Carrageenan-Containing Nasal Spray Alleviates Allergic Symptoms in Participants with Grass Pollen Allergy: A Randomized, Controlled, Crossover Clinical Trial.

Purpose: Nonpharmacological, barrier-forming nasal sprays are used to manage symptoms of allergic rhinitis. We aim to evaluate the safety and effectiveness of Callergin (investigational product, IP), a nasal spray containing barrier-forming iota-carrageenan, in the treatment of allergic rhinitis (AR). Methods: In this randomized, controlled, crossover trial, adults with grass pollen allergy underwent a treatment sequence with IP, VisAlpin (comparator product, CP), and no treatment in random order. Treatment blocks consisted in prophylactic administration of the assigned treatment or no treatment, followed by a 3-hr allergen exposure, and were separated by a washout period of 7 days. Primary endpoint was a mean change from baseline in "Total Nasal Symptom Score" (TNSS, sum of rhinorrhea, itching, sneezing, and congestion scores) over 3 hr, recorded every 15 min during the challenge period. Results: A total of 42 participants underwent randomization. Exposure to grass pollen for 3 hr induced a notable TNSS increase from baseline in all participants at all times. Mean TNSS change from baseline over 3 hr was lower when participants received IP compared to no treatment, although the difference did not reach statistical significance (untreated 6.96 ± 2.30; IP 6.59 ± 1.93; difference 0.37 points [95% CI (confidence interval) -0.17 to 0.91]; p=0.170). In a post-hoc analysis, mean TNSS at 3 hr was significantly reduced after IP treatment compared to no treatment (untreated 8.29 ± 2.64; IP 7.70 ± 2.56; difference 0.60 points [95% CI -0.10 to 1.29] p=0.028). While all individual nasal symptoms contributed to this effect, rhinorrhea (p=0.013) and congestion (p=0.076) contributed most. Consistently, nasal secretion weight was slightly reduced with IP treatment (p=0.119). IP was safe and well-tolerated, with similar incidence of adverse events across treatment groups. Conclusion: Prophylactic treatment with the iota-carrageenan nasal spray IP is safe, well-tolerated, and alleviates nasal allergy symptoms in adults with grass pollen-induced AR. Trial Registration: NCT04531358.

The Saliva of Probands Sucking an Iota-Carrageenan Containing Lozenge Inhibits Viral Binding and Replication of the Most Predominant Common Cold Viruses and SARS-CoV-2.

PURPOSE: The aim of this study was to investigate whether sucking of an iota-carrageenan containing lozenge releases sufficient iota-carrageenan into the saliva of healthy subjects to neutralize representatives of the most common respiratory virus families causing common cold and SARS-CoV-2. PATIENTS AND METHODS: In this monocentric, open label, prospective clinical trial, 31 healthy subjects were included to suck a commercially available iota-carrageenan containing lozenge. Saliva samples from 27 subjects were used for ex vivo efficacy analysis. The study's primary objective was to assess if the mean iota-carrageenan concentration of the saliva samples exceeded 5 µg/mL, which is the concentration known to reduce replication of human rhinovirus (hRV) 1a and 8 by 90%. The iota-carrageenan concentration of the saliva samples was analyzed by UV-Vis spectroscopy. The antiviral effectiveness of the individual saliva samples was determined in vitro against a panel of respiratory viruses including hRV1a, hRV8, human coronavirus OC43, influenza virus A H1N1pdm09, coxsackievirus A10, parainfluenza virus 3 and SARS-CoV-2 using standard virological assays. RESULTS: The mean iota-carrageenan concentration detected in the saliva exceeds the concentration needed to inhibit 90% of hRV1a and hRV8 replication by 134-fold (95% CI 116.3-160.8-fold; p < 0.001). Thus, the study met the primary endpoint. Furthermore, the iota-carrageenan saliva concentration was 60 to 30,351-fold higher than needed to reduce viral replication/binding of all tested viruses by at least 90% (p < 0.001). The effect was most pronounced in hCoV OC43; in case of SARS-CoV-2, the IC90 was exceeded by 121-fold (p < 0.001). CONCLUSION: Sucking an iota-carrageenan containing lozenge releases sufficient iota-carrageenan to neutralize and inactivate the most abundant respiratory viruses as well as pandemic SARS-CoV-2. The lozenges are therefore an appropriate measure to reduce the viral load at the site of infection, hereby presumably limiting transmission within a population as well as translocation to the lower respiratory tract. TRIAL REGISTRATION: NCT04533906.

Saponin Micelles Lead to High Mucosal Permeation and In Vivo Efficacy of Solubilized Budesonide.

Due to fast nasal mucociliary clearance, only the dissolved drug content can effectively permeate the mucosa and be pharmaceutically active after intranasal application of suspensions. Therefore, the aim of this study was to increase the budesonide concentration in solution of a nasal spray formulation. Budesonide, a highly water-insoluble corticosteroid, was successfully solubilized using a micellar formulation comprising escin, propylene glycol and dexpanthenol in an aqueous buffered environment ("Budesolv"). A formulation based on this micellar system was well-tolerated in the nasal cavity as shown in a good laboratory practice (GLP) local tolerance study in rabbits. Ex vivo permeation studies into porcine nasal mucosa revealed a faster and more efficient absorption. Budesolv with 300 µg/mL solubilized budesonide resulted in a budesonide concentration of 42 µg/g tissue after only 15 min incubation. In comparison, incubation with the marketed product Rhinocort® aqua 64 (1.28 mg/mL budesonide as suspension) led to 15 µg/g tissue. The in vivo tumor-necrosis-factor (TNF)-α secretion in an acute lung inflammation mouse model was significantly reduced (p < 0.001) following a prophylactic treatment with Budesolv compared to Rhinocort® aqua 64. Successful treatment 15 min after the challenge was only possible with Budesolv (40% reduction of TNF-α, p = 0.0012) suggesting a faster onset of action. The data reveal that solubilization based on saponin micelles presents an opportunity for the development of products containing hardly soluble substances that result in a faster onset and a better topical treatment effect.

Fast effectiveness of a solubilized low-dose budesonide nasal spray in allergic rhinitis.

BACKGROUND: Budesonide, a poorly water-soluble corticosteroid, is currently marketed as a suspension. Budesolv is a novel aqueous formulation containing dissolved budesonide showing increased local availability in preclinical models. Budesolv contains ~85% less corticosteroid than the marketed comparator. OBJECTIVE: The study (EudraCT:2018-001324-19) was designed to assess non-inferiority of Budesolv compared to Rhinocort® Aqua 64 (RA) and early onset of action. METHODS: In a three-way cross-over double-blinded randomized trial, Budesolv 10 was compared to RA and placebo in grass pollen allergic rhinoconjunctivitis volunteers (n = 83 (ITT); n = 75 (PP)). On day 1, participants entered the Vienna Challenge Chamber (VCC) for 6 hours; first treatment took place at 1:45 hours after entry. Participants treated themselves for further 6 days; on day 8, the last treatment was applied before entering the VCC. Subjective symptom scores, nasal airflow and nasal secretion were measured regularly during allergen challenge. RESULTS: Budesolv 10 was equally effective compared to RA with respect to TNSS and nasal airflow after eight days of treatment with a strongly reduced dose (more than 80% reduction). After first dose, only Budesolv 10 showed a significant reduction of nasal and respiratory symptoms starting 90 minutes (P < .05) and 15 minutes (P < .05) after application onwards, respectively, demonstrating an early onset of efficacy. A clinically significant 1 point reduction in nasal symptom score was reached at 195 minutes (P < .05) after application. CONCLUSIONS AND CLINICAL RELEVANCE: The novel preservative-free, aqueous low-dose budesonide formulation is highly efficacious even after an initial single treatment. Thus, Budesolv 10 appears to be an effective acute treatment for allergic rhinitis as well as for AR comorbidities like mild asthma and conjunctivitis.

Pharmacokinetics of topically applied tacrolimus dissolved in Marinosolv, a novel aqueous eye drop formulation.

Corticosteroids and macrolide immunomodulators such as tacrolimus are effective drugs for the topical treatment of inflammatory eye diseases like allergic conjunctivitis or dry eye. However, tacrolimus is practically insoluble in aqueous solutions and is therefore currently formulated as dispersion. This leads to low bioavailability. Here, we present a novel pharmacologically acceptable, aqueous formulation of tacrolimus based on the "Marinosolv formulation platform". Marinosolv allows the solubilization and thereby improvement of the bioavailability of many otherwise practically insoluble drugs, since dissolved drugs permeate faster into tissues, including ocular tissues. To visualize the benefits of Marinosolv in ophthalmic formulations, we investigated the permeation of a fluorescently labeled estradiol dissolved in Marinosolv compared to a formulation containing the compound as dispersion. Permeation was studied ex-vivo and in-vivo in porcine eyes. Further, we evaluated the improved permeation of topically applied tacrolimus dissolved in Marinosolv compared to a commercially available topically applied tacrolimus dispersion. The Marinosolv formulation was also compared to oral tacrolimus treatment, the standard application route for this drug in case of severe posterior uveitis. Finally, the ocular tissue levels of tacrolimus in all groups were determined using HPLC/MS. We demonstrated that tacrolimus dissolved in Marinosolv reached significantly higher levels in ocular tissues compared to the marketed topical product or after oral application and thus may be a suitable novel option for the treatment of several eye diseases, such as allergic conjunctivitis or uveitis. Thus, Marinosolv may be considered as a new vehicle for tacrolimus eye drops.

Green tea polyphenol administration partly ameliorates chemotherapy-induced side effects in the small intestine of mice.

The chemotherapeutic agent irinotecan (IT) is highly effective against several types of cancer, although its use is limited due to severe intestinal toxicity. The aim of this study was to evaluate inflammatory and oxidative stress-related processes contributing to small intestinal mucosa damage and to determine the extent to which green tea polyphenols could ameliorate the detrimental effects induced by IT. In Expt. 1, mice were challenged intraperitoneally with IT or saline on 2 consecutive days. For time kinetic measurements, the IT-treated mice were killed at 3, 24, 48, 72, and 96 h after the 2nd dose of IT. Three hours after IT administration, the ileum glutathione concentration dropped significantly. Lipid peroxidation and inflammation, as measured by macrophage inflammatory protein-2 content, myeloperoxidase activity, and nuclear factor-kappaB translocation, were highest between 24 and 48 h after IT treatment. In Expt. 2, green tea polyphenols (1 g/L) were supplied via drinking water for 7 d before and 3 d after treatment with IT. Green tea polyphenols significantly affected the glutathione:glutathione disulfide ratio but not lipid peroxidation, macrophage inflammatory protein-2 levels, myeloperoxidase activity, or nuclear factor-kappaB activation. Our study reveals that IT administration is associated with oxidative stress and inflammation, both occurring simultaneously to IT-induced mucosal damage. The antioxidative defense is affected soon after IT administration. Green tea polyphenols supplied orally protected against oxidation in our experimental model and could be one approach to reducing the risk of IT-induced side effects in the clinical setting.