Sublingual Formulation Research Articles

A Health Economic Analysis of Non-injectable Epinephrine Compared with Intramuscular Epinephrine

BackgroundNon-injectable epinephrine to treat allergic reactions addresses an unmet need. Intranasal epinephrine is approved and a sublingual form is under development. Inhaled epinephrine is poorly studied for anaphylaxis. These forms have unknown cost-effectiveness. ObjectiveThe aim of this research was to evaluate cost-effectiveness of commercially available non-injectable epinephrine compared with intramuscular epinephrine for treatment of anaphylaxis. MethodsMarkov cohort analyses evaluated the cost-effectiveness of non-injectable epinephrine forms. The base-case assumed exaggerated anaphylaxis fatality rates (50-fold increase) for using inhaled epinephrine given low certainty evidence in anaphylaxis, and deliberately reduced fatality risk for nasal or sublingual forms (10-fold reduction) theorizing higher adherence and early use during an allergic reaction. ResultsIn the base-case scenario, assuming a 10-fold decreased risk in peanut allergy fatality associated with intranasal or sublingual epinephrine treatment for a severe allergic reaction (net monetary benefit [NMB] $2,189,134) vs. intramuscular (IM) epinephrine use (NMB, 2,189,114), intranasal or sublingual epinephrine was the most cost-effective option (incremental cost-effectiveness ratio [ICER] $83,748/QALY), but only at a marginal annual cost of $4. IM epinephrine was cost-effective (ICER, $17,900/QALY) vs. inhaled epinephrine (NMB, $2,183,531), although inhaled epinephrine reached cost-effectiveness (Willingness To Pay [WTP $100,000/QALY]) if associated fatality risk fell below 2.5-fold. Substituting a single non-injectable form of epinephrine for a second injectable device (in patients prescribed two autoinjectors already) would be cost-effective; however, adding a supplemental non-injectable device was not cost-effective, even assuming a 10-fold risk reduction with multiple device carriage (ICER $858,462). ConclusionNon-injectable routes of epinephrine can be cost-effective options provided fatality risk is not significantly elevated. Carriage of redundant epinephrine autoinjectors with non-injectable forms is not cost-effective if associated with excess cost of redundant device packs.

A bibliometric analysis of alternative drug therapy options in the treatment of androgenetic alopecia.

Oral finasteride and topical minoxidil formulations are the only FDA-approved drug therapies for androgenetic alopecia (AGA). Research into dutasteride, topical finasteride, and nontopical minoxidil (low-dose oral and sublingual) formulations in the treatment of AGA has spiked within recent years. Early findings show that these alternative drug therapies may have similar to improved efficacy and safety profiles relative to the conventional treatment options. Conducting a bibliometric analysis, compare trends in publications on these alternative drug therapies, identify key contributors, evaluate major findings from top-cited articles, and elucidate gaps in evidence. A search was conducted on the Web of Science database for publications on the use of alternative drug therapies in the treatment of AGA. A total of 95 publications, published between January 2003-March 2024, and their citation metadata were included in the analysis. Dutasteride showed the greatest (n = 37) and longest (20+ years) history of publications, as well as the highest cumulative citations (n = 914); however, nontopical minoxidil showed a burst in research activity within the last 5 years (n = 33 publications since 2019). A relatively low number of randomized control trials (n = 3) for nontopical minoxidil suggests a need for higher-quality evidence. Our analysis reveals major trends, contributors, and gaps in evidence for alternative drug therapies for AGA, which can help inform researchers on their future projects in this growing field of study. There is enthusiasm for exploring off-label formulations: nontopical forms of minoxidil (oral and sublingual), topical finasteride, and mesotherapy.

Desmopressin dose requirements in patients with permanent arginine vasopressin deficiency: a tertiary center experience

PurposeThe desmopressin daily dose requirement is highly variable among patients with arginine vasopressin (AVP) deficiency (i.e. central diabetes insipidus) and few studies to date have evaluated this topic, with often inconclusive results. The aim of our study was to identify clinical and biochemical predictors of such dose requirements in a cohort of patients with a confirmed diagnosis of permanent AVP deficiency who have good and stable control under substitutive treatment.MethodsWe retrospectively analyzed data of all patients with permanent AVP deficiency undergoing regular follow-up at our Division. Inclusion criteria were the presence of stable disease under therapy for at least 12 months and in good biochemical and clinical control. Patients with AVP deficiency who lacked intact thirst or had a disease duration of less than 12 months were excluded from the analysis.ResultsOut of the 132 patients initially screened, 96 patients (M/F 44/52; age 51 [37–63] years) met the inclusion criteria. Patients on nasal spray therapy (n = 8) had a significantly longer disease duration (p = 0.002) than patients treated with oral lyophilizate (n = 88). In the bivariate analysis, considering only patients treated with the sublingual formulation, the drug dose was correlated positively with estimated glomerular filtration rate (eGFR) and weight (r = 0.410, p < 0.001; r = 0.224, p = 0.036, respectively) and negatively with age (r = – 0.433, p < 0.001). In the multivariate regression analysis taking into account age, weight, and eGFR, only age emerged as a significant predictor of the required sublingual desmopressin dose (β = – 1.426, p = 0.044).ConclusionOur data suggest that patient age appears to be the primary factor associated with the daily sublingual desmopressin dose required to achieve adequate clinical and biochemical control in patients with permanent AVP deficiency.

Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids.

The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies. This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety. Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26 mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms. TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use

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. 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. 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. Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. 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. 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. 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. ClinicalTrials.gov Identifier: NCT02651584.

PREPARATION AND CHARACTERIZATION OF SOLID DISPERSION USEFUL IN MAKING SUBLINGUAL TABLETS OF PIROXICAM

This study aimed to investigate the usage of solid dispersion (SD) to enhance the dissolution rate of the poorly soluble drug piroxicam for sublingual formulation. Poloxamer grade 407 (Kolliphor® P-407), a commercially available polymer, was chosen, and various solid dispersions with different weight ratios of piroxicam and Poloxamer were prepared using the hot melt method. Compatibility tests using FTIR spectroscopy, DSC, and XRD were conducted to assess any chemical or physical interactions between the drug and polymer. In vitro dissolution tests were performed on the solid dispersions. The results of the FTIR spectroscopy study indicated no chemical interaction between the drug and the polymer. Similarly, the DSC and XRD analyses showed no physical interaction between the drug and the polymer. The maximum cumulative percentage release of the pure drug and the solid dispersion at 15 minutes were 40.90±1.83% and 99.56±3.25%, respectively. Based on these findings, it was concluded that the solid dispersion with a ratio of 2:1 (Drug: Poloxamer-407) showed a noteworthy upsurge in the dissolution rate in comparison to the pure drug.

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.

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 2mg and increased less than proportionally from 3 to 30mg. 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.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-‍linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

IR (index of reactivity)-house dust mite sublingual immunotherapy liquid formulation for allergic rhinoconjunctivitis: Systematic review and meta-analysis of randomized and nonrandomized studies

Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS. We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity. For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT' SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS). Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD= -1.27; 95% confidence interval [CI], -1.64, -0.90) and RCT (SMD= -0.56; 95% CI, -0.90, -0.21), and second, MS with SMD equal to -1.35 (95% CI, -1.77, -0.93) and -0.46 (95% CI, -0.67, -0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12-month SS data: -0.87 (interquartile range, -1.02, -0.77) and -0.75 (interquartile range, -0.93, -0.41), respectively. This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.

Should Buprenorphine Be Considered a First-Line Opioid for the Treatment of Moderate to Severe Cancer Pain?

Cancer pain remains a significant problem worldwide, affecting more than half of patients receiving anti-cancer treatment and most patients with advanced disease. Opioids remain the cornerstone of therapy, and morphine, given its availability, multiple formulations, price, and evidence base, is typically considered the first-line treatment for moderate to severe cancer pain. Buprenorphine has emerged in recent decades as an alternative opioid for treating chronic pain and substance use disorder (SUD). However, it remains controversial whether buprenorphine should be considered a first-line opioid for moderate to severe cancer pain. In this "Controversies in Palliative Care" article, three expert clinicians independently answer this question. Specifically, each group provides a synopsis of the key studies that inform their thought process, share practical advice on their clinical approach, and highlight the opportunities for future research. All three groups agree that there is a place for the use of buprenorphine as a first-line opioid in cancer pain. Specifically, they mention populations of elderly patients, patients with renal failure, and those with (SUD). They also underscore many unique and favorable characteristics of buprenorphine, such as the low risk for respiratory depression, lack of adverse effects on testosterone levels in men, no risk of serotonin syndrome when combined with antidepressants, and ease of use given its transdermal, transmucosal, and sublingual formulations. However, further studies are needed to guide the use of buprenorphine for cancer pain-primarily randomized clinical trials (RCTs) comparing buprenorphine with other opioids in various pain syndromes.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1)

BackgroundGlobally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2).MethodsTwenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5–15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen.DiscussionThe results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial.Trial registrationANZCTR, ACTRN12623000486628. Registered on 12 May 2023.

Allergic Rhinitis.

Allergic rhinitis (AR) affects more than 400 million people worldwide, making it 1 of the most prevalent chronic diseases. Childhood AR is increasing, and almost half of patients with AR develop symptoms before age 6 years. Although a diagnosis of AR is associated with higher socioeconomic status, underserved and urban populations have more indoor aeroallergen sensitizations and are likely underdiagnosed with AR, further exacerbating health-care disparities. AR negatively impacts quality of life, school performance, and overall health outcomes. Untreated AR in children increases the risk for poor asthma control, increased asthma severity, and exacerbations. Many patients believe that they have seasonal allergies only but in reality have both perennial and seasonal AR, which may change the approach to allergen avoidance measures and treatment recommendations. Pharmacotherapy of AR has expanded, with many intranasal corticosteroids, intranasal antihistamines, and second-generation oral antihistamines approved for pediatric use. Allergen immunotherapy, including both subcutaneous and sublingual forms, are approved for children and are disease modifying, potentially reducing further allergen sensitization and progression to asthma. Many of the currently available biological therapies indicated for pediatric asthma and/or atopic diseases reduce AR symptoms as well. Children with moderate to severe or refractory AR or those with comorbidities should be referred to allergists for diagnostic testing and expanded management options, including immunotherapy and potential biological treatment.

Development of canagliflozin nanocrystals sublingual tablets in the presence of sodium caprate permeability enhancer: formulation optimization, characterization, in-vitro, in silico, and in-vivo study

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (−18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ’s antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets.

Efficacy and Safety of TNX-102 SL (Sublingual Cyclobenzaprine) for the Treatment of Fibromyalgia: Results From the Randomized, Placebo-Controlled RELIEF Trial.

To evaluate the efficacy and safety of TNX-102 SL, a once-nightly sublingual formulation of cyclobenzaprine, in reducing pain in patients with fibromyalgia. RELIEF was a double-blind, randomized, placebo-controlled trial. Overall, 503 patients received TNX-102 SL 2.8 mg for 2 weeks, followed by 5.6 mg for 12 weeks (248 patients), or matching placebo (255 patients). The primary endpoint was change from baseline at week 14 in weekly average of daily pain scores. Secondary endpoints included Patient Global Impression of Change (PGIC) scores, Fibromyalgia Impact Questionnaire Revised (FIQR) scores, Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Fatigue scores, and daily sleep quality. Safety was assessed by adverse events (AEs). Reduction in daily pain from baseline at week 14 was significantly greater with TNX-102 SL (LS mean change [95% CI], -1.9 [-2.1 to -1.7]) vs placebo (-1.5 [-1.7 to -1.3]; P=0.01). TNX-102 SL was not associated with significant improvement in PGIC at week 14 but was associated with improvements in FIQR scores, PROMIS scores, and daily sleep quality. Overall, 59.7% of patients receiving TNX-102 SL and 46.3% receiving placebo reported treatment-emergent AEs; the most common were oral hypoesthesia (17.3% with TNX-102 SL vs 0.4% with placebo), oral paresthesia (5.6% vs 0.4%, respectively), and product taste abnormal (4.4% vs 0.4%, respectively). In this phase 3, randomized, controlled trial of patients with fibromyalgia, treatment with TNX-102 SL was associated with significant reductions in daily pain and was safe and well tolerated.

Sublingual Dexmedetomidine for the Treatment of Agitation in Patients with Schizophrenia and Bipolar Disorder

Acute agitation is common amongst individuals with bipolar disorder and schizophrenia and represents a medical emergency. Commonly used medications for agitation, such as benzodiazepines and antipsychotics, are often delivered intramuscularly and may cause adverse effects. Non-invasive, effective, and safe alternative treatment options are needed. The purpose of this review article is to describe the efficacy and safety of sublingual formulation of dexmedetomidine (Igalmi), a selective α2-adrenergic receptor agonist, U.S. Food and Drug Administration approved for the treatment of acute agitation in adults with schizophrenia or bipolar I and II disorder. In two phase 3 trials, two dose strengths of sublingual dexmedetomidine 180 μg and 120 μg were safe and effective in managing acute agitation in patients with bipolar disorder or schizophrenia. Both doses significantly reduced Positive and Negative Syndrome Scale-Exited Component scores two hours after receiving a single dose as compared to placebo, indicating a substantial improvement in agitation. The beneficial effects of sublingual dexmedetomidine were achieved without serious adverse events with the most common side effect being mild somnolence. The clinical trial data suggest that sublingual dexmedetomidine represents a safe and effective treatment option in the armamentarium for acute agitation for people with schizophrenia or bipolar disorder.

Combined method of the cervical insufficiency correction: Dr. Arabin vaginal perforated obstetric pessary and various forms of tableted micronized progesterone

Objectives: a comparative assessment of the effectiveness of a combined therapeutic and prophylactic method for cervical insufficiency (CI) correcting by using Dr. Arabin vaginal perforated obstetric pessary and various forms of tableted micronized progesterone – vaginal and sublingual.Material and methods. 215 pregnant women with CI were under observation. The main group included 129 pregnant women with CI, in whom therapeutic and preventive measures included a combination of obstetric perforated pessary by Dr. Arabin and sublingual form of micronized progesterone 100 mg three times a day up to 36 weeks of pregnancy. The compression group included 86 pregnant women with CI treated with Dr. Arabin vaginal perforated obstetric pessary and micronized progesterone vaginal tablets 200 mg twice daily up to 36 weeks’ gestation. All women during the gestational period also received vitamin-mineral complexes for pregnant women, ω3-polyunsaturated fatty acids and magnesium preparations.Course of pregnancy, obstetric and perinatal consequences were assessed.Results. The study of combined methods in the CI correction led to similar results in pregnancy outcomes and childbirth: there was no statistically significant difference between the main group and comparison group in the frequency of premature rupture of membranes (χ2 = 6.65% vs. 0.47), labor before 32 weeks (1.55 versus 4.65%, χ2 = 1.83, p = 0.18) labor in 33–36 weeks (4.65 versus 6.98%, χ2 = 0.53, p = 0.47), emergency labor (93.80 versus 88.37%, χ2 = 1.98, p = 0.16), operative delivery by cesarean section (13.95 vs. 2.33% versus 6.98%, χ2 = 2.78, p = 0.10), bleeding in the postpartum period (2.33 vs. 6.98%, χ2 = 2.78, p = 0.10), neonatal morbidity (4.65 versus 10.47%, χ2 = 2.69, p = 0.10), low birth weight – less than 1,500 g (1.55 vs. 5.81%, χ2 = 2.98, р = 0.08), middleweight babies (3,420.24 ± 48.98 vs. 3,360.23 ± 66.38 g, p = 0.47). Comparing the compliance of treatment and preventive measures was established that women in labor in the obstetric pessary + sublingual progesterone group rated them at 9.19 ± 0.11 points, in the obstetric pessary + vaginal progesterone group – at 7.83 ± 0.0.01 points).Conclusions. Combined methods of CI correction using Dr. Arabin vaginal perforated obstetric pessary in combination with tableted micronized progesterone are effective and safe when using both vaginal and sublingual forms of progesterone. But the method of using a pessary and sublingual progesterone is more optimal, convenient and compliant. Both techniques can be widely used in clinical practice.

A Review of the Metabolism and Relevance to Form and Formulation of Ketamine

IntroductionKetamine is a phenylcyclohexylamine derivative comprising a racemic mixture of S- and R-ketamine that possesses anesthetic, analgesic, anti-inflammatory, and antidepressant activity. Oral (including extended release [PO]), intravenous (IV) sublingual (SL), transmucosal (TM), intranasal (IN), intramuscular (IM), rectal (PR), and subcutaneous (SC) formulations have been developed since its commercialization in 1970.ObjectivesTo review and understand the impact of different forms and formulations on the pharmacokinetics of ketamine.MethodsThe extant literature on ketamine metabolism and formulations was reviewed and discussed.ResultsIV (racemic) ketamine (KET) has been shown to improve depressed mood within 4 hours with maximal effect at 24 hours. KET is a chiral molecule with two optimal isomers, R- and S-KET. KET is stereoselectively metabolized by CYP2B6 and CYP3A4 initially via nitrogen demethylation to active metabolite, norketamine (NK); there is no interconversion between R- and S-KET. NK is further metabolized to hydroxynorketamine (HNK) by CYP3A4 and CYP3A5; and dehydronorketamine (DHNK) by CYP2B6. Additional metabolic pathways exist including a direct enantioselective hydroxylation of KET to 6-hydroxyketamine (HK). Bioavailablity is greatest (100%) with the IV racemic KET formulation, but as low as 8% for oral S-KET due to extensive first-pass metabolism; the KET: NK ratio is a measure of first pass metabolism. NK plasma levels are higher with oral S-KET than KET as a result of local intestinal metabolism effects. Additionally, greater plasma concentrations are noted with IV bolus doses of S-KET vs. racemic KET or R-KET. S-KET possesses a longer elimination half-life than racemic KET due to inhibition by R-KET. KET is primarily renally eliminated and twice as fast in children vs. adults.ConclusionsComplex interactions are reported between ketamine form (racemic/enantiomer), formulation, dose, and route of administration that impact on clinical variables and thus, outcome.Disclosure of InterestNone Declared

Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent

ABSTRACT Introduction Especially when acutely ill, individuals with schizophrenia and bipolar disorder can present with agitated behavior. The initial approach to agitation management are non-pharmacologic strategies such as verbal de-escalation techniques; however, pharmacologic interventions may be needed. Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist, and a sublingual formulation has been approved in the US for the treatment of agitation associated with schizophrenia and bipolar disorder in adults. Areas covered The authors review the published literature on sublingual dexmedetomidine using the US National Library of Medicine’s PubMed.gov resource. Pharmacodynamics, pharmacokinetics, and efficacy and tolerability findings are summarized. The authors also provide a discussion to its potential place in the treatment armamentarium. Expert opinion Sublingual dexmedetomidine is an effective and well-tolerated pharmacologic option for the treatment of agitation associated with schizophrenia and bipolar disorder. The sublingual method of administration allows for a rapid onset of action with treatment effects beginning as early as 20 minutes after administration. Adverse effects include somnolence, hypotension, oral paresthesia, hypoesthesia, and dry mouth. Further study will be needed to evaluate sublingual dexmedetomidine in real-world patients receiving concomitant psychotropic medications.

Industry update, December 2022.

Industry update, December 2022.