among proposed concerns with injectables, higher cost and insurance coverage of the new medicine were most worrisome. A large majority of people with HIV (PWH) are aware of the newest treatment available, and just over half of our sample expressed interest in LAI. Older age was associated with lower interest in LAI. LAI is appealing for its convenience, privacy, and avoidance of drug interactions, while the increased costs associated with LAI need to be addressed.

Discovery of novel anti-infective agents.

Academic and other non-profit institutions have a long-term vision to improve human health where commercial interests can be limited for profit organizations. Medicinal chemistry to these diseases with no commercial benefit needs is well suited in the academic environment and this chapter outlines some work conducted at Calibr-Skaggs around antibiotic drug development that has led to initiation of multiple clinical trials over the last decade.

Porous PLGA microparticles prepared with nanosized/micronized sugar particles as porogens.

The objective of this study was to explore the use of nanosized/micronized sugar particles as porogens for preparing porous poly(lactide-co-glycolide) (PLGA) microparticles by a solid-in-oil-in-water (S/O/W) solvent evaporation method. Porous PLGA microparticles containing dexamethasone were prepared with different nanosized/micronized sugars (sucrose, trehalose and lactose), types of PLGA, and osmogens (NaCl or sucrose) in the external water phase. The microparticles were characterized for morphology, thermal properties, particle size, surface area, encapsulation efficiency and drug release/swelling during release. The addition of nanosized/micronized sugar particles resulted in porous PLGA microparticles with high encapsulation efficiencies. The porosity of the microparticles was caused both by the influx of water into the polymer droplets and the encapsulation and subsequent dissolution of sugar particles during the manufacturing process. The porosity (pore size) of the microparticles and, as a result, the drug release pattern could be well controlled by the particle size and weight fraction of the sugar particles. Because of a larger inner surface area, nanosized sugar particles were more efficient porogen than micronized sugar particles to obtain porous PLGA microparticles with flexible release patterns.

A Phase I, Open-Label, Sequential, Single-Dose Clinical Trial to Evaluate the Pharmacokinetic, Pharmacodynamic, and Safety of IVL3001, a Finasteride-Based Novel Long-Acting Injection for Androgenetic Alopecia.

INTRODUCTION: Hair loss is driven by multiple factors, including genetics. Androgenetic alopecia (AGA) is a condition in which treatments necessitate prolonged compliance with prescribed medications. We have developed IVL3001, a long-acting injectable (LAI) formulation of finasteride encapsulated within poly lactic-co-glycolic acid microspheres, to enhance the efficacy of the finasteride and to achieve consistent positive outcomes in adults. An open-label, sequential, single-dose phase I clinical trial was designed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of IVL3001. METHODS: A total of 40 non-smoking, healthy adult males were divided into three cohorts where the IVL3001 group received a single subcutaneous injection of 12-36 mg IVL3001 and 1 mg finasteride (Propecia®) once daily for 28 days. The plasma concentrations of finasteride, dihydrotestosterone (DHT), and testosterone were measured using liquid chromatography-tandem mass spectrometry. The tolerability of the injections was assessed, and compartment models were developed to predict the effective dose and assess PK/PD profiles. RESULTS: IVL3001 and finasteride 1 mg tablets were well tolerated. IVL3001 showed consistent plasma concentrations without bursts or fluctuations. Consistent with its mechanism of action, IVL3001 reduced DHT levels. Simulation data showed that the administration of 12-36 mg of IVL3001 every 4 weeks achieved plasma concentrations similar to finasteride, with comparable DHT reduction. CONCLUSION: The present study represents the first clinical trial to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), and tolerability of finasteride long-acting injectables (LAI) in adults. The rapid onset of action sustained effective drug concentration and the prolonged half-life of IVL3001 suggest that it offers multiple benefits over conventional oral formulations in terms of therapeutic response and compliance. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04945226.

Exploring the relationship between bulk Young's Modulus of materials and milling efficiency during wet bead milling of pharmaceutical compounds.

Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young's Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young's Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance (ϕ), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.

Cabotegravir and rilpivirine long acting injectables in a pregnant woman living with HIV.

This case report describes bimonthly LAI CAB/RPV prior to and throughout pregnancy. CAB concentration was comparable to non-pregnant individuals, RPV was 70-75% lower. No virologic failure orvertical transmission occurred. Despite placental transfer, no congenital malformations were noted. Bimonthly CAB/RPV LAI may not be suitable for pregnant women and monitoring of exposed infants is warranted.

Training student pharmacists to administer long-acting injectable medications.

Objective/Process: In June of 2022, the State of Maryland Board of Pharmacy issued regulations permitting pharmacist administration of maintenance injectable medications. Subsequently, the University of Maryland School of Pharmacy created a laboratory to train student pharmacists based on these regulations on administering long-acting maintenance injections. This training included a review of regulations, reconstitution and administration of medications, and education for patients and caregivers on long-acting injectable medications. This is the first training the authors are aware of incorporating both reconstitution and administration of these medications. The objective of this paper is to describe the laboratory details and future directions of the training course. Results/Conclusions: The first training laboratory trained 94 student pharmacists in the administration technique of long-acting injectable medications. The program has been adapted for practicing pharmacists and other healthcare providers. Thus far, more than 300 practitioners have participated in the learning lab.

Bottom-up production of injectable itraconazole suspensions using membrane technology.

Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers advantages in surface property control and operational ease over top-down methods. However, downstream separation and concentration pose challenges. This proof-of-concept study explores membrane diafiltration as a comprehensive solution for downstream processing of API crystal suspensions produced via anti-solvent crystallization. It involves switching the residual solvent (N-methyl-2-pyrrolidone, NMP) with water, adjusting the excipient (d-α-Tocopherol polyethylene glycol 1000 succinate, TPGS) quantity, and enhancing API loading (solid concentration) in itraconazole crystal suspensions. NMP concentration was decreased from 9 wt% to below 0.05 wt% (in compliance with European Medicine Agency guidelines), while the TPGS concentration was decreased from 0.475 wt% to 0.07 wt%. This reduced the TPGS-to-itraconazole ratio from 1:2 to less than 1:50 and raised the itraconazole loading from 1 wt% to 35.6 wt%. Importantly, these changes did not adversely affect the itraconazole crystal stability in suspension. This study presents membrane diafiltration as a one-step solution to address downstream challenges in bottom-up API crystal suspension production. These findings contribute to optimizing pharmaceutical manufacturing processes and hold promise for advancing the development of long-acting API crystal suspensions via bottom-up production techniques at a commercial scale.

Patient Education and Decision Support for Long-Acting Injectable HIV Antiretroviral Therapy: Protocol for Tool Development and Pilot Testing with Ryan White HIV/AIDS Program Medical Case Management Programs in New York.

BACKGROUND: Long-acting injectable (LAI) HIV antiretroviral therapy (ART) presents a major opportunity to facilitate and sustain HIV viral suppression, thus improving health and survival among people living with HIV and reducing the risk of onward transmission. However, realizing the public health potential of LAI ART requires reaching patients who face barriers to daily oral ART adherence and thus can clinically benefit from alternative treatment modalities. Ryan White HIV/AIDS Program Part A medical case management (MCM) programs provide an array of services to address barriers to HIV care and treatment among economically and socially marginalized people living with HIV. These programs have demonstrated effectiveness in improving engagement along the continuum of care, but findings of limited program impact on durable viral suppression highlight the need to further innovate and hone strategies to support long-term ART adherence. OBJECTIVE: This study aims to adapt and expand Ryan White MCM service strategies to integrate LAI ART regimen options, with the larger goal of improving health outcomes in the populations that could most benefit from alternatives to daily oral ART regimens. METHODS: In 3 phases of work involving patient and provider participants, this study uses role-specific focus groups to elicit perceptions of LAI versus daily oral ART; discrete choice experiment (DCE) surveys to quantify preferences for different ART delivery options and related supports; and a nonrandomized trial to assess the implementation and utility of newly developed tools at 6 partnering Ryan White HIV/AIDS Program Part A MCM programs based in urban, suburban, and semirural areas of New York. Findings from the focus groups and DCEs, as well as feedback from advisory board meetings, informed the design and selection of the tools: a patient-facing, 2-page fact sheet, including frequently asked questions and a side-by-side comparison of LAI with daily oral ART; a patient-facing informational video available on YouTube (Google Inc); and a patient-provider decision aid. Implementation outcomes, measured through provider interviews, surveys, and service reporting, will guide further specification of strategies to integrate LAI ART options into MCM program workflows. RESULTS: The study was funded in late April 2021 and received approval from the institutional review board in May 2021 under protocol 20-096. Focus groups were conducted in late 2021 (n=21), DCEs ran from June 2022 to January 2023 (n=378), and tools for piloting were developed by May 2023. The trial (May 2023 through January 2024) has enrolled >200 patients. CONCLUSIONS: This study is designed to provide evidence regarding the acceptability, feasibility, appropriateness, and utility of a package of patient-oriented tools for comparing and deciding between LAI ART and daily oral ART options. Study strengths include formative work to guide tool development, a mixed methods approach, and the testing of tools in real-world safety-net service settings. TRIAL REGISTRATION: Clinicaltrials.gov NCT05833542; https://clinicaltrials.gov/study/NCT05833542. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56892.

Pre-emptive ice pack cryotherapy for reducing pain caused by long-acting deltoid injectable antipsychotic treatment: A single-center open-label study.

PURPOSE: This empirical study aims to investigate the efficacy of pre-emptive cryotherapy in reducing pain that is caused by the deltoid intramuscular (IM) injection of long-acting injectable (LAI) antipsychotics in clinical settings. PATIENTS AND METHODS: This study included 29 outpatients receiving LAI antipsychotic treatment. The evaluations of pain during (1) the usual procedure (control), (2) pre-emptive use of ice pack cryotherapy (pre-cooling), and (3) pre-emptive use of a room-temperature ice pack (pre-touching) were conducted using a numerical rating scale (NRS) for comparison. All patients were administered with LAI antipsychotics via deltoid IM. Furthermore, the results of the Positive and Negative Symptom Scale (PANSS), clinical global impressions (CGI) scale, and Global Assessment of Functioning (GAF) scale that were administered during the control procedure were evaluated. RESULTS: The median NRS pain scores during the IM injection of LAI antipsychotics were 4.0 (3.0-5.0), 2.0 (1.0-3.0), and 3.0 (2.5-6.0) for the control, pre-cooling, and pre-touching conditions, indicating a significant difference (p = 6.0 × 10-6). The NRS pain scores for the pre-cooling condition were significantly lower than those for the control and pre-touching conditions (p = 2.5 × 10-5 and 6.7 × 10-5, respectively). No significant correlation was observed between the NRS pain scores for the control condition and the PANSS, CGI scale, or GAF scale scores. Furthermore, no adverse events were recorded during the study period. CONCLUSION: Pain during the deltoid IM injection of LAI antipsychotics was found to be reduced by pre-emptive skin cooling. To date, this is the first study to confirm the effectiveness of pre-emptive cryotherapy for relieving such pain in clinical situations.

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.

Alzheimer's disease current therapies, novel drug delivery systems and future directions for better disease management.

Alzheimer's disease (AD), is a neurodegenerative disorder that escalates with time, exerting a significant impact on physical and mental health and leading to death. The prevalence of AD is progressively rising along with its associated economic burden and necessitates effective therapeutic approaches in the near future. This review paper aims to offer an insightful overview of disease pathogenesis, current FDA-approved drugs, and drugs in different clinical phases. It also explores innovative formulations and drug delivery strategies, focusing on nanocarriers and long-acting medications (LAMs) to enhance treatment efficacy and patient adherence. The review also emphasizes preclinical evidence related to nanocarriers and their potential to improve drug bioavailability, pharmacokinetics, and pharmacodynamics parameters, while also highlighting their ability to minimize systemic side effects. By providing a comprehensive analysis, this review furnishes valuable insights into different pathophysiological mechanisms for future drug development. It aims to inform the development of treatment strategies and innovative formulation approaches for delivering existing molecules in Alzheimer's disease, ultimately striving to improve patient compliance.

Tailoring the use of excipients in bottom-up production of naproxen crystal suspensions via membrane technology.

Long-acting crystal suspensions of active pharmaceutical ingredients (API) mostly comprised of an API, a suspension media (water) and excipients and provide sustained API release over time. Excipients are crucial for controlling particle size and to achieve the stability of the API crystals in suspension. A bottom-up process was designed to produce long-acting crystal suspensions whilst investigating the excipient requirements during the production process and the subsequent storage. PVP K30 emerged as the most effective excipient for generating stable naproxen crystals with the desired size of 1 to 15 µm, using ethanol as solvent and water as anti-solvent. Calculations, performed based on the crystal properties and assuming complete PVP K30 adsorption on the crystal surface, revealed lower PVP K30 requirements during storage compared to initial crystal generation. Consequently, a membrane-based diafiltration process was used to determine and fine-tune PVP K30 concentration in the suspension post-crystallization. A seven-stage diafiltration process removed 98 % of the PVP K30 present in the suspension thereby reducing the PVP-to-naproxen ratio from 1:2 to 1:39 without impacting the stability of naproxen crystals in suspension. This work provides insights into the excipient requirements at various production stages and introduce the membrane-based diafiltration for precise excipient control after crystallization.

Injectable long-acting ivacaftor-loaded poly (lactide-co-glycolide) microparticle formulations for the treatment of cystic fibrosis: In vitro characterization and in vivo pharmacokinetics in mice.

Optimizing a sustained-release drug delivery system for the treatment of cystic fibrosis (CF) is crucial for decreasing the dosing frequency and improving patients' compliance with the treatment regimen. In the current work, we developed an injectable poly(D,L-lactide-co-glycolide) (PLGA) microparticle formulation loaded with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that increases the open probability of the CFTR anion channel, using a single emulsion solvent evaporation technique. We aimed to study the effect of different parameters on the characteristics of the prepared formulations to select an optimized microparticle formulation to be used in an in vivo pharmacokinetic study in mice. First, a suite of ivacaftor-loaded microparticles were prepared using different formulation parameters in order to study the effect of varying these parameters on microparticle size, morphology, drug loading, encapsulation efficiency, and in vitro release profiles. Prepared microparticles were spherical with diameters ranging from 1.91-6.93 µm, percent drug loading (% DL) of 3.91-10.3%, percent encapsulation efficiencies (% EE) of 26.6-100%, and an overall slow cumulative release profile. We selected the formulation that demonstrated optimal combined % DL and % EE values (8.25 and 90.7%, respectively) for further studies. These microparticles had an average particle size of 6.83 µm and a slow tri-phasic in vitro release profile (up to 6 weeks). In vivo pharmacokinetic studies in mice showed that the subcutaneously injected microparticles resulted in steady plasma levels of ivacaftor over a period of 28 days, and a 6-fold increase in AUC 0 - t (71.6 µg/mL*h) compared to the intravenously injected soluble ivacaftor (12.3 µg/mL*h). Our results suggest that this novel ivacaftor-loaded microparticle formulation could potentially eliminate the need for the frequent daily administration of ivacaftor to people with CF thus improving their compliance and ensuring successful treatment outcomes.

Biodegradable Long-Acting Injectables: Platform Technology and Industrial Challenges.

Long-acting injectables have been used to benefit patients with chronic diseases. So far, several biodegradable long-acting platform technologies including drug-loaded polymeric microparticles, implants (preformed and in situ forming), oil-based solutions, and aqueous suspension have been established. In this chapter, we summarize all the marketed technology platforms and discuss their challenges regarding development including but not limited to controlling drug release, particle size, stability, sterilization, scale-up manufacturing, etc. Finally, we discuss important criteria to consider for the successful development of long-acting injectables.