Sublingual Delivery Research Articles

Sufentanil sublingual formulation for the treatment of acute, moderate to severe postoperative pain in adult patients

ABSTRACTIntroduction: Sufentanil is a highly selective µ-opioid agonist commonly used by intravenous and intrathecal routes for acute pain. Sublingual sufentanil formulation for patient controlled analgesia (PCA) uses an innovative administration device that suspends a 15 µg nanotablet with a fixed lockout interval. The system is a non-invasive, less burdensome method of opioid delivery compared to intravenous and intrathecal routes. Sublingual nanotablet PCA transmucosal bioavailability is 59% and the meaningful analgesic onset time is 60 minutes.Areas covered: This paper focuses on the effectiveness, safety and feasibility of sufentanil PCA sublingual formulation for the management of postoperative pain. The paper is based on PubMed searches and the European Medicine Agency assessment report.Expert commentary: Under-treatment of acute pain is a substantial clinical problem. The initial experiences with the sublingual delivery system are encouraging. Sufentanil sublingual nanotablets intended for PCA device use are approved in Europe, and approval is pending in the United States.

Preparing an Adjuvanted Thermoresponsive Gel Formulation for Sublingual Vaccination.

Thermoresponsive gels have unique physicochemical properties that may enable more effective mucosal delivery of active compounds. The thermoresponsive gel (TRG) formulation developed by our group for sublingual delivery maintains fluid-like liquid properties at 2 °C-8 °C and forms a gel at the physiological temperature (~37 °C) within a few seconds. Here, we describe the preparation of a thermoresponsive gel vaccine formulation. Our preclinical studies with various antigens suggest that the mucoadhesive, adjuvanted TRG formulation enabled increased contact of the vaccine antigen with the mucosa, resulting in increased mucosal response(s) with a potential for antigen dose reduction.

Novel instantly-soluble transmucosal matrix (ISTM) using dual mechanism solubilizer for sublingual and nasal delivery of dapoxetine hydrochloride: In-vitro/in-vivo evaluation

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive first pass metabolism. The usefulness of transmucosal (sublingual and intranasal) drug delivery to improve bioavailability of D, a weak basic drug, has been hampered by its poor solubility in the neutral pH of the body fluids. In this study, instantly-soluble transmucosal matrices (ISTMs) of D, containing dual mechanism solubilizer (Pluronic F-127/citric acid mixture), were prepared by lyophilization technique to enhance matrix disintegration, dissolution and transmucosal permeation. The matrices were evaluated for in-vitro disintegration, wetting time, in-vitro dissolution, ex vivo transmucosal permeation, scanning electron microscopy and in-vivo studies. Dissolution studies confirmed the higher ability of ISTMs to enhance the early time point dissolution and maintain complete drug dissolution in pH 6.8 compared to conventional lyophilized matrices. The optimized ISTM gave approximately 77.54 and 88.40 folds increase of D dissolution after 1 and 3min relative to the drug powder in pH 6.8. ISTMs containing the highest F127 concentration (2%) and the lowest gelatin and mannitol concentrations (1%) exhibited the shortest in-vitro disintegration times (<10s), the fastest dissolution in the neutral pH of body fluids (∼99% in 3min) and the highest enhancement of transmucosal permeation. The relative bioavailabilities of D after sublingual and intranasal administration of ISTMs to rabbits were about 124.58% and 611.15%, respectively, in comparison to the oral market tablet. The significant increase of drug dissolution in nasal fluids, rapid permeation rate together with the improved bioavailability propose that ISTMs could be promising for intranasal delivery of drugs suffering from oral hepatic metabolism and have limited solubility in nasal fluids.

Rapid-Onset Sildenafil Sublingual Drug Delivery Systems: In Vitro Evaluation and In Vivo Pharmacokinetic Studies in Rabbits

The aim of the present study was to prepare sublingual delivery systems for sildenafil and evaluate its relative bioavailability after sublingual administration in rabbits to attain a rapid onset of action with good efficacy at lower doses. For sublingual application, sildenafil and its citrate were formulated in 2 different dosage forms: the first was a sublingual spray consisting of sildenafil in 2 microemulsion systems, oleic acid or propylene glycol (PG), and the second was sublingual tablets prepared with various granulated sublingual sprays adsorbed onto a silicate adsorbant (Florite® R), binders (Cyclocel® or EMDEX®), and disintegrants (Ac-Di-Sol® or Kollidon® CL). Results showed that sublingual absorption of sildenafil spray prepared with PG was fairly rapid. At a 0.5-mg dose, the mean onset of action was 1.3 ± 0.6 min and lasted for about 1.5 h according to the pharmacokinetic studies. In vivo studies also showed that for sublingual tablets formulated with sildenafil in PG adsorbed onto Florite® R at a 1:1 weight ratio then mixed with Cycloel® and Ac-Di-Sol®, the onset action was fast at 1.9 ± 0.4 min and lasted for about 1 h at 0.5 mg. These findings suggest the potential for the sublingual delivery of sildenafil instead of the conventional oral administration.

Effect of Lipophilicity and Drug Ionization on Permeation Across Porcine Sublingual Mucosa.

Sublingual route is one of the oldest alternative routes studied for the administration of drugs. However, the effect of physical-chemical properties on drug permeation via this route has not been systemically investigated. The objective of this study was to determine the effect of two key physicochemical properties, lipophilicity and ionization, on the transport of drugs across porcine sublingual mucosa. A series of β-blockers were used to study the effect of lipophilicity on drug permeation across the sublingual mucosa, while nimesulide (pKa 6.5) was used as a model drug to study the effect of degree of ionization on sublingual mucosa permeation of ionized and unionized species. Permeation of β-blockers increased linearly with an increase in the lipophilicity for the range of compounds studied. The permeability of nimesulide across sublingual mucosa decreased with an increase of pH. The flux of ionized and unionized forms of nimesulide was determined to delineate the contribution of ionized and unionized species to the total flux. At low pH, the apparent flux was primarily contributed by unionized species; however, when the pH is increased beyond its pKa, the primary contributor to the apparent flux, nimesulide, is ionized species. The contribution of each species to the apparent flux was shown to be determined by the thermodynamic activity of ionized or unionized species. This study identified the roles of lipophilicity and thermodynamic activity in drug permeation across the sublingual mucosa. The findings can help guide the design of sublingual drug delivery systems with optimal pH and solubility.

Formulation and evaluation of sublingual delivery of piroxicam using thermosensitive polymer with an inverted Franz diffusion cell.

The aim of the study was to prepare a sublingual formulation for piroxicam using a thermosensitive polymer and to evaluate its permeation through porcine sublingual mucosa. Formulation technique utilized the transition property of poloxamer from solution state at room temperature to gel state at oromucosal temperature (37 °C). The permeation of the drug was evaluated using an inverted Franz diffusion cell technique that allowed the dosage form to be directly applied onto the substrate with required volume of saliva. The formulation was characterized for microscopy of the piroxicam crystals, sol-gel transition property and in-vitro diffusion study. Poloxamer-based formulation enhanced solubility and increased permeability of the piroxicam. Poloxamer formulation with 0.1% w/w piroxicam delivered a cumulative amount of 11.99 ± 7.82 and 11.23 ± 1.79 μg/cm(2), while non-poloxamer formulation delivered 3.57 ± 2.20 and 4.60 ± 6.90 μg/cm(2) with 0.1 and 0.5 ml artificial saliva, respectively, through porcine sublingual tissue in 6 h. A similar delivery profile was observed for 0.05% w/w piroxicam formulation as well.

Sublingual immunotherapy for asthma.

Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. However, it is not clear whether the sublingual delivery route is safe and effective in asthma. To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. We identified trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/) and reference lists of all primary studies and review articles. The search is up to date as of 25 March 2015. We included parallel randomised controlled trials (RCTs), irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. Two review authors independently screened the search results for included trials, extracted numerical data and assessed risk of bias, all of which were cross-checked for accuracy. We resolved disagreements by discussion.We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We rated all outcomes using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) and presented results in the 'Summary of findings' table. Fifty-two studies met our inclusion criteria, randomly assigning 5077 participants to comparisons of interest. Most studies were double-blind and placebo-controlled, but studies varied in duration from one day to three years. Most participants had mild or intermittent asthma, often with co-morbid allergic rhinitis. Eighteen studies recruited only adults, 25 recruited only children and several recruited both or did not specify (n = 9).With the exception of adverse events, reporting of outcomes of interest to this review was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence. Allocation procedures generally were not well described, about a quarter of the studies were at high risk of bias for performance or detection bias or both and participant attrition was high or unknown in around half of the studies.One short study reported exacerbations requiring a hospital visit and observed no adverse events. Five studies reported quality of life, but the data were not suitable for meta-analysis. Serious adverse events were infrequent, and analysis using risk differences suggests that no more than 1 in 100 are likely to suffer a serious adverse event as a result of treatment with SLIT (RD 0.0012, 95% confidence interval (CI) -0.0077 to 0.0102; participants = 2560; studies = 22; moderate-quality evidence).Within secondary outcomes, wide but varied reporting of largely unvalidated asthma symptom and medication scores precluded meaningful meta-analysis; a general trend suggested SLIT benefit over placebo, but variation in scales meant that results were difficult to interpret.Changes in inhaled corticosteroid use in micrograms per day (MD 35.10 mcg/d, 95% CI -50.21 to 120.42; low-quality evidence), exacerbations requiring oral steroids (studies = 2; no events) and bronchial provocation (SMD 0.69, 95% CI -0.04 to 1.43; very low-quality evidence) were not often reported. This led to many imprecise estimates with wide confidence intervals that included the possibility of both benefit and harm from SLIT.More people taking SLIT had adverse events of any kind compared with control (OR 1.70, 95% CI 1.21 to 2.38; low-quality evidence; participants = 1755; studies = 19), but events were usually reported to be transient and mild.Lack of data prevented most of the planned subgroup and sensitivity analyses. Lack of data for important outcomes such as exacerbations and quality of life and use of different unvalidated symptom and medication scores have limited our ability to draw a clinically useful conclusion. Further research using validated scales and important outcomes for patients and decision makers is needed so that SLIT can be properly assessed as clinical treatment for asthma. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma, so we cannot comment on the safety of SLIT for those with moderate or severe asthma. SLIT is associated with increased risk of all adverse events.

Chitosan: a propitious biopolymer for drug delivery.

Scientists have always been interested in the use of natural polymers for drug delivery. Chitosan, being a natural cationic polysaccharide has received a great deal of attention in the past few years. It is obtained by deacetylation of chitin and is regarded as the second most ubiquitous polymer subsequent to cellulose on earth. Unlike other natural polymers, the cationic charge possessed by chitosan is accountable for imparting interesting physical and chemical properties. Chitosan has been widely exploited for its mucoadhesive character, permeation enhancing properties and controlled release of drugs. Moreover it's non-toxic, biocompatible and biodegradable properties make it a good candidate for novel drug delivery system. This review provides an insight on various chitosan based formulations for drug delivery. Some of the current applications of chitosan in areas like ophthalmic, nasal, buccal, sublingual, gastro-retentive, pulmonary, transdermal, colon-specific and vaginal drug delivery have been discussed. In addition, active targeting of drugs to tumor cells using chitosan has been described. Lastly a brief section covering the safety aspects of chitosan has also been reviewed.

Development, optimization, and characterization of polymeric electrospun nanofiber: a new attempt in sublingual delivery of nicorandil for the management of angina pectoris

The objective of the current investigation was to develop a novel biocomposite polymeric nanofiber for sublingual delivery of nicorandil in an attempt to reduce mucosal ulceration and to improve drug bioavailability. Polymeric nanofibers were achieved using vitamin B12 and a blend of hyaluronic acid and polyvinyl alcohol as polymeric constituents. The electrospinning method was used to prepare drug (nicorandil)-loaded nanofibers. The resulting nanofibers were characterized for morphology, drug loading, XRD, DSC, in vitro drug release, degree of swelling, and pharmacokinetic behavior. The prepared nanofibers were found to be uniform, non-beaded, and non-woven, with fiber diameter ranging from 200–450 nm. In vitro drug release substantiated the controlled release behavior of the developed formulation. Histopathology studies demonstrated no evidence of mucosal ulceration at the site of application. Pharmacokinetic studies established the preclinical safety and showed the maintenance of an effective therapeutic level for a prolonged period. The present investigation gives inputs showing that the biocomposite nanofiber assists as a perfect carrier system for sublingual delivery of anti-anginal drugs.

(459) Evaluation of liquid spray technology for sublingual drug delivery

Sublingual drug administration may be appropriate in multiple disease states, such as in patients who require rapid onset of effect (eg, transmucosal immediate-release fentanyl for breakthrough cancer pain [fentanyl sublingual spray]) or have conditions that negatively impact oral medication administration (eg, dysphagia, xerostomia), or when hepatic first-pass metabolism avoidance is desired. It is important for a sublingual spray device to accurately deliver microliter quantities of appropriate droplet size (eg, to prevent lung deposition) and have a simple, easy-to-use, durable mechanical design (eg, no springs). This study evaluated the characteristics of liquid spray technology for sublingual delivery. Two formulations (A and B) were evaluated and contained 30% v/v dehydrated alcohol, 5% v/v propylene glycol, 0.2% v/v peppermint oil, pH 9 borate buffer (quantity sufficient), and hydroxypropyl-beta-cyclodextrin (1:2); formulation B also contained 1% v/v hydroxypropyl cellulose (HPC-EP). Formulations were sprayed using a 0.1-mL multidose pump and evaluated for dose volume, spray pattern (methylene blue added; actuation 30 mm from target), and droplet size distribution using a Malvern Mastersizer particle size analyzer (n=25 spray samples). For formulations A and B, dose volumes were similar (mean volume, 100.4 and101.5 microliters, respectively; maximum single volume, 103.2 and 103.7 microliters). Spray patterns varied only slightly for formulations A versus B (small diameter mean [range], 50.6 millimeters [35.4-62.0] vs 34.0 millimeters [29-46.0], respectively; mean ratio largest/smallest diameter [range], 1.1 [1.0-1.3] vs 1.2 [1.1-1.5]). However, droplet size distribution varied with formulation A versus B (mean percentage share of droplet diameters at 10 micrometers [range], 1.7 [0.7-2.7] vs 0.7 [0.2-1.3], respectively). Overall, the characteristics of a liquid spray technology support further development for sublingual drug delivery. A formulation of fentanyl for sublingual administration is currently available, and research evaluating additional pain or addiction pharmacologic candidates for sublingual delivery in pain-related and other conditions is warranted. Supported by Insys Therapeutics. Sublingual drug administration may be appropriate in multiple disease states, such as in patients who require rapid onset of effect (eg, transmucosal immediate-release fentanyl for breakthrough cancer pain [fentanyl sublingual spray]) or have conditions that negatively impact oral medication administration (eg, dysphagia, xerostomia), or when hepatic first-pass metabolism avoidance is desired. It is important for a sublingual spray device to accurately deliver microliter quantities of appropriate droplet size (eg, to prevent lung deposition) and have a simple, easy-to-use, durable mechanical design (eg, no springs). This study evaluated the characteristics of liquid spray technology for sublingual delivery. Two formulations (A and B) were evaluated and contained 30% v/v dehydrated alcohol, 5% v/v propylene glycol, 0.2% v/v peppermint oil, pH 9 borate buffer (quantity sufficient), and hydroxypropyl-beta-cyclodextrin (1:2); formulation B also contained 1% v/v hydroxypropyl cellulose (HPC-EP). Formulations were sprayed using a 0.1-mL multidose pump and evaluated for dose volume, spray pattern (methylene blue added; actuation 30 mm from target), and droplet size distribution using a Malvern Mastersizer particle size analyzer (n=25 spray samples). For formulations A and B, dose volumes were similar (mean volume, 100.4 and101.5 microliters, respectively; maximum single volume, 103.2 and 103.7 microliters). Spray patterns varied only slightly for formulations A versus B (small diameter mean [range], 50.6 millimeters [35.4-62.0] vs 34.0 millimeters [29-46.0], respectively; mean ratio largest/smallest diameter [range], 1.1 [1.0-1.3] vs 1.2 [1.1-1.5]). However, droplet size distribution varied with formulation A versus B (mean percentage share of droplet diameters at 10 micrometers [range], 1.7 [0.7-2.7] vs 0.7 [0.2-1.3], respectively). Overall, the characteristics of a liquid spray technology support further development for sublingual drug delivery. A formulation of fentanyl for sublingual administration is currently available, and research evaluating additional pain or addiction pharmacologic candidates for sublingual delivery in pain-related and other conditions is warranted. Supported by Insys Therapeutics.

Fast dissolving cyclodextrin complex of piroxicam in solid dispersion Part I: Influence of β-CD and HPβ-CD on the dissolution rate of piroxicam

Sublingual drug delivery is an interesting route for drug having significant hepatic first-pass metabolism or requiring rapid pharmacological effect as for patients suffering from swallowing difficulties, nausea or vomiting. Sublingual absorption could however be limited by the kinetic of drug dissolution. This study evaluated influences of cyclodextrins (β-CD or HP-β-CD) and their different inclusion process (spray-drying or freeze-drying) on the drug dissolution kinetic of solid dispersions in poly(ethylene glycol) (PEG, Mw 6000Da) of piroxicam, used as poor hydrosoluble drug model. A secondary objective was to determine influences of drug dispersion process in PEG (evaporation or melting methods) on the drug dissolution kinetic of piroxicam. Piroxicam solid dispersions containing or not cyclodextrins were characterized by different scanning calorimetry (DSC), Thermogravometry analyser (TGA) and Fourier transform-infrared spectroscopy (FT-IR) spectroscopy. In vitro drug dissolution study of these solid dispersions was then performed. The results demonstrated the high potential and interest of solid dispersions of drug previously included in cyclodextrins for sublingual delivery of hydrophobic drugs. This study also showed the advantages of evaporation method on the melting ones during drug dispersion in PEG. Indeed, drug complexation with cyclodextrins as dispersion by melting prevented the presence in solid dispersions of drug in crystalline form which can represent up to 63%. Moreover, dispersion in PEG by evaporation method gave more porous drug delivery system than with melting methods. This allowed complete (limited at most at 80–90% with melting methods) and quick drug dissolution without rebound effect like with melting ones.

Adhesive polyvinyl alcohol (PVA)-chitosan films for sublingual drug delivery

Adhesive polyvinyl alcohol (PVA)-chitosan films for sublingual drug delivery

Enhanced insulin absorption from sublingual microemulsions: effect of permeation enhancers.

Microemulsions of insulin (50IU/mL) comprising permeation enhancers were formulated for sublingual delivery. Circular dichroism (CD) spectra indicated conformational stability, while chemical stability was confirmed by high-performance liquid chromatography (HPLC). CD spectra of insulin in combination with permeation enhancers revealed attenuation of molar ellipticity at 274nm in the order TCTP > TC-AOT > TC > TC-NMT > Sol P > insulin solution. The molar ellipticity ratios at 208/222nm confirmed dissociation of insulin in the microemulsions with the same rank order. Matrix-assisted laser diffraction ionization mass spectra (MALDI) revealed a significant shift in intensity signals towards monomer and dimers with a substantially high ratio of monomers, especially in the presence of the TCTP and TC-AOT. Permeation through porcine sublingual mucosa correlated with the dissociation data. A high correlation between the ratio of molar ellipticity at 208/222nm and serum glucose levels (r (2) > 0.958) and serum insulin levels (r (2) > 0.952) strongly suggests the role of dissociation of insulin on enhanced absorption. While all microemulsions revealed a reduction in serum glucose levels and increase in serum insulin levels, significant differences were observed with the TCTP and TC-AOT microemulsions. High pharmacological availability >60% and bioavailability >55% compared to subcutaneous insulin at a low dose of 2IU/kg appears highly promising. The data clearly suggests the additional role of the permeation enhancers on dissociation of insulin on enhanced sublingual absorption from the microemulsions.

Sublingual Delivery of Frovatriptan: An Indication of Potential Alternative Route.

Frovatriptan, a 5-HT1B and 5-HT1D receptor agonist, is used for the treatment of acute migraine attack. This molecule is classified into second line therapy because of its slow onset of action (peak response obtained after 4 hours of administration) and low bioavailability (25%). Moreover, its therapy is the most costly among all triptans. Attempt has been made in present work to suggest a way out to fasten its onset of action and to enhance its bioavailability. Prepared tablets were evaluated by physicochemical tests, in vitro permeation studies, ex vivo permeation studies, and histopathological studies. Suitable mathematical calculations were performed to calculate the minimum amount of bioavailability that could be enhanced. Tablets containing chitosan (5% w/w) were found to give optimum results. Prepared tablets can double the bioavailability of frovatriptan and can initiate its response within 10 minutes of its administration. Suggestive alternative has the potential to increase the efficacy of frovatriptan for treating acute migraine attack.

Mucoadhesive polymers-based film as a carrier system for sublingual delivery of glutathione.

The sublingual mucosa provides a promising route for the delivery of glutathione (GSH). However, challenges are encountered in developing sublingual mucoadhesive drug delivery formulations such as: prolonging drug retention, uniform drug content, desirable drug release profiles, adequate drug permeation and efficient delivery of GSH. The aim of this study was to develop a suitable mucoadhesive polymer-based sublingual film. The mucoadhesive films were prepared by casting method. Several characterization studies including thickness, weight uniformity, surface pH, elongation, mucoadhesiveness, swelling and erosion were carried out on preliminary formulations to optimise formulations for in-vitro drug release and ex-vivo permeation studies. The optimal mucoadhesive polymer-based films showed acceptable physical properties and good mucoadhesion, and remained attached to excised porcine sublingual mucosa for sufficient time, providing a sustained delivery of GSH through the mucosal epithelial. The optimal mucoadhesive films may provide a promising drug delivery platform to develop commercial sublingual products of GSH as well as a wide range of protein and peptide drugs.

FORMULATION AND EVALUATION OF SUBLINGUAL TABLET FOR NARATRIPTA

Naratriptan is used for the treatment of migraine. Formulation and Evaluation of sublingual tablets of Naratriptan for pre and post Compression parameters was undertaken. The tablets were prepared by direct compression method using super disintegrates. After selection of superdisintegrants tablets were prepared by using polymer for reducing the flushing action of saliva and provide enough time for drug absorbed. The prepared tablets were evaluated for their physical and chemical property. The permeation study was performed on Goat mucosa for optimized batch. No interactions were found between drug and excipients. Formulation F2 containing Crosspovidone shows immediate drug release. Formulation F6 containing Chitoson shows fast drug release as compared to superdisintegrants alone. Sublingual tablets were prepared by direct compression method using Crosspovidone as a superdisintegrants. But it is more effective in combination with Chitoson. As a result, sublingual tablet administration of Naratriptan formulated with appropriate excipients and especially with Chitoson seems promising alternative to traditional routes. Keyword:-Sublingual delivery, Naratriptan, Superdisintegrants, Chitoson, Permeability, Migraine, Crosspovidone

Overview and appraisal of the current concept and technologies for improvement of sublingual drug delivery.

Sublingual drug delivery is capable of achieving high bioavailability by avoiding first-pass liver extraction and enzymatic degradation in the gastrointestinal tract, as well as achieving rapid onset of effect. Thus, this route of administration can offer attractive therapeutic advantages for certain drugs as a convenient substitute for parenteral administration and has been applied successfully to a number of therapeutic conditions, especially urgent cardiovascular conditions and acute severe pain control. However, due to inherent limitations such as small sublingual mucosa area for absorption, primarily passive mechanism of transport, short residence time, and potential local irritation, a relatively small number of sublingual products have been successfully developed to date. In this Review, key concepts and technologies for potential improvement of sublingual drug delivery are reviewed. The optimal application of these concepts and technologies, together with clinical need for non-parenteral delivery, will hopefully broaden the development of sublingual drug delivery in the future.

Insulin-loaded alginic acid nanoparticles for sublingual delivery

Alginic acid nanoparticles (NPs) containing insulin, with nicotinamide as permeation enhancer were developed for sublingual delivery. The lower concentration of proteolytic enzymes, lower thickness and enhanced retention due to bioadhesive property, were relied on for enhanced insulin absorption. Insulin-loaded NPs were prepared by mild and aqueous based nanoprecipitation process. NPs were negatively charged and had a mean size of ∼200 nm with low dispersity index. Insulin loading capacities of >95% suggested a high association of insulin with alginic acid. Fourier Transform Infra-Red Spectroscopy (FTIR) spectra and DSC (Differential Scanning Calorimetry) thermogram of insulin-loaded NPs revealed the association of insulin with alginic acid. Circular dichroism (CD) spectra confirmed conformational stability, while HPLC analysis confirmed chemical stability of insulin in the NPs. Sublingually delivered NPs with nicotinamide exhibited high pharmacological availability (>100%) and bioavailability (>80%) at a dose of 5 IU/kg. The high absolute pharmacological availability of 20.2% and bioavailability of 24.1% in comparison with subcutaneous injection at 1 IU/kg, in the streptozotocin-induced diabetic rat model, suggest the insulin-loaded alginic acid NPs as a promising sublingual delivery system of insulin.

Sublingual Vaccine with GroEL Attenuates Atherosclerosis

Autoimmune responses to heat-shock protein 60 (HSP60) contribute to the progression of atherosclerosis, whereas immunization with HSP60 may induce atheroprotective responses. We assessed the capacity of an atheroprotective vaccine that targeted a recombinant HSP60 from Porphyromonas gingivalis (rGroEL) to induce a protective mucosal immune response. Female apolipoprotein E-deficient spontaneously hyperlipidemic (Apoeshl) mice received sublingual delivery of rGroEL prior to P. gingivalis 381 injection. The animals were euthanized 16 weeks later. Sublingual immunization with rGroEL induced significant rGroEL-specific serum IgG responses. Antigen-specific cells isolated from spleen produced significantly high levels of IL-10 and IFN-γ after antigen re-stimulation in vitro. Flow cytometric analysis indicated that the frequencies of both IL-10+ and IFN-γ+ CD4+ Foxp3+ cells increased significantly in submandibular glands (SMG). Furthermore, sublingual immunization with rGroEL significantly reduced atherosclerosis lesion formation in the aortic sinus and decreased serum CRP, MCP-1, and ox-LDL levels. These findings suggest that sublingual immunization with rGroEL is associated with the increase of IFNγ+ or IL-10+ Foxp3+ cells in SMG and a systemic humoral response, which could be an effective strategy for the prevention of naturally occurring or P. gingivalis-accelerated atherosclerosis.

Rapidly dissolving poly(vinyl alcohol)/cyclodextrin electrospun nanofibrous membranes

We electrospun supramolecular complexes of poly(vinyl alcohol) (PVA), hydroxypropyl-β-cyclodextrin (HPβCD), and a poorly water soluble model drug (ketoprofen) to produce moisture-sensitive fibers for potential sublingual drug delivery applications. Fast dissolving/disintegrating membranes are of particular importance in sublingual delivery of drugs and other functional moieties, and materials such as nanofibers with a high specific surface area may be well-suited for such applications. Surprisingly, the concentrations of PVA and HPβCD required to produce uniform blend fibers are lower than the respective neat components. We find that PVA plays a synergistic role in facilitating fiber formation, enabling us to produce fibers with a high cyclodextrin (e.g. 90 wt%) content. We attribute the mechanism of fiber formation to the presence of HPβCD aggregates and PVA chain networks, analogous to depletion flocculation. Fibers with the highest HPβCD content release the most drugs in the shortest amount of time, and the amount of drug loading and the dissolution rate of the drug-containing fibers can be tuned by over two orders of magnitude by varying the HPβCD/PVA ratio.