Allergen Release Profiles of Fast-Dissolving Freeze-Dried Orodispersible Sublingual Allergy Immunotherapy Tablets.

Background: Sublingual allergy immunotherapy tablets (SLIT-tablets) provide a well-tolerated and clinically efficacious treatment for allergic disease such as allergic rhinitis and allergic asthma. In SLIT, uptake of allergen by immune-competent cells in the oral mucosa activates the immune system and leads to tolerance toward the sensitizing allergen. The ability to deliver the full allergen content into solution within the recommended sublingual holding time is therefore an essential quality of SLIT-tablets that must be supported by the tablet formulation for all relevant allergen sources. SLIT-tablets based on a fast-dissolving orodispersible freeze-dried formulation (Zydis) are currently available for 5 of the most prevalent allergens: tree (birch and related species from the birch-homologous group), grass, ragweed, Japanese cedar, and house dust mite. Objectives: The purpose of this study was to examine the allergen release properties of three freeze-dried SLIT-tablets containing tree, ragweed, and Japanese cedar extracts, respectively. The correlation between SLIT-tablet allergen release and the level of allergen-specific T-cell activation was examined for the tree SLIT-tablet. Methods: Allergen release kinetics and tablet disintegration times for the 3 freeze-dried SLIT-tablets were examined. For all 3 tablets, the magnitude of solubilized major allergen relative to time in solution was compared to external controls to achieve a measure of the total allergen release. Additional assessments of allergen release occurring after the initial timepoint (15 or 30 seconds in solution) were done independently of external controls by linear regression analyses. For the tree SLIT-tablet, the immunological potency of the released major allergen was assessed at each experimental timepoint by a Bet v-specific T-cell activation assay. Results: All 3 SLIT-tablets disintegrated within 1 second after contact with assay buffer without any detectible residue. Complete release of major allergens (Bet v 1, Amb a 1, and Cry j 1, respectively) was seen at the earliest experimental time points (15 or 30 seconds). For the tree SLIT-tablet, full T-cell activation was achieved at 30 seconds (earliest experimental time point). Conclusions: The freeze-dried SLIT-tablet formulation consistently provides rapid and complete release of allergen from a wide range of species in a standardized in vitro assay. Full release of the SLIT-tablet allergen content within the sublingual holding time is a prerequisite for maximal exposure of allergens to the sublingual mucosa immune system. The freeze-dried SLIT-tablet formulation examined here supports short sublingual holding times and furthermore offers a convenient administration form of allergy immunotherapy.

The Importance of Tablet Formulation on Allergen Release Kinetics and Efficiency: Comparison of Freeze-dried and Compressed Grass Pollen Sublingual Allergy Immunotherapy Tablet Formulations.

PURPOSE: Efficient delivery of allergens to the sublingual mucosa is a prerequisite for successful sublingual immunotherapy (SLIT) for allergy, and in order to become available to immune-competent cells embedded in the sublingual mucosa, allergens need to be delivered in a soluble form. Delivery of solubilized allergens poses a particular challenge for tablet-based allergy immunotherapy, in which allergens are administered under the tongue in the form of dry tablets and need to be dissolved rapidly in a small volume of saliva, with little or no agitation. The purposes of this article were to compare the properties of 2 different pharmaceutical SLIT-tablet formulations, freeze-dried and compressed, and to examine how the tablet formulation affects the efficiency with which allergen is delivered from the dry state of the tablet into soluble form. METHODS: Two SLIT-tablet formulations, both indicated for grass pollen allergic rhinitis and containing grass pollen extract as the active ingredient, were examined with regard to tablet disintegration times, allergen dissolution kinetics, dependency on solvent volume and agitation, and the achieved recovery of the grass allergen content in soluble form with each tablet. FINDINGS: The freeze-dried and the compressed SLIT-tablet formulations differed markedly with respect to efficiency of allergen release. The freeze-dried tablet disintegrated faster and released grass allergen into solution with a release rate higher than that of the compressed formulation and, in contrast to the compressed formulation, achieved full recovery of the allergen content in soluble form in a small volume of solvent. IMPLICATIONS: Rapid and complete release of soluble allergen in a small volume of solvent, as demonstrated by the freeze-dried formulation, are key elements of efficient sublingual allergen delivery by SLIT-tablets. Complete allergen release means that the full allergen dose of the tablet is recovered from the tablet and made available to the sublingual immune system in soluble form, and rapid release ensures that the immune system becomes exposed to the highest possible dose of soluble allergen for the maximal duration before swallowing. In contrast, a SLIT-tablet formulation that provides incomplete and slower allergen release will likely require a higher allergen content compared to the more efficient formulation, in order to achieve the same dose of soluble allergen, consequently leading to an excess load of allergen that becomes swallowed without having been made immunologically available.

Sublingual immunotherapy tablets as a disease-modifying add-on treatment option to pharmacotherapy for allergic rhinitis and asthma.

Allergic rhinitis (AR) with or without conjunctivitis (AR/C) is associated with a significant health and economic burden, and is often accompanied by asthma. Pharmacotherapies are the mainstay treatment options for AR and asthma, but guidelines also recommend allergy immunotherapy (AIT). Unlike pharmacotherapies, AIT has the ability to modify the underlying immunologic mechanisms of AR and asthma with the potential for long-term benefits after treatment is discontinued. Immunotherapy may also prevent progression of AR/C to asthma. Sublingual immunotherapy (SLIT)-tablets are a self-administered alternative to subcutaneous immunotherapy that provide the benefits of AIT without the cost and inconvenience of frequent office visits or the discomfort of injections. SLIT-tablets are also an option that can be utilized by primary care clinicians. Pharmacotherapies are generally effective in mild disease although a number of patients remain uncontrolled. SLIT-tablets have proven efficacy for AR in adults, children, and poly-sensitized allergic patients. Indirect comparisons indicate that SLIT-tablets have superior or comparable efficacy compared with traditional pharmacotherapies for seasonal AR, and superior efficacy for perennial AR. House dust mite (HDM) SLIT-tablets have also demonstrated clinically relevant benefits for asthma, with significant observed reductions in daily inhaled corticosteroid use, risk of asthma exacerbations, and asthma symptoms. SLIT-tablets are well tolerated, with minimal risk of systemic allergic reactions. The most common treatment-related adverse events are oral site reactions such as oral pruritus and throat irritation. Based on the favorable efficacy and safety profile, as well as the convenience of at-home oral administration and disease-modifying effects, SLIT-tablets should be considered as an alternative or add-on treatment to pharmacotherapy for AR/C, and as an add-on treatment for HDM allergic asthma.

SQ grass sublingual allergy immunotherapy tablet for disease-modifying treatment of grass pollen allergic rhinoconjunctivitis.

BACKGROUND: Allergy immunotherapy is a treatment option for allergic rhinoconjunctivitis (ARC). It is unique compared with pharmacotherapy in that it modifies the immunologic pathways that elicit an allergic response. The SQ Timothy grass sublingual immunotherapy (SLIT) tablet is approved in North America and throughout Europe for the treatment of adults and children (≥5 years old) with grass pollen-induced ARC. OBJECTIVE: The clinical evidence for the use of SQ grass SLIT-tablet as a disease-modifying treatment for grass pollen ARC is discussed in this review. METHODS: The review included the suitability of SQ grass SLIT-tablet for patients with clinically relevant symptoms to multiple Pooideae grass species, single-season efficacy, safety, adherence, coseasonal initiation, and cost-effectiveness. The data from the long-term SQ grass SLIT-tablet clinical trial that evaluated a clinical effect 2 years after a continuous 3-year treatment period were presented in the context of regulatory criteria that define a clinically meaningful effect. RESULTS: This trial demonstrated that the clinical effect of the SQ grass SLIT-tablet is maintained, which is also supported by the immunologic findings. CONCLUSION: Therefore, the SQ grass SLIT-tablet has an indication as a disease-modifying therapy in Europe, and a sustained effect is recognized in the United States.

Network meta-analysis shows commercialized subcutaneous and sublingual grass products have comparable efficacy.

BACKGROUND: Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been shown to effectively treat grass pollen allergies, although direct comparisons are sparse. OBJECTIVE: To estimate the relative efficacy of SLIT tablets compared with SCIT and SLIT drops in commercially available products though network meta-analysis. METHODS: A literature search of MEDLINE, Embase, and Cochrane Library publications. Randomized, double-blind clinical trials of SCIT, SLIT drops, and SLIT tablets for grass pollen were included. Bayesian network meta-analyses estimated the standardized mean difference (SMD) across 3 immunotherapy modalities on allergic rhinoconjunctivitis symptom and medication score data from publications or received from authors. Both fixed and random effects models were investigated. RESULTS: Thirty-seven studies were included in meta-analyses for symptom scores and 31 studies for medication scores. In the random effects model, SCIT and SLIT tablets were significantly different from placebo for symptom scores: SMDs (95% CI) of -0.32 (-0.45 to -0.18) and -0.32 (-0.41 to -0.23), respectively. No significant difference was identified for SLIT drops compared with placebo (SMD, -0.17; -0.37 to 0.04). For medication scores, significant differences compared with placebo were observed for SCIT (SMD, -0.33; 95% CI, -0.52 to -0.13), SLIT tablets (SMD, -0.23; 95% CI, -0.29 to -0.17), and SLIT drops (SMD, -0.44; 95% CI, -0.83 to -0.06). Network meta-analysis revealed no significant differences in SMDs (95% credible interval) for symptom scores (0.0145 [-0.19 to 0.23]) or medication scores (0.133 [-0.31 to 0.57]) between SLIT tablets and SCIT, or for symptom scores (-0.175 [-0.37 to 0.02]) and medication scores (0.188 [-0.18 to 0.56]) between SLIT tablets and SLIT drops. CONCLUSIONS: The comparisons for grass pollen immunotherapy products commercialized in at least 1 country indicate comparable reductions in allergic rhinoconjunctivitis symptoms and supplemental medication use for SLIT tablets and SCIT in the first pollen season.

A review of 20 years' experience with the NovoPen family of insulin injection devices.

NovoPen, the first insulin pen injector, was introduced in 1985. This article reviews the published evidence over two decades of use of the NovoPen family of injection devices in diabetes management. A search for NovoPen publications from 1985 onwards was conducted in the following databases: MEDLINE/PubMed, Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, Database of Abstract Reviews and Effects, and Cochrane Controlled Trials Register. Publications were examined and underwent a selection process to identify studies of NovoPen devices (NovoPen [1], NovoPen 2, NovoPen 1.5 and NovoPen 3) in the diabetes/insulin therapy area that contained evidence of the effects of NovoPen in a variety of categories. Of the studies identified, most showed that insulin regimens using the NovoPen family of devices are at least as effective (and in some cases superior) in maintaining glycaemic control and are as safe (in terms of hypoglycaemia) as conventional insulin regimens employing syringes. The published evidence identified also showed that insulin administration via NovoPen devices was for most patients easier, more convenient and quicker than with conventional syringes and that most patients preferred the various NovoPen devices over syringes. There was also some evidence that the use of discreet devices, like those of the NovoPen family, facilitates adherence to intensive insulin therapy regimens, helps to improve lifestyle flexibility and reduces injection pain compared with conventional syringe-based regimens. Together these benefits of NovoPen devices are considered likely to improve both patients' quality of life and compliance with therapy. In conclusion, a large body of published evidence accumulated over the past two decades testifies to the patient-related benefits of the NovoPen family of insulin injection devices in the treatment of diabetes.

Accuracy and precision of the NovoPen 3 insulin delivery device after mechanical and temperature stresses.

OBJECTIVE: To evaluate the precision, accuracy, and durability of an insulin pen injection device (NovoPen 3) at three preset doses (2 IU, 35 IU, and 70 IU) after exposure to various stress and durability tests that were intended to simulate daily use by patients. METHODS: Twenty-nine reusable NovoPen 3 insulin delivery devices were tested. The precision and accuracy of 10 insulin pen devices were evaluated after they were subjected to multiple thermal and vibration stress tests. Another 10 pen devices were subjected to a free-fall test. Nine other insulin pens were subjected to endurance testing that simulated 5 years of injections. RESULTS: The accuracy (as measured by the relative error of the delivered dose of insulin) of the insulin pen injection devices was within 1% of the preset dose after all stress or endurance tests. A free-fall test produced no indication of damage except for broken clips and snap catches on the caps, which did not affect the integrity or performance of the insulin pens. The precision of the pen devices (as measured by relative standard deviations of delivered volumes of insulin) was likewise high after thermal stress, vibration stress, free-fall testing, or 5-year endurance testing. CONCLUSION: Overall, this study showed that the insulin pen injection devices tested were durable under conditions of stress likely to be encountered in daily patient use. Neither a wide variety of repetitive stresses nor insulin injection cycles corresponding to 5 years of use affected the accuracy or precision enough to have clinical significance for reliable insulin delivery.