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

Abstract

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.

Factors affecting nasal drug delivery and design strategies for intranasal drug delivery

“…纤毛的快速清除限制了药物与黏膜的接触时间，从而影响药物的吸收效率。黏液-纤毛清除是呼吸系统的自我清除机制，其中鼻黏液层在呼吸道的防御中起重要作用 ［ 24 ］ 。吸入的药物、颗粒等附着于黏液层，被运送至鼻咽部，最终进入胃肠道。在此过程中，纤毛摆动提供驱动力，黏液则收集和处理外来颗粒。纤毛的清除效率取决于纤毛长度、密度和摆动速率以及鼻黏液的体积和黏弹性等。生理条件下，黏液在鼻腔内以5 mm/min的速率运输，在人体鼻腔中的运输时间为15~20 min。一般而言，所有促进鼻黏液生成、降低鼻黏液黏度或提高纤毛摆动频率的因素都可能会增强黏液-纤毛清除系统，从而减少药物吸收 ［ 25 ］ 。而当纤毛清除受损时，药物在鼻黏膜的滞留时间延长，从而增强渗透。王东方等 ［ 26 ］ 对慢性鼻炎患者与健康人群的鼻腔纤毛输送功能进行对照观察发现，慢性鼻炎患者的鼻腔纤毛输送功能减退，因此，在制剂研发时也应考虑到鼻腔的病理学状态（如感染、过敏和哮喘等）对黏液或纤毛状态的影响。…”

Predicting systemic and pulmonary tissue barrier concentration of orally inhaled drug products

“…Whenever possible, the base range of these parameters were within the known bounds of experimental values. For example, the SLL thickness in the terminal alveolar sacs has been reported with values of 0.01-0.08 μm by Olsson et al, [44] 0.1-0.2 μm by Wauthoz and Amighi, [45] 0.07 μm by Patton and Byron [10] 3.7 [50,51] Fu,plasma Fraction unbound (%) 0.125 0.1-0.12 [52] 0.12 [53] 16.1 [19] 0.02 1.16 [19] 0.013-0.020 [52] 0.1 [53,54] B2P Blood-toplasma (ratio) 0.9 0.8-0.9 [55] 0.6-0.9 [52] 0.6 0.7 [56] 0.95 [57] 0.6-0.8 [52] 1.83 [19] Bq Oral bioavailability 0.1 0.11 [14,49] 0.01 0.01 [49] 0 [57] <0.01 [58] Systemic clearance Clearance (mL/min) 1591.65 1000-1400[59] 900-1800 [60] 1416 [14] 1400 [49,54] a 1400 [52] 847.28 1216 [14] 1150 [49,53] 1100-1500 [61] a 840 [52] a 1190 [54] Lung mucus and SLL Diffusion coeff (µ 2 /sec) 400.639 230-510 [62] 325.02 600 [43] 22.7 [57] Terminal alveolar sacs region Solubility coeff (µg/mL) 18.365 16(aq) [63] 28(aq) [64] 1004 (PB) [65] 0.524 <0.15(aq) [52] 0.14(aq) ...…”

“…The previously published values and our final optimized values of the parameters are shown in Table 1. 3.7 [50,51] Fu,plasma Fraction unbound (%) 0.125 0.1-0.12 [52] 0.12 [53] 16.1 [19] 0.02 1.16 [19] 0.013-0.020 [52] 0.1 [53,54] B2P Blood-toplasma (ratio) 0.9 0.8-0.9 [55] 0.6-0.9 [52] 0.6 0.7 [56] 0.95 [57] 0.6-0.8 [52] 1.83 [19] Bq Oral bioavailability 0.1 0.11 [14,49] 0.01 0.01 [49] 0 1416 [14] 1400 [49,54] a 1400 [52] 847.28 1216 [14] 1150 [49,53] 1100-1500 [61] a 840 [52] a 1190 [54] Lung mucus and SLL Diffusion coeff (µ 2 /sec) 400.639 230-510 [62] 325.02 600 [43] 22.7 [57] Terminal alveolar sacs region Solubility coeff (µg/mL) 18.365 16(aq) [63] 28(aq) [64] 1004 (PB) [65] 0.524 <0.15(aq) [52] 0.14(aq) [49] Tracheobronchial and Alveolar region 23.237 470 (SDS) [66] 49 (in silico) [67] 21(aq) [52] 30 (surfactant) [19] 0.011 45 [43] 2 (SLF) [68] 13.1...…”