Sublingual Film Research Articles

Patient-reported motor responses to apomorphine sublingual film based on home dosing and response diaries

Objective: To evaluate the efficacy of self-administered apomorphine sublingual film (APL-130277; APL) versus placebo for on-demand treatment of “OFF” episodes in patients with Parkinson's disease (PD) based on patient-reported home dosing and response diaries from a pivotal study.

Impact of baseline factors on response to apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

Objective: Describe the impact of baseline factors on response to apomorphine sublingual film (APL-130277; APL) among patients with Parkinson's disease (PD) and “OFF” episodes in a pivotal controlled trial. APL was efficacious and generally well tolerated for the on-demand treatment of “OFF” episodes; the study met its primary endpoint of change in MDS-UPDRS Part III score at 30 minutes postdose at week 12 (least squares mean difference from placebo, -7.6 points; P=0.0002) and its key secondary endpoint of self-rated FULL “ON” response rate within 30 minutes postdose at week 12 (P=0.0426).

Exposure-response efficacy model of apomorphine sublingual film for the on-demand treatment of “OFF” episodes in patients with Parkinson's disease

Objective: To use a longitudinal exposure-response model to characterize the relationship between apomorphine exposure and efficacy with apomorphine sublingual film (APL-130277; APL) using the MDS-UPDRS Part III score in patients with Parkinson's disease and “OFF” episodes.

FABRICATION OF AN ABUSE DETERRENT AND MICROEMULSION-BASED SUBLINGUAL FILM OF BUPRENORPHINE HYDROCHLORIDE FOR BREAKTHROUGH PAIN MANAGEMENT

Objective: The present research work aims to develop an abuse deterrent rapidly dissolving buprenorphine microemulsion loaded sublingual film for the treatment of breakthrough pain.
 Methods: The Buprenorphine microemulsion loaded sublingual films were prepared using Capmul MCM C8 (oil), tween 20 (surfactant) and propylene glycol (co-surfactant) with different grades of film-forming polymer (HPMC) using film casting machine. The films were evaluated for in vitro disintegration and dissolution study, tensile strength, folding endurance, content uniformity, surface pH, thickness and weight variation, % loading of buprenorphine microemulsion in sublingual film, scanning electron microscope, ex vivo permeation study, droplet size and polydispersity index, Zeta potential, % moisture content, stability and abuse deterrent potential were evaluated.
 Results: The optimized film formulation showed desired mechanical properties with minimum disintegration time of 21s and exhibited 34.45 % loading of Buprenorphine microemulsion. Permeation studies through goat sublingual mucosa, indicated 87% Buprenorphine release, through Buprenorphine microemulsion loaded sublingual film, whereas only 30% Buprenorphine release when it was directly added to film without microemulsion strategy.
 Conclusion: The present study concludes that abuse deterrent and fast acting buprenorphine microemulsion-incorporated sublingual film of buprenorphine HCL and naloxone HCL is a promising alternative to mostly marketed buprenorphine injectable delivery systems and a non-invasive route of administration for breakthrough pain management.

Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

IntroductionThe efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of “OFF” episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. MethodsAdult patients with levodopa-responsive PD and “OFF” episodes were enrolled. In practically defined “OFF,” patients were observed for a FULL “ON” after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10–35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. ResultsAmong 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL “ON” (66.1% at 10–20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). ConclusionAmong eligible patients with PD and “OFF” episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of “OFF” episodes.

Sublingual indocyanine green films for non-invasive swallowing assessment and inflammation detection through NIR/SWIR optical imaging

Indocyanine green (ICG) is the most commonly used FDA-approved agent for clinical optical imaging, administered through injections only, due to its poor membrane permeability. Although ICG has vast potential for non-invasive non-radioactive imaging in patients, the clinical applications are limited by the invasive administration and short half-life in blood circulation. To expand the clinical value of ICG, non-toxic chitosan-based ICG-loaded films were designed for sublingual administration for near-infrared (NIR) and short-wave infrared (SWIR) optical imaging. Two film formulations were developed with different ICG release rates. Mold-casted self-emulsifying films rapidly released ICG (80% in 4 h) in the form of nanosized droplets, which were mostly swallowed and produced significant contrast of upper digestive tract to enable in vivo swallowing evaluations using NIR/SWIR imaging. Regular films released ICG slowly (80% in 25 h), allowing for steady absorption of ICG to systemic circulation. Inflammation in mouse feet was detected within 30 min after sublingual administration with a 1.43-fold fluorescence increase within 1 h at the inflammation sites, comparable to a 1.76-fold increase through intravenous injection. Administering ICG using sublingual films displayed notable potential for non-invasive diagnosis and monitoring of inflammatory conditions and swallowing disorders, addressing a current need for alternatives to ICG parenteral administration.

LC-MS/MS simultaneous quantification of apomorphine and its major metabolites in human plasma: Application to clinical comparative bioavailability evaluation for the apomorphine sublingual film and a subcutaneous product

A liquid chromatography-tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the simultaneous quantification of apomorphine and its metabolites apomorphine sulfate and norapomorphine in human plasma for supporting clinical development of a novel apomorphine sublingual thin film (APL) for the treatment of Parkinson’s disease. Analytes and internal standards (IS) were extracted from human plasma by Oasis HLB SPE cartridge, followed by a reversed phase LC–MS/MS analysis using multiple reaction monitoring (MRM) in positive mode (m/z 268 → 237 for apomorphine, 348 → 237 for apomorphine sulfate, and 348 → 237 for norapomorphine). Stable isotope-labeled compounds were used as IS for respective analytes. The validated curve ranges were 0.02–20 ng/mL, 10–1000 ng/mL, and 0.5–20 ng/mL for apomorphine, apomorphine sulfate and norapomorphine, respectively. Extraction recoveries were found to be 73.4 % (apomorphine), 81.1 % (apomorphine sulfate), and 58.6 % (norapomorphine). Established long-term plasma frozen storage stabilities were 504 days at -20 °C and276 days at −60 °C, respectively. The method has been successfully used for analyzing pharmacokinetics (PK) samples collected from a comparative bioavailability study of APL and the marketed apomorphine subcutaneous (s.c.) product Apo-go®. The results demonstrated that the 15-mg APL film administrated via sublingual produced comparable PK characteristics of apomorphine when compared to the commercial product Apo-go (2-mg) via s.c. administration, hence establishing the dose regimen for this sublingual formulation. It was also noticed that the sublingual 15-mg APL film produced a significantly higher apomorphine sulfate metabolite level than the 2-mg s.c. Apo-go, and both treatments yielded a negligible level of norapomorphine metabolite in humans.

Motor Responses to Apomorphine Sublingual Film Compared With Levodopa in Patients With Parkinson’s Disease and “OFF” Episodes (337)

Motor Responses to Apomorphine Sublingual Film Compared With Levodopa in Patients With Parkinson’s Disease and “OFF” Episodes (337)

How Motivations for Using Buprenorphine Products Differ From Using Opioid Analgesics: Evidence from an Observational Study of Internet Discussions Among Recreational Users.

BackgroundOpioid use disorder (OUD) poses medical and societal concerns. Although most individuals with OUD in the United States are not in drug abuse treatment, buprenorphine is considered a safe and effective OUD treatment, which reduces illicit opioid use, mortality, and other drug-related harms. However, as buprenorphine prescriptions increase, so does evidence of misused, abused, or diverted buprenorphine. Users’ motivations for extratreatment use of buprenorphine (ie, misuse or abuse of one’s own prescription or use of diverted medication) may be different from the motivations involved in analgesic opioid products. Previous research is based on small sample sizes and use surveys, and none directly compare the motivations for using buprenorphine products (ie, tablet or film) with other opioid products having known abuse potential.ObjectiveThe aim of the study was to describe and compare the motivation-to-use buprenorphine products, including buprenorphine/naloxone (BNX) sublingual film and oxycodone extended-release (ER), as discussed in online forums.MethodsWeb-based posts from 2012 to 2016 were collected from online forums using the Web Informed Services internet monitoring archive. A random sample of posts was coded for motivation to use. These posts were coded into the following motivation categories: (1) use to avoid withdrawal, (2) pain relief, (3) tapering from other drugs, (4) opioid addiction treatment, (5) recreational use (ie, to get high), and (6) other use. Oxycodone ER, an opioid analgesic with known abuse potential, was selected as a comparator.ResultsAmong all posts, 0.81% (30,576/3,788,922) discussed motivation to use one of the target products. The examination of query-selected posts revealed significantly greater discussion of buprenorphine products than oxycodone ER (P<.001). The posts mentioning buprenorphine products were more likely than oxycodone ER to discuss treatment for OUD, tapering down use, and/or withdrawal management (P<.001). Buprenorphine-related posts discussed recreational use (375/1020, 36.76%), although much less often than in oxycodone ER posts (425/508, 83.7%). Despite some differences, the overall pattern of motivation to use was similar for BNX sublingual film and other buprenorphine products.ConclusionsAn analysis of spontaneous, Web-based discussion among recreational substance users who post on online drug forums supports the contention that motivation-to-use patterns associated with buprenorphine products are different from those reported for oxycodone ER. Although the findings presented here are not expected to reflect the actual use of the target products, they may represent the interests and motivations of those posting on the online forums. Buprenorphine-related posts were more likely to discuss treatment for OUD, tapering, and withdrawal management than oxycodone ER. Although the findings are consistent with a purported link between the limited availability of medication-assisted therapies for substance use disorders and use of diverted buprenorphine products for self-treatment, recreational use was a motivation expressed in more than one-third of buprenorphine posts.

Toxicity of agents used for opioid withdrawal: a case-based approach.

Toxicity of agents used for opioid withdrawal: a case-based approach.

Fast Dissolving Sublingual Strips: A Novel Approach for the Delivery of Isosorbide Dinitrate

Background: Isosorbide dinitrate (ISDN) is used for treating the angina attacks. In addition, oral ISDN is available in immediate and sustained release formulations and the bioavailability of ISDN is about 20-25% when taken orally. Further, the ISDN films are developed for sublingual drug delivery by improving drug bioavailability. The present study aimed to design and evaluate the physicochemical properties of the film formulation for sublingual delivery of ISDN. Methods: In the present study, sublingual films were prepared by the solvent casting technique using the hydroxypropyl methylcellulose (HPMC) polymers (i.e., 100, 150 and 200 mg) with a different drug to polymer ratios (i.e., 1:5, 1:7.5 and 1:10). Then, ISDN was evaluated for the film appearance, drug content, surface pH, mucoadhesion force, differential scanning calorimetry (DSC), in vitro drug release, and ex vivo permeability. Results: Based on the results, F3 formulation (1:10 ISDN to HPMC ratio) showed acceptable thickness (0.93 mm), weight (11.14 mg), surface pH (7.82), moisture absorption capacity (6.08%), elasticity (&gt;200), mucoadhesion force (18.05 N/cm2), and drug content (6.22%). Furthermore, the results demonstrated that HPMC polymer improved the characteristics of the films, modified the bioadhesiveness, and finally, enhanced elasticity. However, DSC thermogram failed to show any crystalline drug substance in the films except for F1 (immediate release) and the endothermic peak of ISDN was absent in F2 and F3 films. Therefore, the drug which was entrapped into the film was in an amorphous or disturbed-crystalline phase of the molecular dispersion or dissolved in the melted polymer in the polymeric matrix. Moreover, the drug release from the films was faster compared to the tablet® (P&lt;0.05). Conclusion: In general, the formulation of F1 was observed to be an appropriate candidate for developing the sublingual film for the remedial use.

Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 study

Many patients with Parkinson's disease have potentially disabling off episodes that are not predictably responsive to levodopa. In this study, we assessed the safety and efficacy of apomorphine sublingual film as an on-demand therapy for off episodes in patients with Parkinson's disease. This randomised, double-blind, placebo-controlled study was done by movement disorder specialists at 32 sites in the USA and one in Canada. Patients with Parkinson's disease who had 2 h or more of off time per day with predictable morning off periods, were responsive to levodopa, and were on stable doses of anti-parkinsonian medication were eligible. In an open-label titration phase, increasing doses of apomorphine sublingual film (10-35 mg) were administered until a tolerable full on response was achieved. Patients were then randomly assigned (1:1) with an interactive web-response system to receive the effective dose of apomorphine sublingual film or matching placebo in a 12-week, double-blind maintenance phase. Randomisation was not stratified, and the block size was four. All patients and study personnel were masked to treatment assignments. The primary endpoint was the in-clinic change from predose to 30 min post-dose in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 (motor) score at week 12, analysed on a modified intention-to-treat population by use of a mixed-effect model for repeated measures. Safety analyses were done on all enrolled patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT02469090. Between June 18, 2015, and Dec 11, 2017, 109 patients were enrolled and randomly assigned to receive apomorphine sublingual film (n=54) or placebo (n=55). All patients received the assigned study treatment, and 34 (63%) of 54 patients receiving apomorphine sublingual film and 46 (84%) of 55 receiving placebo completed the study. Least squares mean (SE) change from predose to 30 min post-dose in MDS-UPDRS part 3 score at week 12 was -11·1 (SE 1·46, 95% CI -14·0 to -8·2) with apomorphine sublingual film and -3·5 (1·29, -6·1 to -0·9) with placebo (difference -7·6, SE 1·96, 95% CI -11·5 to -3·7; p=0·0002). Mild-to-moderate oropharyngeal events were the most common side-effect, reported in 17 (31%) of 54 patients receiving apomorphine sublingual film and in four (7%) of 55 patients receiving placebo, leading to treatment discontinuation in nine (17%) patients treated with apomorphine and in one (2%) patient treated with placebo. Other treatment-emergent adverse events were transient nausea (in 15 [28%] patients receiving apomorphine sublingual film), somnolence (seven [13%]), and dizziness (five [9%]). Orthostatic hypotension, syncope, dyskinesia, hallucinations, prolongation of the QT interval, and impulse control disorders were infrequent (prevalence ≤2% of all patients) or did not occur. One patient treated with apomorphine sublingual film (with known cardiac risk factors) had a fatal cardiac arrest. Although nearly a third of patients discontinued treatment primarily because of oropharyngeal side-effects, apomorphine sublingual film provided an efficacious, on-demand treatment for off episodes for most patients with Parkinson's disease in this trial. The long-term safety and efficacy of apomorphine sublingual film are currently being investigated. Cynapsus Therapeutics and Sunovion.

Silodosin oral films: Development, physico-mechanical properties and in vitro dissolution studies in simulated saliva

Sublingual film dosage forms for drugs used for fast symptomatic treatment have promise because they allow a rapid onset of action. The aim of this study was to prepare films of silodosin intended for sublingual administration for the symptomatic treatment of benign prostatic hyperplasia in men. Hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were used as film-forming polymers. The effects of the polymers and the surfactant tocopherol polyethylene glycol succinate (TPGS) on the physico-mechanical properties and dissolution behavior of the films in simulated saliva were investigated. The eight silodosin oral films developed (F1–F8) contained 8 mg silodosin per 6 cm2 film and HPMC or HPMC-AS in drug:polymer ratios of 1:5 or 1:3, while four also contained TPGS (0.5% w/w). The films were characterized using DSC, TGA, SEM, and PXRD and the mechanical properties were investigated by measuring tensile strength, elongation at break and Young's modulus. The mechanical properties of the films were dependent on the ratio of polymer used. The in vitro dissolution and drug release studies indicated that HPMC-AS films disintegrated more quickly than HPMC films. Silodosin was shown to be dispersed within the polymers. Despite silodosin being submicronized in the HPMC films, the dissolution and drug release rate (time for 80% release) from HPMC films was significantly faster than from HPMC-AS films. TPGS increased the drug release rate to a greater extent with HPMC than with HPMC-AS. The degree of saturation of formulation F4 was >1, which shows potential for improving oral absorption of silodosin.

FORMULATION AND EVALUATION OF SUBLINGUAL FILMS OF APIXABAN

The concept of sublingual film dosage form has become popular as new delivery system. This system will provide maximum therapeutic efficacy, increased bioavailability and maximum stability by reducing the frequency of dosage. It will also avoid first pass metabolism of the drugs. This system provides more rapid drug absorption from the pre gastric area which may provide quick onset of action. The present research aimed to prepare sublingual films of apixaban reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The film was prepared using solvent casting method and optimized employing 32 factorial design considering two independent variables film forming polymer (HPMC E5) and PEG 400. Disintegration time, drug release and folding endurance were taken as dependent variables. The prepared optimized formulation showed minimum disintegration time (35 s), highest dissolution rate (99 %) and satisfactory physicochemical properties. It is evident from the above results that the developed formulation can be an innovative dosage form to improve the drug delivery, onset of action as well as improve patient compliance.&#x0D; Key Words: Apixaban, Sublingual films, HPMC

Population Pharmacokinetics Model of Apomorphine/Apomorphine-Sulphate Administered as a Sublingual Film or Subcutaneously in Healthy Subjects and Patients With Parkinson’s Disease (P3.8-034)

Population Pharmacokinetics Model of Apomorphine/Apomorphine-Sulphate Administered as a Sublingual Film or Subcutaneously in Healthy Subjects and Patients With Parkinson’s Disease (P3.8-034)

Efficacy and Safety of Apomorphine Sublingual Film for The Treatment of “OFF” Episodes in Patients With Parkinson’s Disease: Phase 3, Double-Blind, Placebo-Controlled Trial (P2.8-053)

Efficacy and Safety of Apomorphine Sublingual Film for The Treatment of “OFF” Episodes in Patients With Parkinson’s Disease: Phase 3, Double-Blind, Placebo-Controlled Trial (P2.8-053)

口腔粘膜付着性ロラゼパムフィルムの開発 II—薬剤の唾液による口腔内流失回避を目的とした二層フィルム製剤の調製—

口腔粘膜付着性ロラゼパムフィルムの開発 II—薬剤の唾液による口腔内流失回避を目的とした二層フィルム製剤の調製—

Suboxone Treatment and Recovery Trial (STAR-T): Study Protocol for a Randomised Controlled Trial of Opioid Medication Assisted Treatment with Adjunctive Medication Management Using Therapeutic Drug Monitoring and Contingency Management.

Introduction Opioid assisted treatment (OAT) with buprenorphine (BUP) is front-line medical maintenance intervention for illicit and prescription opioid use disorder (OUD). In many clinics, opioid medication is dispensed for several days for self-administration. This provides flexibility to the patient but may compromise the effectiveness of OAT because of nonadherence or medication diversion. OAT can be delivered as an entirely supervised intervention, but many patients discontinue treatment under this arrangement and dispensing costs may be prohibitive. An alternative is to enable patients to receive take-home doses contingent on OAT adherence guided by a medication management framework using Therapeutic Drug Monitoring (TDM) alongside negative urine drug screens (UDS) to provide evidence of abstinence. TDM is recommended to monitor adherence with BUP but it has not been applied in OAT programs and evaluation research to date. Methods The Suboxone Treatment and Recovery Trial (STAR-T) is a single site, 16-week, parallel-group, randomised controlled trial. The aim of the study is to determine the effectiveness of a medication management framework including TDM and UDS to enable patients enrolled on outpatient OAT (with buprenorphine/naloxone [sublingual film formulation; BUP/NX-F; Suboxone™]) to receive stepped take-home doses. Following stabilisation during inpatient care, adult participants with illicit or prescription OUD were allocated (1:1) to receive (1) BUP/NX-F plus medication management for take-home doses based on TDM, UDS, and contingency management protocol (the experimental group) or (2) BUP/NX-F plus UDS only (treatment-as-usual, the control group). The primary outcome is the mean percentage of negative UDS over 16 weeks. The secondary outcome is treatment retention defined as completion of 16 weeks of OAT without interruption. There will be an exploratory analysis of the association between participant characteristics, clinical data, and outcomes. Conclusions Providing BUP/NX-F take-home doses contingent on adherence and opioid abstinence may enable OAT to be delivered flexibly and effectively. Trial Registration ISRCTN41645723 is retrospectively registered on 15/11/2015.

Development and in vitro/in vivo evaluation of dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films

Dihydroergotamine mesylate (DHE), ergotamine derivative, has been offered for clinical use to stop or treat symptoms of an emerging migraine as injection for more than a half century. It is shown that bioavailability of DHE greatly changes between the subjects and up to 99% of the orally absorbed dose may be cleared by first pass metabolism. The aim of this study was to design and optimize DHE fast-dissolving sublingual films for migraine treatment. For this purpose pullulan and maltodextrin was chosen as film-forming polymers and propylene glycol as plasticizer. For optimization process Box Behnken design was used. The formed films were free from air bubbles, cuttings, or cracks. Disintegration, mechanical strength and dissolution of films were compared. It is found that pullulan and maltodextrin formed films with the most desired properties at the concentration of 1.5% and 2%. The application of optimum formulation to rabbits showed that bioavailability of formulation is about 23.35% with a tmax 20 min. Due to this fast onset of action and higher bioavailability than oral administration, it is suggested that the polymer combinations of pullulan and maltodextrin formed successful films and were considered as an alternative dosage form for DHE in migraine therapy.

Preparation and evaluation of fast dissolving sublingual film of lisinopril

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