Injectable Formulation Research Articles

Dynamic Hydrogels against Infections: From Design to Applications.

Human defense against infection remains a global topic. In addition to developing novel anti-infection drugs, therapeutic drug delivery strategies are also crucial to achieving a higher efficacy and lower toxicity of these drugs for treatment. The application of hydrogels has been proven to be an effective localized drug delivery approach to treating infections without generating significant systemic adverse effects. The recent emerging dynamic hydrogels further show power as injectable formulations, giving new tools for clinical treatments. In this review, we delve into the potential applications of dynamic hydrogels in antibacterial and antiviral treatments and elaborate on their molecular designs and practical implementations. By outlining the chemical designs underlying these hydrogels, we discuss how the choice of dynamic chemical bonds affects their stimulus responsiveness, self-healing capabilities, and mechanical properties. Afterwards, we focus on how to endow dynamic hydrogels with anti-infection properties. By comparing different drug-loading methods, we highlight the advantages of dynamic chemical bonds in achieving sustained and controlled drug release. Moreover, we also include the design principles and uses of hydrogels that possess inherent anti-infective properties. Furthermore, we explore the design principles and applications of hydrogels with inherent anti-infective properties. Finally, we briefly summarize the current challenges faced by dynamic hydrogels and present a forward-looking vision for their future development. Through this review, we expect to draw more attention to these therapeutic strategies among scientists working with chemistry, materials, as well as pharmaceutics.

Development and characterization of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with finasteride and in vivo evaluation of their efficacy in hair growth

Introduction: Alopecia is a condition that affects the hair follicle. Currently, a wide variety of treatments are available, including topical, oral and injectable formulations. Oral therapies are the most adhered to; however, they generally present more adverse effects. As a well-established oral drug therapy, finasteride is presented, which inhibits the enzyme 5-α-reductase, and blocks the conversion of testosterone into dihydrotestosterone. This drug is capable of promoting hair growth, however can lead to adverse effects. Therefore, in this study, poly(lactic-co-glycolic acid) nanoparticles with finasteride were developed, aiming to improve the efficiency of this drug and reduce its systemic side effects. Methodology: Nanoparticles without the drug and with the drug at 10, 20 and 30mg were developed. The system was characterized by Dynamic Light Scattering, Zeta Potential, Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy. Results and Conclusion: The drug-free nanoparticles had a reaction yield of 91.8%, nanoparticles with 10mg of finasteride showed a yield of 82.6%, with 20mg a yield of 92.9%, and with 30mg a yield of 89.3%. The average diameter ranged from 162.2nm for drug-free nanoparticles, 176.1nm for nanoparticles with 10mg of finasteride, 179.6nm for nanoparticles with 20mg, and 187.7nm for nanoparticles with 30mg. Nanoparticles with 10mg of finasteride showed an encapsulation efficiency of 48.2%, nanoparticles with 20mg an efficiency of 90.7%, and nanoparticles with 30mg an efficiency of 83.2%. The development of nanoparticles and the encapsulation of finasteride were successful. Next, an in vivo study will be conducted to evaluate its efficacy in promoting hair growth orally.

CPL-01, an investigational long-acting ropivacaine, demonstrates safety and efficacy in open inguinal hernia repair

BackgroundThere is an unmet medical need for effective nonopioid analgesics that can decrease pain while reducing systemic opioid use. CPL-01, an extended-release injectable formulation of ropivacaine, is designed to safely provide analgesia and reduce or eliminate opioid use in the postoperative period.MethodsSubjects undergoing open inguinal hernia with mesh were prospectively randomized to 1 of 3 doses of CPL-01 (10, 20, or 30 ml of 2% CPL-01, n = 14, 12, and 14, respectively), Naropin (150 mg, n = 40), or saline placebo (n = 13) infiltrated into the surgical site prior to closure. Pain and rescue medication usage was assessed, and Numeric Rating Scale (NRS) pain scores were adjusted for opioid usage using windowed worst observation carried forward (wWOCF) imputation. The primary efficacy endpoint was the mean area under the curve (AUC) of the NRS pain intensity scores with activity.ResultsNinety-three subjects were treated, and 91 subjects completed 72 h of post-operative monitoring. Subjects who received the highest dose of CPL-01 in Cohort 3 showed a clinically meaningful reduction in postoperative pain intensity scores, which was the lowest value for any treatment in all cohorts, showing a trend towards statistical significance as compared to the pooled placebo group (p = 0.08), and numerically better than the 40 subjects who received Naropin. Opioid use through 72 h in subjects who received CPL-01 in Cohort 3 was approximately half of that shown in the placebo and Naropin groups; approximately 2/3 of the CPL-01 subjects (9/14) required no opioids at all through the first 72 h after the operation. More CPL-01 subjects avoided severe pain and were ready for discharge earlier than other groups. CPL-01 was safe and well-tolerated, with no clinically meaningful safety signals, and showed predictable and consistent extended-release pharmacokinetics.ConclusionResults suggest that CPL-01 may be the first long-acting ropivacaine to address postoperative pain while reducing the need for opioids.

An ecotoxicological view on malaria vector control with ivermectin-treated cattle

Malaria remains an enduring challenge in sub-Saharan Africa, affecting public health and development. Control measures can include the use of insecticides that target adult Anopheles mosquitoes transmitting the malaria-causing Plasmodium parasite. Such mosquitoes can also bite livestock, allowing vector populations to be maintained at levels that enable parasite transmission. Thus, one way to control the spread of malaria includes the use of endectocide-treated livestock which renders the blood of cattle toxic to such mosquito populations. Here we present an ecotoxicological perspective on malaria vector control, using cattle treated with the endectocide ivermectin to target zoophagic and opportunistic Anopheles coluzzii mosquitoes. Our study employs an innovative, long-acting injectable ivermectin formulation with over 6 months of sustained mosquitocidal activity. Robust vector population modelling underscores its promising field effectiveness. Environmental implications (soil sorption and dissipation) of excreted ivermectin and potential ecotoxicological risks to non-target dung organisms in West Africa are discussed, in addition to actionable, locally inspired risk mitigation measures to protect sub-Saharan soils and agroecosystems from chemical pollution. We highlight how ecotoxicology and environmental chemistry improve livestock-based vector control with ivermectin for effective and more sustainable malaria management.

Perfluorodecalin allows resuspension and prevents sediment solidification of extended-release drug formulations in primary packaging.

In this technical note we show with two simple experiments how Perfluorodecalin (PFD), an injectable perfluorocarbon, can be used as an agent for resuspending microparticulate suspensions in primary packaging containers for injection. Furthermore, we explain how this can be a substantial improvement regarding patient compliance in comparison to the commonly used gas headspace for resuspension. Our experiments are conducted with poly(lactic-co-glycolic acid) particles (often used in extended-release pharmaceutical formulations for injection) and in primary packaging that is commonly used in injection devices (glass cartridges). The results show that our method is feasible for resuspension and moreover even sediment solidification/caking is reduced. The differences between the two datasets collected are statistically significant with p < 0.01 in both cases.

Abstract PO1-05-08: Enhanced ER+ tumor growth inhibition of fulvestrant from effective oral delivery yielding elevated plasma concentrations

Abstract Fulvestrant has been a backbone of endocrine therapy (ET) for ER+/HER2- metastatic breast cancer (mBC) for over 20 years due to its nanomolar potency, purely antagonistic behavior, and well-tolerated adverse event (AE) profile. It remains the only selective estrogen receptor degrader (SERD) approved in ER+/HER2- mBC regardless of ESR1 mutation status. While ESR1 mutations reduce fulvestrant binding affinity, they do not implicitly lead to acquired resistance as with aromatase inhibitors (AIs) and can be overcome by increasing exposure.1 Further, preclinical evidence suggests that higher exposure to fulvestrant correlates with higher efficacy in rodents.2 Unfortunately, fulvestrant is currently delivered at its maximum feasible dose due to its poor solubility and a lack of effective drug delivery technologies. In response, several novel oral SERDs have been brought into clinical development to improve upon the efficacy of fulvestrant. However, multiple have failed to prove superior to fulvestrant in its intramuscular (IM) injection formulation and improvements from elacestrant (EMERALD) and camizestrant (SERENA-2) are largely attributed to patients with ESR1 mutations after prior ETs. Therefore, enabling higher exposure of fulvestrant could prolong progression-free survival and improve quality of life for ET-naïve mBC patients and those that have progressed on ETs. VeraMorph has leveraged a proprietary oral drug delivery technology to overcome the limitations of fulvestrant’s poor solubility and potentially help mitigate acquired resistance by improving exposure via daily oral dosing. The oral dosages, which consist of a novel polymer-based soft gummy, stabilize fulvestrant in simulated intestinal media up to 5 mg/mL without influencing fulvestrant permeability or causing cytotoxic effects. Pharmacokinetic (PK) studies of oral fulvestrant in rodents have demonstrated maximum plasma concentrations up to 450 ng/mL, a level roughly 20 times that of the average exposure from the monthly IM formulation in clinical settings. PK studies also demonstrated that oral exposure increased with a roughly dose-proportional relationship, with a reduction in AUC from day 1 to day 8 upon repeat dosing. In a cell-derived xenograft (CDX) study utilizing ER+ MCF-7 tumors implanted in athymic nude mice, once daily dosing via oral gavage of oral fulvestrant at 125 mg/kg was able to achieve a statistically significant 55% reduction in tumor growth by day 42 relative to a 50 mg/kg dose of the IM formulation delivered subcutaneously once per week, which was determined to create an equivalent exposure to the monthly IM human dose in separate studies. Oral fulvestrant yielded no observed adverse effects up to 125 mg/kg in both the 42-day CDX study in mice or an 8-day safety study in rats. Further, onset of action and acquired resistance are being tested by monitoring cell viability (via the MTT assay) with MCF-7 cells exposed to time profiles of fulvestrant exposure resembling oral and monthly intramuscular delivery. The study demonstrated that oral dosing reaches minimal cell viability 1-2 weeks faster than IM dosing. Also, preliminary data suggests that the onset of acquired resistance (as demonstrated by a resumption of cell growth) may occur faster from the steady exposure of IM dosing relative to the modulation of daily oral dosing. These results suggest that oral fulvestrant has the potential to finally realize the full potential of fulvestrant as an effective ET for metastatic breast cancer with a well-tolerated AE profile, enhanced efficacy, and reduced susceptibility to acquired resistance with applicability across all mBC patients. 1 Brett JO, Spring LM, Bardia A, Wander SA (2021) Breast Cancer Research, 23(1):1–15. 2 Wardell SE, et. al. (2020) Breast Cancer Research and Treatment, 179(1):67–77. Citation Format: Doug Godfrin, Matthew Butchbach. Enhanced ER+ tumor growth inhibition of fulvestrant from effective oral delivery yielding elevated plasma concentrations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-08.

Intranasal and intravenous apomorphine outperform ropinirole ocular drops for induction of emesis in dogs within ten minutes: a randomized, controlled clinical trial.

The primary goal was to compare the efficacy of administration of apomorphine (APO) administered by intranasal (IN), transconjunctival (TC), SC and IV routes with ropinirole eye drops for induction of emesis in dogs with a secondary goal to evaluate the time of emesis as well as difficulty in administration. 125 client-owned dogs. Dogs were randomly enrolled between October 1, 2021, and March 30, 2022, into groups of 25: IV APO, IN APO, TC APO, SC APO, and ropinirole eye drops. The IV, SC, and TC groups were dosed at 0.03 mg/kg, the IN group was dosed at 0.06 mg/kg, and the ropinirole group was dosed according to manufacturer guidelines. Data collected included success rate of emesis within 600 seconds, time to emesis, time to administer, and difficulty score. Results were compared to IV with P values and CIs being adjusted for multiple comparisons. Emesis was successful within 600 seconds using IV APO in 22 of 25 dogs. By comparison, IN APO induced emesis in 18 of 25 dogs (P = .63). Ropinirole (14/25), SC APO (6/25), and TC APO (4/25) were significantly less successful (P = .047, P = < .001, and P < 0.001, respectively). When emesis was successful, it occurred most rapidly with TC APO, followed by IN APO and then ropinirole. It was most difficult to administer IV APO and TC APO. Similar to IV APO, IN APO was a rapid, easy, and effective method of inducing emesis in dogs and should be considered when IV administration is not possible. Ropinirole was easy to administer but successfully induced emesis less reliably within a 10-minute timeframe. APO administered TC using the commercially compounded injectable formulation was ineffective.

Skin ‘Bleaching’ Practices and Associated Adverse Health Effects in Zimbabwe: A Canonical Correlational Study of Harare

The study aimed to identify the ingredients, processes and practitioners involved in the skin lightening practices in Zimbabwe and to identify the associated, adverse health effects as well as to establish the user demographics. A technical field survey was carried out in Harare, Zimbabwe from October 2022 to March 2023. Out of a total of 450 potential participants, 382 individuals in 3 broad groups were successfully interviewed; these included 150 skin lightening practitioners and traders, 118 skin lightening products users and 114 individuals who have never practiced skin bleaching. A semi structured technical questionnaire was used for each group of participants and the collected data were analysed qualitatively and quantitatively. The study observed that both sexes are involved in skin lightening in Zimbabwe, the majority (52%) being women aged between 31-45 years. The established industry, is divers, including registered healthcare providers, commercial trade, informal markets and others. The majority of practitioners (65%) have less than 5 practising years. There are over 30 different skin lightening products available either as prescription medications, OTC treatments, commercial products, network marketing products as well as illegal bootleg concoctions. The products extends from creams, lotions and serums, to oral and injectable dosage forms. The most prevalent products being corticosteroid creams. 75% of users reported both reversible and non-reversible adverse health side effects and outcomes including skin irritations, inflammation, rashes, erythema, oedemas, ochronosis, dermal atrophy, photophobia, insomnia and unexplained weight gain. The most prevalent side effect being pruritus and irritations. It was observed that there is no formal registration, regulation or legislation covering the products, processes and practice of skin lightening in Zimbabwe.

Amplifying endogenous stem cell migration for in situ bone tissue formation: Substance P analog and BMP mimetic peptide-loaded click-crosslinked hyaluronic acid hydrogel

Endogenous stem cell-driven in situ bone tissue formation has recently garnered increasing attention. Therefore, our study sought to refine methods to enhance the migration and subsequent osteogenic differentiation of these cells. Our innovative approach involves using an injectable hydrogel that combines click cross-linking sites and a BMP-2 mimetic peptide (BP) with hyaluronic acid (HA). This injectable formulation, hereinafter referred to as SPa + Cx-HA-BP, incorporates a substance P analog peptide (SPa) with Cx-HA-BP, proving versatile for in vitro and in vivo applications without cytotoxicity. The controlled release of SPa creates a gradient that guides endogenous stem cells towards the Cx-HA scaffold from specific tissue niches. Both Cx-HA and SPa+Cx-HA induced minimal changes in the expression of genes associated with osteogenic differentiation. In contrast, these genes were robustly induced by both SPa + Cx-HA+BP and SPa + Cx-HA-BP, in which BP was respectively integrated via physical and chemical methods. Remarkably, chemically incorporating BP (Cx-HA-BP) resulted in 4–9 times higher osteogenic gene expression than physically mixed BP in Cx-HA+BP. This study validates the role of SPa role in guiding endogenous stem cells toward the hydrogel and underscores the substantial impact of sustained BP presence within the hydrogel. Collectively, our findings offer valuable insights for the development of innovative strategies to promote endogenous stem cell-based tissue regeneration. The developed hydrogel effectively guides stem cells from their natural locations and facilitates sustained osteogenic differentiation, thus holding great promise for applications in regenerative medicine.

SPICE: the connection between cosmic reionization and stellar feedback in the first galaxies

ABSTRACT We present SPICE, a new suite of radiation-hydrodynamic, cosmological simulations targeting the epoch of reionization. The goal of these simulations is to systematically probe a variety of stellar feedback models, including ‘bursty’ and ‘smooth’ forms of supernova energy injection, as well as poorly explored physical scenarios such as hypernova explosions and radiation pressure on dust. We show that even subtle differences in the behaviour of supernova feedback drive profound differences in reionization histories, with burstier forms of feedback causing earlier reionization. However, we also find that some global galaxy properties, such as the dust-attenuated luminosity functions and star formation main sequence, remain degenerate between models. In particular, we show that stellar feedback and its strength determine the morphological mix of galaxies emerging by $z \, = \, 5$ and that the reionization history is inextricably connected to intrinsic properties such as galaxy kinematics and morphology. While star-forming, massive discs are prevalent if supernova feedback is ‘smooth’, ‘bursty’ feedback preferentially generates dispersion-dominated systems. Different modes of feedback produce different strengths of outflows, altering the interstellar/circumgalactic medium in different ways, and in turn strongly affecting the escape of Lyman continuum (LyC) photons. We establish a correlation between galaxy morphology and LyC escape fraction, revealing that dispersion-dominated systems have escape fractions 10–50 times higher than their rotation-dominated counterparts at all redshifts. At the same intrinsic luminosity, dispersion-dominated systems should thus preferentially generate large H ii regions as compared to their rotation-dominated counterparts. Since dispersion-dominated systems are more prevalent if stellar feedback is more explosive, reionization occurs earlier in our simulation with burstier feedback. We argue that statistical samples of post-reionization galaxy morphologies (using both stellar and gaseous components) probed with telescopes such as JWST, ALMA, and MUSE can constrain stellar feedback at z &amp;gt; 5 and models of cosmic reionization.

Evaluating preferences for medication formulation and treatment model among people who use opioids non-medically: A web-based cross-sectional study

IntroductionOver the past decade, treatment for opioid use disorder has expanded to include long-acting injectable and implantable formulations of medication for opioid use disorder (MOUD), and integrated treatment models systematically addressing both behavioral and physical health. Patient preference for these treatment options has been underexplored. Gathering data on OUD treatment preferences is critical to guide the development of patient-centered treatment for OUD. This cross-sectional study assessed preferences for long-acting MOUD and integrated treatment using an online survey. MethodsAn online Qualtrics survey assessed preferences for MOUD formulation and integrated treatment models. The study recruited participants (n = 851) in October and November 2019 through advertisements or posts on Facebook, Google AdWords, Reddit, and Amazon Mechanical Turk (mTurk). Eligible participants scored a two or higher on the opioid pain reliever or heroin scales of the Tobacco, Alcohol Prescription Medication and other Substance Use (TAPS) Tool. Structured survey items obtained patient preference for MOUD formulation and treatment model. Using stated preference methods, the study assessed preference via comparison of preferred options for MOUD and treatment model. ResultsIn the past year, 824 (96.8 %) participants reported non-prescribed use of opioid pain relievers (mean TAPS score = 2.72, SD = 0.46) and 552 (64.9 %) reported heroin or fentanyl use (mean TAPS score = 2.73, SD = 0.51). Seventy-four percent of participants (n = 631) reported currently or previously receiving OUD treatment, with 407 (48.4 %) receiving MOUD. When asked about preferences for type of MOUD formulation, 452 (53.1 %) preferred a daily oral formulation, 115 (13.5 %) preferred an implant, 114 (13.4 %) preferred a monthly injection and 95 (11.2 %) preferred a weekly injection. Approximately 8.8 % (n = 75) would not consider MOUD regardless of formulation. The majority of participants (65.2 %, n = 555) preferred receiving treatment in a specialized substance use treatment program distinct from their medical care, compared with receiving care in an integrated model (n = 296, 34.8 %). ConclusionsThough most participants expressed willingness to try long-acting MOUD formulations, the majority preferred short-acting formulations. Likewise, the majority preferred non-integrated treatment in specialty substance use settings. Reasons for these preferences provide insight on developing effective educational tools for patients and suggesting targets for intervention to develop a more acceptable treatment system.

Novel Injectable Hydrogel Formulations and Gas Chromatography Analysis of the Residual Crosslinker in Formulations Intended for Pharmaceutical and Cosmetic Applications.

Novel hyaluronic acid (HA) crosslinked with pentaerythritol tetra-acrylate (PT) injectable hydrogels was invented. These injectable hydrogel/dermal filler formulations were synthesised using HA and the acrylate PT as a crosslinker under basic pH conditions using thermal crosslinking methods (oven heating), which provides a simple, safe, and eco-friendly method for crosslinking in 4 h under 45 °C. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) analyses were conducted to represent the difference between the formulations in terms of peak formation and pore size, respectively. The crosslinking was partial as is considered to be typical for dermal injectable fillers. The rheological properties of these formulations showed that these novel dermal injectables are highly promising, and the newly developed fillers could be used with better results for dermal anti-wrinkle corrections, shaping, and volumising reasons. Furthermore, crosslinker (PT) residual analysis was carried out to state the formulations that are valid and acceptable for intradermal usage. The results from the GC method validation revealed it was a suitable method for this study. The GC analysis of all five injectable hydrogel/filler formulations demonstrated the formulations HA-PT 1, 2, 3 and 4 were formulated using (0.05-0.1)% w/w PT containing residual PT monomers within the safe limits that were determined to be below (0.008% w/w). This work has shown the development of a novel injectable hydrogel/filler formulation for pharmaceutical and cosmetic applications can be prepared in a more sustainable and simple way using pentaerythritol tetra-acrylate as a crosslinker agent, which holds great promise for the industry's future advancement.

Effect of PLGA raw materials on in vitro and in vivo performance of drug-loaded microspheres.

Poly(lactide-co-glycolide) and poly(lactic-co-glycolic acids) (PLGAs) play a critical role in the development of commercial long-acting injectable microsphere formulations. However, very little information is available describing the impact of PLGA manufacturer and monomer distribution along the polymer chain (e.g., glycolic blockiness (Rc) and average lactic block length (LL)) on the degradation and release behavior of PLGA drug carriers in vitro and in vivo. Here, we compared the in vitro and in vivo performance of (a) four leuprolide-loaded microsphere formulations prepared from similar low-molecular-weight acid-capped PLGAs (10-14 kD, i.e., Expansorb® DLG 75-2A, Purasorb® PDLG 7502A, Resomer® RG 752H and Wako® 7515) and (b) two triamcinolone acetonide-loaded (Tr-A) microsphere formulations from similar medium-molecular-weight ester-capped PLGAs (i.e., Expansorb® DLG 75-4E and Resomer® RG 753S). Lupron Depot® and Zilretta® were used as reference commercial products. The six 75/25 PLGAs displayed block lengths that were either above or below values expected from a random copolymer. Drug release and polymer degradation were monitored simultaneously in vitro and in vivo using a cage implant system. The four leuprolide-loaded formulations showed similar release and degradation patterns with some notable differences between each other. Microspheres from the Expansorb® polymer displayed lower LL and higher Rc relative to the other 3 PLGA 75/25 microspheres, and likewise exhibited distinct peptide release and degradation behavior compared to the other 3 formulations. For each formulation, leuprolide release was erosion-controlled up to about 30% release after the initial burst followed by a faster than erosion release phase. In vitro release was similar as that in vivo over the first phase but notably different from the latter release phase, particularly for the most blocky Expansorb® formulation. The Purasorb® and Wako® formulations displayed highly similar performance in release, degradation, and erosion analysis. By contrast, the two ester-capped Expansorb® DLG 75-4E and Resomer® RG 753S used to prepare Tr-A microspheres shared essentially identical LL and higher Rc and behaved similarly although the Expansorb® degraded and released the steroid faster in vivo, suggestive of other factors responsible (e.g., residual monomer). The in vivo release performance for both drugs from the six microsphere formulations was similar to that of the commercial reference products. In summary, this work details information on comparing the similarities and differences in in vitro and in vivo performance of drug-loaded microspheres as a function of manufacturing and microstructural variables of different types of PLGA raw materials utilized and could, therefore, be meaningful in guiding the source control during development and manufacturing of PLGA microsphere-based drug products. Future work will expand the analysis to include a broader range of LL and higher Rc, and add additional important formulation metrics (e.g., thermal analysis, and residual monomer, moisture, and organic solvent levels).

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.

Exploring the anti-tumor effect of silver nanoparticles in oral and skin cancer in vivo: Systematic review and meta-analysis

This study aimed to analyze the in vivo anti-tumor effect of silver nanoparticles (AgNPs) against oral and skin cancer. The PRISMA guidelines were followed, and a registration in PROSPERO was performed. A search of databases was carried out in September 2023. The data were analyzed using the inverse variance method with a random effect model. All studies assessed anti-tumor efficacy against melanoma, and 21 days after treatment with AgNPs showed a reduction in tumor volume (SMD -6.58; PI [-9.82, -3.34]). Administration of AgNPs in injectable and topical form was effective in reducing tumors, erythema and preventing metastases without causing side effects. We concluded that AgNPs showed antitumor action against mice melanoma by reducing tumor volume and preventing cell proliferation and metastasis.

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder.

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

Long-Acting Poly(ADP-ribose) Polymerase Inhibitor Prodrug for Humans.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for once or twice daily oral use in the treatment of cancers with BRCA defects. However, for some patients, oral administration of PARPi may be impractical or intolerable, and a long-acting injectable formulation is desirable. We recently developed a long-acting PEGylated PARPi prodrug, PEG∼talazoparib (TLZ), which suppressed the growth of PARPi-sensitive tumors in mice for very long periods. However, the release rate of TLZ from the conjugate was too fast to be optimal in humans. We prepared several new PEG∼TLZ prodrugs having longer half-lives of drug release and accurately measured their pharmacokinetics in the rat. Using the rates of release of TLZ from these prodrugs and the known pharmacokinetics of free TLZ in humans, we simulated the pharmacokinetics of the macromolecular prodrugs and released TLZ in humans. From several possibilities, we chose two conjugates that could be administered intravenously every 2 weeks and maintain TLZ within its known therapeutic window. We describe situations where the PEG∼TLZ conjugates would find utility in humans and suggest how the intravenously administered long-acting prodrugs could in fact be more effective than daily oral administration of free TLZ.

Hyaluronic acid-based injectable formulation developed to mitigate metastasis and radiation-induced skin fibrosis in breast cancer treatment

The standard treatment for early-stage breast cancer involves breast-conserving surgery followed by adjuvant radiotherapy. However, approximately 20 % of patients experience distant metastasis, and adjuvant radiotherapy often leads to radiation-induced skin fibrosis (RISF). In this study, we develop an on-site injectable formulation composed of selenocystamine (SeCA) and hyaluronic acid (HyA), referred to as SeCA cross-linked HyA (SCH) agent, and investigate its potential to mitigate metastasis and prevent RISF associated with breast cancer therapy. SCH agents are synthesized using the nanoprecipitation method to modulate cell-cell tight junctions and tissue inflammation. The toxicity assessments reveal that SCH agents with a higher Se content (Se payload 17.4 μg/mL) are well tolerated by L929 cells compared to SeCA (Se payload 3.2 μg/mL). In vitro, SCH agents significantly enhance cell–cell tight junctions and effectively mitigate migration and invasion of breast cancer cells (4T1). In vivo, SCH agents mitigate distant lung metastasis. Furthermore, in animal models, SCH agents reduce RISF and promote wound repair. These findings highlight the potential of SCH agents as a novel therapeutic formulation for effectively mitigating metastasis and reducing RISF. This holds great promise for improving clinical outcomes in breast cancer patients undergoing adjuvant radiotherapy.

Emerging Trends on Nanovaccine Administration and Functionalization Strategies for Immunization

The knowledge base in the field of vaccination research and development has greatly improved. In the present era, utilizing a novel vaccine design and optimization strategy improves the vaccination efficiency and activity. In this regard, a novel drug delivery system produces nanosized, vaccine-loaded carrier molecules, which is called Nanovaccine. The advancement in nanovaccine and improved technology comes under preclinical and clinical trials, whereas different routes of administration strategy are applied against infectious diseases. The nanovaccine has high efficiency and immunogenicity compared to the traditional vaccine. Its long-lasting effect reduces the booster dose as well. One of the factors like routes of administration affects the efficiency of nanovaccine. The parenteral and mucosal vaccination is a traditional administration approach. In order to increase the safety and effectiveness of vaccines, innovative administration methods such as needless injection and polymeric formulations are now being developed. The presented paper shows a mechanism involved in nanovaccine delivery, and a method of administration via a different route, to learn more about their possible effects on immunogenicity, effectiveness, safety, sustained release and dose frequency reduction. The various advanced vaccine delivery methods, with special emphasis on its industrial and regulatory requirements for the higher production of nanovaccine, are also discussed.

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙μg/mL) compared to oral free-GEM (19.04 hr∙μg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.