Cutting-edge research frontiers in oral cavity vaccines for respiratory diseases: a roadmap for scientific advancement.

Intramuscular vaccines present limitations in eliciting robust mucosal immunity and preventing respiratory pathogens transmission. Sublingual vaccine administration offers promising advantages, including interconnected mucosal protection. Despite these advantages, only a few clinical trials have explored sublingual vaccines, underscoring the necessity of optimizing next-generation vaccine formulas. Critical research priorities include understanding vector behavior in the oral environment, understanding their interactions with mucosal immunity and developing formulations enabling sustained mucosal contact to facilitate efficient transduction. Consequently, tonsil organoids, as representative human mucosal models, could offer critical insights into sublingual immunization. Thus, a multi-disciplinary approach integrating pharmacological, immunological, and manufacturing considerations is pivotal for sublingual vaccines in targeting pathogen-aggravated prevalent respiratory diseases including asthma, COPD and lung cancer, as well as the antimicrobial resistance crisis.

Grass pollen allergoids conjugated with mannan for subcutaneous and sublingual immunotherapy: a dose-finding study.

Background: Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen (Phleum pratense and Dactylis glomerata) administered via either the subcutaneous or sublingual route. Methods: A randomized, double-blind, placebo-controlled trial with a double-dummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. Participants who received active treatment through SC, received placebo through SL. Participants who received active treatment through SL, received placebo SC. One Group, as control, received bot SC and SL placebo. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed. Results: Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required. Conclusion: Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search (EudraCT), identifier 2014-005471-88; https://www.clinicaltrials.gov, identifier NCT02654223.

Buprenorphine/naloxone - one formulation that doesn't fit all: a case report.

BACKGROUND: Sublingual buprenorphine, approved for treatment of opioid use disorder since 2002, is most commonly available in co-formulation with naloxone. Naloxone is an opioid antagonist minimally absorbed when sublingual (SL) buprenorphine/naloxone is taken as prescribed; it is thought to reduce potential for misuse via intravenous administration. However, growing data and clinical experience demonstrate that previously accepted assumptions about the pharmacokinetics of these medications may not apply to all patients. CASE PRESENTATION: We present a patient whose adverse post-administration side effects on SL buprenorphine/naloxone resolved with transition to SL buprenorphine monoproduct. DISCUSSION: Naloxone can be detected in nearly all patients taking SL buprenorphine/naloxone, though with apparent variability in clinical effect. In a minority of patients, naloxone can contribute to adverse and potentially treatment-limiting side effects. Furthermore, the naloxone component is commonly misunderstood by patients and providers and can foster mistrust in the therapeutic relationship if providers are perceived to be withholding a more tolerable formulation. Prescribers should have a low threshold to offer buprenorphine alone when clinically appropriate.

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use: A Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited. Objective: To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use. Design, Setting, and Participants: Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023. Intervention: Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. Main Outcomes and Measures: Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales. Results: Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, -3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, -1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups. Conclusions and Relevance: In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use. Trial Registration: ClinicalTrials.gov Identifier: NCT02651584.

3D printed scaffolds as delivery devices for nanocrystals: A proof of concept loading Atorvastatin with enhanced properties for sublingual route of administration.

Increasing the solubility of drugs is a recurrent objective of pharmaceutical research, and one of the most widespread strategies today is the formulation of nanocrystals (NCs). Beyond the many advantages of formulating NCs, their incorporation into solid dosage forms remains a challenge that limits their use. In this work, we set out to load Atorvastatin NCs (ATV-NCs) in a delivery device by combining 3D scaffolds with an "in situ" loading method such as freeze-drying. When comparing two infill patterns for the scaffolds at two different percentages, the one with the highest NCs load was chosen (Gyroid 20 % infill pattern, 13.8 ± 0.5 mg). Colloidal stability studies of NCs suggest instability in acidic media, and therefore, the system is postulated for use as a sublingual device, potentially bypassing stomach and hepatic first-pass effects. An ad hoc dissolution device was developed to mimic the release of actives. The nanometric size and properties acquired in the process were maintained, mainly in the dissolution rate and speed, achieving 100 % dissolution of the content in 180 s. Based on these results, the proof of concept represents an innovative approach to converting NCs suspensions into solid dosage forms.

[ROUTES OF MEDICAL CANNABIS ADMINISTRATION- IS SMOKING THE PREFERRED ROUTE?]

INTRODUCTION: The number of medical cannabis licenses in Israel is increasing persistently (over 120,000 approved licenses in October 2022), reaching about 1.5% of adult population. Medical cannabis products are available in two main forms: inflorescence (administered by smoking or evaporation) and cannabis oil (administered sub-lingually). Data from the Israel ministry of health, regarding the split between these forms, show a major preference for inflorescence products over cannabis oils. This preference is increasing over time. This article reviews the main differences between the administration of these forms and their effects on the quality of treatment. It's conclusion is that for the most common cases of cannabis treatment, sublingual oils should be preferred and that the medical community has an important role in driving this change.

Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.

Development and Verification of a Full Physiologically Based Pharmacokinetic Model for Sublingual Buprenorphine in Healthy Adult Volunteers that Accounts for Nonlinear Bioavailability.

Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome. The study aimed to develop a full physiologically based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e., untransformed or log transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. SIGNIFICANCE STATEMENT: The physiologically based pharmacokinetic (PBPK) model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for maternal-fetal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome.

Novel fast dissolving freeze dried sublingual baicalin tablets for enhanced hepatoprotective effect: in-vitro characterization, cell viability, and in-vivo evaluation.

Baicalin (BG), a natural product, has been used in the prevention and treatment of drug-induced liver injury (DILI); however, its poor solubility and extensive liver metabolism limit its pharmacological use. The aim of the present study was the formulation of fast-dissolving freeze-dried sublingual tablets (FFSTs) to increase BG dissolution, avoid first-pass metabolism, and overcome swallowing difficulties. FFSTs were prepared following a 23 factorial design. The effect of three independent variables namely matrix former, Maltodextrin, concentration (4%, and 6%), binder concentration (2%, and 3%), and binder type (Methocel E5, and Methocel E15) on the FFSTs' in-vitro disintegration time and percentage dissolution was studied along with other tablet characteristics. Differential scanning calorimetry, scanning electron microscopy, in-vitro HepG2 cell viability assay, and in-vivo characterization were also performed. F8 (6% Maltodextrin, 2% Mannitol, 2% Methocel E5), with desirability of 0.852, has been furtherly enhanced using 1%PEG (F10). F10 has achieved an in-vitro disintegration time of 41 secs, and 60.83% in-vitro dissolution after 2 min. Cell viability assay, in-vivo study in rats, and histopathological studies confirmed that pretreatment with F10 has achieved a significant hepatoprotective effect against acetaminophen-induced hepatotoxicity. The outcome of this study demonstrated that FFSTs may present a patient-friendly dosage form against DILI.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Allergen Immunotherapy: The Evidence Supporting the Efficacy and Safety of Subcutaneous Immunotherapy and Sublingual Forms of Immunotherapy for Allergic Rhinitis/Conjunctivitis and Asthma.

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT.

Extended-release versus oral buprenorphine as opioid maintenance treatment during pregnancy-maternal and neonatal outcomes.

OBJECTIVE: To get information on subcutaneous extended-release buprenorphine as opioid maintenance treatment during pregnancy, we compared it to orally administered buprenorphine and buprenorphine-naloxone treatments. We hypothesized that maternal and neonatal outcomes do not differ between the treatment groups. Study design In this population-based cohort study, 60 pregnant individuals receiving non-changed opioid maintenance treatment for opioid use disorder with a buprenorphine product from the time before conception to the time after delivery and their newborns were included. They were divided into three groups based on the pharmacotherapy with subcutaneous extended-release buprenorphine, sublingual buprenorphine, or buprenorphine-naloxone. Statistical analyses were conducted using Fischer's exact tests, ANOVA tests, and Kruskal-Wallis tests. All the statistical tests were two-tailed. RESULTS: The frequency of pregnancy or delivery complications did not significantly differ between the group receiving extended-release buprenorphine and the other groups. During pregnancy, 38 % of the women used illicit drugs concomitantly, with equal frequency in the extended-release buprenorphine group and the other groups. Of the neonates, 93 % were born full-term and 90 % got at least eight Apgar points in one minute age, without significant differences between the groups (p = 0.57). The need for pharmacotherapy for neonatal opioid withdrawal syndrome was the lowest in the extended-release buprenorphine group (25 %) and highest in the sublingual buprenorphine group (67 %). Still, the difference between the treatment groups did not reach statistical significance (p = 0.17). Among all neonates, the breastfed infants were less likely to receive pharmacotherapy for withdrawal symptoms than the formula-fed ones (p = 0.048). CONCLUSIONS: Extended-release buprenorphine with steady drug concentration seems to be a promising pharmacotherapy option during pregnancy for mothers. Maternal health during pregnancy may contribute to the well-being of newborns. Larger trials are urgently needed to confirm these results..

Discontinuation of medication treatment for opioid use disorder after a successful course: The discontinuation phase of the CTN-0100 (RDD) trial.

INTRODUCTION AND BACKGROUND: Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD. RESEARCH DESIGN AND METHODS: The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine. DISCUSSION/CONCLUSION: It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue. CLINICALTRIALS: gov Identifier: NCT04464980.

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

SQ sublingual immunotherapy tablets for children with allergic rhinitis: A review of phase three trials.

AIM: To provide paediatricians with a summary of efficacy and safety of SQ sublingual immunotherapy (SLIT) tablets from phase three, randomised, double-blind, placebo-controlled trials in children and adolescents with allergic rhinitis or rhinoconjunctivitis, with and without asthma. METHODS: PubMed searches were conducted and unpublished data were included if necessary. RESULTS: Of the 93 publications, 12 were identified reporting 10 trials. One trial was excluded as paediatric-specific efficacy data were unavailable. The nine eligible trials evaluated grass, house dust mite, ragweed and tree SLIT tablets. Consistent reductions in allergic rhinitis or rhinoconjunctivitis symptoms and medication use were observed with SQ SLIT tablets versus placebo. In a five-year trial, sustained reduction of allergic rhinoconjunctivitis symptoms, asthma symptoms and medication use were observed with SQ grass SLIT tablet versus placebo. The number-needed-to-treat to prevent asthma symptoms and medication use in one additional child during follow-up was lowest in younger children. SQ SLIT tablets were generally well tolerated across trials. CONCLUSION: Evidence supports use of SQ SLIT tablets in children and adolescents with allergic rhinitis or rhinoconjunctivitis, with and without asthma. Long-term data demonstrate disease-modifying effects of SQ grass SLIT tablet and suggest the clinical relevance of initiating allergy immunotherapy earlier in the disease course.

Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants.

Sunobinop is an investigational, potent, selective partial agonist at the nociceptin/orphanin FQ peptide receptor in vitro. Three phase 1 studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating single- and multiple-dose administration of sunobinop in healthy participants. Study 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study. Study 2 was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Study 3 was a randomized, open-label, single-dose, 4-way crossover study of oral and sublingual sunobinop comparing morning (AM) and bedtime (PM) administration. Seventy participants were included. Systemic exposure (peak plasma concentration [Cmax], area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration [AUC0-t], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf]) of sunobinop was characterized by dose proportionality from 0.6 to 2 mg and increased less than proportionally from 3 to 30 mg. The PKs of sunobinop were similar, regardless of AM or PM administration, for both the oral and sublingual formulations. The majority of absorbed sunobinop was excreted unchanged in the urine within 8 hours of dosing, thereby showing rapid elimination with no appreciable accumulation following 14 consecutive days of once-daily dosing and suggesting exclusive renal elimination. Most treatment-emergent adverse events (TEAEs) were mild in severity; 1 severe TEAE occurred and all TEAEs resolved by the end of the studies. Sunobinop was generally well-tolerated and safe across the range of doses evaluated and presents a clinical profile suitable for continued development.

Systemic delivery of proteins using novel peptides via the sublingual route.

Therapeutic proteins often require needle-based injections, which compromise medication adherence especially for those with chronic diseases. Sublingual administration provides a simple and non-invasive alternative. Herein, two novel peptides (lipid-conjugated protamine and a protamine dimer) were synthesized to enable sublingual delivery of proteins through simple physical mixing with the payloads. It was found that the novel peptides promoted intracellular delivery of proteins via increased pore formation on the cell surface. Results from in vitro models of cell spheroids and human sublingual tissue substitute indicated that the novel peptides enhanced protein penetration through multiple cell layers compared to protamine. The novel peptides were mixed with insulin or semaglutide and sublingually delivered to mice for blood glucose (BG) control. The effects of these sublingual formulations were comparable to the subcutaneous preparations and superior to protamine. In addition to peptide drugs, the novel peptides were shown to enable sublingual absorption of larger proteins with molecular weights from 22 to 150 kDa in mice, including human recombinant growth hormone (rhGH), bovine serum albumin (BSA) and Immunoglobulin G (IgG). The novel peptides given sublingually did not induce any measurable toxicities in mice.

The Devil's in the Depot Details: Case of Iatrogenic Opioid Intoxication After Buprenorphine Injection Requiring Surgical Excision.

ABSTRACT: Monthly long-acting injectable buprenorphine (LAI-BUP) is a treatment option for moderate to severe opioid use disorder. Safe administration of LAI-BUP requires preexisting opioid tolerance to prevent sedation and respiratory depression. In the event of adverse medication effects including oversedation, LAI-BUP can be surgically excised up to 14 days after administration ( https://www.sublocadehcp.com/dosing-administration ). However, the manufacturer does not provide guidance on the proper procedure for excision, and no case reports have been published documenting this procedure. We report a case of a man with methamphetamine use disorder and multiple unintentional fentanyl overdoses who inadvertently received LAI-BUP for overdose protection. This resulted in significant sedation for days, ultimately necessitating excision 5 days after administration. His sedation improved moderately at 24 hours after excision and significantly by 36 hours after excision. Providers seeking to use LAI-BUP to prevent overdose among those with unintentional opioid exposure must ensure sublingual buprenorphine tolerance before injection to avoid iatrogenic harm. Although manufacturer instructions mention that LAI-BUP can be excised under local anesthesia within 14 days of insertion, ideal excision is best performed in a setting with surgical instruments and cautery-such as the operating room-as the depot can adhere strongly to the surrounding subcutaneous tissue.

Salivary Therapeutic Monitoring of Buprenorphine in Neonates After Maternal Sublingual Dosing Guided by Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Opioid use disorder (OUD) during pregnancy is associated with high mortality rates and neonatal opioid withdrawal syndrome (NOWS). Buprenorphine, an opioid, is used to treat OUD and NOWS. Buprenorphine active metabolite (norbuprenorphine) can cross the placenta and cause neonatal respiratory depression (EC 50 = 35 ng/mL) at high brain extracellular fluid (bECF) levels. Neonatal therapeutic drug monitoring using saliva decreases the likelihood of distress and infections associated with frequent blood sampling. METHODS: An adult physiologically based pharmacokinetic model for buprenorphine and norbuprenorphine after intravenous and sublingual administration was constructed, vetted, and scaled to newborn and pregnant populations. The pregnancy model predicted that buprenorphine and norbuprenorphine doses would be transplacentally transferred to the newborns. The newborn physiologically based pharmacokinetic model was used to estimate the buprenorphine and norbuprenorphine levels in newborn plasma, bECF, and saliva after these doses. RESULTS: After maternal sublingual administration of buprenorphine (4 mg/d), the estimated plasma concentrations of buprenorphine and norbuprenorphine in newborns exceeded the toxicity thresholds for 8 and 24 hours, respectively. However, the norbuprenorphine bECF levels were lower than the respiratory depression threshold. Furthermore, the salivary buprenorphine threshold levels in newborns for buprenorphine analgesia, norbuprenorphine analgesia, and norbuprenorphine hypoventilation were observed to be 22, 2, and 162 ng/mL. CONCLUSIONS: Using neonatal saliva for buprenorphine therapeutic drug monitoring can facilitate newborn safety during the maternal treatment of OUD using sublingual buprenorphine. Nevertheless, the suitability of using adult values of respiratory depression EC 50 for newborns must be confirmed.

Safety and Effectiveness of Bypassing Oral Immunotherapy Buildup With an Initial Phase of Sublingual Immunotherapy for Higher-Risk Food Allergy.

BACKGROUND: Because of its favorable safety, sublingual immunotherapy (SLIT) for food allergy has been proposed as an alternative treatment for those in whom oral immunotherapy (OIT) is of higher risk-older children, adolescents, adults, and those with a history of severe reactions. Although safe, SLIT has been shown to be less effective than OIT. OBJECTIVE: To describe the safety of multifood SLIT in pediatric patients aged 4 to 18 years and the effectiveness of bypassing OIT buildup with an initial phase of SLIT. METHODS: Patients aged 4 to 18 years were offered (multi)food SLIT. Patients built up to 2 mg protein SLIT maintenance over the course of 3 to 5 visits under nurse supervision. After 1 to 2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC) (cumulative dose, 300 mg protein) with the goal of bypassing OIT buildup. RESULTS: Between summer 2020 and winter 2023, 188 patients were enrolled in SLIT (median age, 11 years). Four patients (2.10%) received epinephrine during buildup and went to the emergency department, but none experienced grade 4 (severe) reaction. A subset of 20 patients had 50 low-dose OFCs to 300 mg protein and 35 (70%) OFCs were successful, thereby bypassing OIT buildup. CONCLUSIONS: In combination with very favorable safety of SLIT, with no life-threatening reactions and few reactions requiring epinephrine, we propose that an initial phase of SLIT to bypass supervised OIT buildup be considered for children in whom OIT is considered to be of higher risk.