(T1530-06-34) Designing Novel Modified Release Self-Emulsifying Drug Delivery Systems (n-SNEDDS) for Nasal Delivery with Enhanced Therapeutic Outcomes

Purpose: Nasal delivery leverages the nasal cavity's rich vasculature for swift systemic absorption while employing specialized excipients to prolong drug residence time, thereby enhancing efficacy and patient compliance. Modified-release nasal formulations typically utilize mucoadhesive and thermo-responsive polymers, such as poloxamers and chitosan, which transition from liquid to gel upon contact with nasal mucosa. This in situ gelation ensures prolonged mucosal contact by delaying nasal ciliary clearance, facilitating sustained drug release.^1,2,3 In our study, we have used an innovative method to deliver modified release formulation as nasal self-nano emulsifying drug delivery system (n-SNEDDS). Traditionally utilized to improve the oral bioavailability of poorly water-soluble drugs, recent research has explored its potential in nasal drug delivery, aiming to enhance drug solubility, absorption, ane targeting^4,5. The advantages of this novel n-SNEDDS formulation are 1) Improved solubility and permeation, thereby enhancing fast absorption, 2) Sustained release for 24 hours in in vitro conditions to achieve longer duration of action and 3) Ability to carry BCS II, III and IV classes of drugs for solubility and permeation enhancement. In addition, it does not require any mucoadhesive and/or gelling polymers to increase residence time and it can be easily formulated and atomized as a spray which spontaneously interacts with mucus to form a viscous gel in the interior of the nose. Traditional nasal gels, unless administered by a special nozzle, cannot be self-administered deep into nasal absorptive mucosal layer, thereby inducing a time lag for its therapeutic onset.

Methods: Three classes of drugs, belong to each BCS class, are chosen and named as BCS-II (Aq. Solubility: ≥10 µg/ml, LogP >3, pKa < 4), BCS-III (Aq. Solubility: ≥ 20 mg/ml, LogP < 4, pKa >6) and BCS-IV (Aq. Solubility: ≥10 ng/ml, LogP < 5, pKa < 7). To avoid an oil-based core for drug loading which might require digestion, therefore leading to slower drug release, a type IV SNEDDS⁶ system is chosen with 5 surfactant systems with the following compositions: A. PEGylated Caprylic/Capric Glycerides (HLB 14.6), B. Polyoxyethylene-80-sorbitan monooleate (HLB 16), C. Polyglyceryl 3-oleate (HLB 6.2), D. Sorbitan monooleate (HLB 4.3) and E. Cetearyl glucoside (HLB 11). A DOE was constructed using extreme vertices (Minitab^®) and optimized ratio of surfactants are obtained with improved solubility were analyzed by HPLC for all 3 drug molecules. Permeability assay was modified for nasal delivery using Parallel Artificial Membrane Permeability Assay (PAMPA, Pion^®)⁷ and verified by permeation across porcine nasal mucosa using Franz cell type diffusion apparatus (Phoenix Robotic Diffusion Station, Teledyne LABS^®).

Results: The n-SNEDDS model was designed by DOE where the individual surfactant levels were varied from 2% - 10% w/v achieving high aqueous solubility enhancements. for BCS II drug (over 800 x), BCS III (over 400x) & BCS Class IV (over 500x). For permeation studies, each drug was loaded in SNEDDS surfactant mixture with complete nasal formulations made using drug loaded SNEDDS (20 - 35% w/v) qs. to 100% with 20mM phosphate buffer (pH 6). No tonicity adjusters or preservatives were added. The resultant formula was sprayable with a standard, commercially available nasal device with acceptable size ranges (around 100 µ), plume and spray geometries (data not shown). The complete formulation made for each BCS drug was analyzed for in vitro permeation for 24 hours using nasal PAMPA⁷ by appropriate dilutions. The results for apparent permeability (P_app) ratios compared to control for BCS II, III and IV were 3.83, 3.43 and 1.94 respectively after 24 hours (Fig 2). The permeation parameters for same formulations with porcine mucosa provided more insights on the flux and release kinetics of drugs (Fig 1 and 2). All drugs showed first order release kinetics till 6 hours (fast onset of action), after which it showed zero order release (sustained release) profile till 24 hours (curve fitting data not shown). Interestingly, when n-SNEDDS formulation was applied on nasal mucosa, there was a visible interaction of surfactants with mucus, thereby resulting in the formulation of viscoelastic matrix on the mucosal tissue on the donor side. It is hypothesized that part of the drug release occurred through the gel matrix which influenced overall release kinetics of all formulations. The flux results showed increase of BCS II, III and IV by 29.67, 6.41 and 46.46 times respectively (fig 2). The permeability results were more definitive for diffusion cells compared to PAMPA due to the dynamic media exchange in the former. However, PAMPA, even though it is single point study, showed directional correlation of enhanced permeation by utilization of n-SNEDDS.

Conclusion: A single, unified composition of surfactants can be used as a loading platform for a wide range of BCS class drugs and formulated as nasal sprays. The formulation can be atomized deep into the nasal absorptive mucosa which interacts with mucin thereby turning into a viscoelastic matrix suitable for modified drug release without any addition of mucoadhesives and/or other viscosity builders.

References: 1. Protopapa, C.; Siamidi, A.; Pavlou, P.; Vlachou, M. Excipients Used for Modified Nasal Drug Delivery: A Mini-Review of the Recent Advances. Materials 2022, 15, 6547. https://doi.org/10.3390/ma15196547
2. Bachert C, Bousquet J, Hellings P. Rapid onset of action and reduced nasal hyperreactivity: new targets in allergic rhinitis management. Clin Transl Allergy. 2018 Jun 25;8:25. doi: 10.1186/s13601-018-0210-2. PMID: 29983907; PMCID: PMC6016145.
3. Patel P, Roland PS, Marple BF, Benninger PJ, Margalias H, Brubaker M, Beezley SF, Drake M, Potts SL, Wall GM. An assessment of the onset and duration of action of olopatadine nasal spray. Otolaryngol Head Neck Surg. 2007 Dec;137(6):918-24. doi: 10.1016/j.otohns.2007.08.005. Erratum in: Otolaryngol Head Neck Surg. 2008 Feb;138(2):258. Beezley, Susan F [corrected to Beezley, Sally F]. PMID: 18036421.
4. Meirinho S, Rodrigues M, Santos AO, Falcão A, Alves G. Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration. Pharmaceutics. 2022 Jul 18;14(7):1487. doi: 10.3390/pharmaceutics14071487. PMID: 35890385; PMCID: PMC9319231.
5. Leichner, C., Baus, R.A., Jelkmann, M. et al. In vitro evaluation of a self-emulsifying drug delivery system (SEDDS) for nasal administration of dimenhydrinate. Drug Deliv. and Transl. Res. 9, 945–955 (2019). https://doi.org/10.1007/s13346-019-00634-1
6. Pouton, C. W. (2000). Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur. J. Pharm. Sci. 11(Suppl. 2), S93–S98.
7. Henriques P, Bicker J, Silva S, Doktorovová S, Fortuna A. Nasal-PAMPA: A novel non-cell-based high throughput screening assay for prediction of nasal drug permeability. Int J Pharm. 2023 Aug 25;643:123252. doi: 10.1016/j.ijpharm.2023.123252. Epub 2023 Jul 20. PMID: 37479103

Acknowledgements: Special thanks to Abitec Corp. for providing surfactants for experimentation


Release profile of drugs from n-SNEDDS formulations across porcine nasal mucosa


Nasal PAMPA studies and permeation parameters obtained from diffusion cell experiments