Naresh Mittapelly1,2, Maharshi Thalla1,3, Gitu Pandey1, Venkatesh Teja Banala1, Shweta Sharma1, Abhishek Arya1, Sandeep Mishra4, Kalyan Mitra5, Shubha Shukla4, Prabhat Ranjan Mishra6,7,8. 1. Pharmaceutics Division (PCS-002), CSIR-Central Drug Research Institute, Lucknow, India. 2. Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India. 3. National Institute of Pharmacy Education and Research (NIPER), Raebareli, India. 4. Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India. 5. Electron Microscopy Division, CSIR-Central Drug Research Institute, Lucknow, India. 6. Pharmaceutics Division (PCS-002), CSIR-Central Drug Research Institute, Lucknow, India. mishrapr@hotmail.com. 7. Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India. mishrapr@hotmail.com. 8. National Institute of Pharmacy Education and Research (NIPER), Raebareli, India. mishrapr@hotmail.com.
Abstract
PURPOSE: The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation. METHODS: D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo. RESULTS: The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 ± 72.5 nm and PDI 0.152 ± 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model. CONCLUSION: Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule. Graphical Abstract Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats.
PURPOSE: The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation. METHODS: D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo. RESULTS: The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 ± 72.5 nm and PDI 0.152 ± 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model. CONCLUSION: Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule. Graphical Abstract Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats.
Entities:
Keywords:
3 T3 cells; ACh E activity; High pressure homogenization; Morriswatermaze test; STZ induced memory impairment