Intranasal Delivery of a Silymarin Loaded Microemulsion for the Effective Treatment of Parkinson’s Disease in Rats: Formulation, Optimization, Characterization, and In Vivo Evaluation

A mucoadhesive microemulsion of lipophilic silymarin (SLMMME) was developed to treat Parkinson’s disease (PD). Optimization of the SLM microemulsion (ME) was performed using Central Composite Design (CCD). The composition of oil, surfactant, co-surfactant, and water was varied, as per the design, to optimize their ratio and achieve desirable droplet size, zeta potential, and drug loading. The droplet size, zeta potential, and drug loading of optimized SLMME were 61.26 ± 3.65 nm, −24.26 ± 0.2 mV, and 97.28 ± 4.87%, respectively. With the addition of chitosan, the droplet size and zeta potential of the developed ME were both improved considerably. In vitro cell toxicity investigations on a neuroblastoma cell line confirmed that SLMMME was non-toxic and harmless. In comparison to ME and drug solution, mucoadhesive ME had the most flow through sheep nasal mucosa. Further, the in vitro release showed significantly higher drug release, and diffusion of the SLM loaded in MEs than that of the silymarin solution (SLMS). The assessment of behavioral and biochemical parameters, as well as inflammatory markers, showed significant (p < 0.05) amelioration in their level, confirming the significant improvement in neuroprotection in rats treated with SLMMME compared to rats treated with naïve SLM.

2.1. Materials

For research purposes, Merck Pvt. Ltd. sold SLM to us. Cremophor RH 40 was purchased from BASF Personal Care, while Capryol 90, Labrafac PG, Labrafil M 1944 CS (LMCS), Labrasol, and Transcutol P (TP) were received as gift samples from Gattefosse. Abitec Corporation provided Capmul MCM (Columbus, OH, USA). Tween 80 (T80), Tween 20 (T20), methanol, Span 80, propylene glycol, Span 20, hydrochloric acid, disodium hydrogen phosphate, nitro blue tetrazolium (NBT), orthophosphoric acid, monobasic sodium phosphate, ethanoic acid, dimethyl ketone, L-glutathione reduced, 2-thiobarbituric acid (TBA), sodium chloride, aceto-caustin or trichloroacetic acid (TCA), propylene glycol 400, and N-1-naphthyl ethylenediamine dihydrochloride were acquired from Merck USA. Almond oil, peanut oil, sesame oil, castor oil, and olive oil were purchased from Welch, Holme & Clark Co., Inc. (Newark, NJ, USA). Rotenone was obtained from the Japanese company TCI. Merck (USA) provided L-dopa and lodosyn (carbidopa). Ellman’s Reagent (DTNB), edetic acid (EDTA), and hydrochloride salt of hydroxylamine were procured from Himedia laboratories, Mumbai, India. Edifas B, 1-butyl alcohol, pyridine, disodium carbonate, trisodium citrate, tris-HCI buffer, sodium salt of nitrous acid, and p-aminobenzenesulfonamide were procured from Central Drug House, Mumbai, India. The ELISA kit (Lot no. CB8281) for rat synuclein alpha was bought from Biorbyt (San Francisco, CA, USA). MyBioSource, in the United States, provided an ELISA kit (Lot no. 201908) for rat’s abrineurin or BDNF protein. Raybiotech, Inc. (Peachtree Corners, GA, USA), in the United States, delivered the immunoassay kits for rat TNF-alpha and IL-6. A homogenizer (RQ-127, REMI, Mumbai, India), analytical balance (AX 200; Shimadzu Japan), ultra-fast liquid chromatography (Shimadzu, Kyoto, Japan), UV-spectrophotometer (UV-1800, Shimadzu, Japan), incubator (REMI, India), ELISA plate reader (iMark Microplate Reader, BIORAD, Hercules, CA, USA), actophotometer (INCO Pvt Ltd., Mumbai, India), rotarod apparatus (INCO, Pvt Ltd., India), centrifuge (CM-12 Plus, REMI, India), and pH meter (Phan, Lab India, Mumbai, India) were employed to conduct this research work. SK.N.SH (Human Neuroblastoma Cell Line; ATCC HTB-11) were gifted by the National Centre of Cell Science, Pune, India.

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Imran, M.; Almehmadi, M.; Alsaiari, A.A.; Kamal, M.; Alshammari, M.K.; Alzahrani, M.O.; Almaysari, F.K.; Alzahrani, A.O.; Elkerdasy, A.F.; Singh, S.K. Intranasal Delivery of a Silymarin Loaded Microemulsion for the Effective Treatment of Parkinson’s Disease in Rats: Formulation, Optimization, Characterization, and In Vivo Evaluation. Pharmaceutics 2023, 15, 618. https://doi.org/10.3390/pharmaceutics15020618