Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations

• Published in: Drug development and industrial pharmacy 2013-11, Vol.39 (11), p.1851-1863
• Main Authors: Parejiya, Punit B., Barot, Bhavesh S., Patel, Hetal K., Shelat, Pragna K., Shukla, Arunkumar
• Format: Article
• Language: English
• Subjects: Administration, Oral; Antidepressive Agents - administration & dosage; Antidepressive Agents - analysis; Antidepressive Agents - chemistry; Artificial Neuron Network; Benecel; Chemical Phenomena; Compritol; Cyclopropanes - administration & dosage; Cyclopropanes - analysis; Cyclopropanes - chemistry; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - analysis; Delayed-Action Preparations - chemistry; Drug Compounding; Drug Delivery Systems; Drug Stability; Excipients - chemistry; Hardness; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Kinetics; Lepidium sativum; Lepidium sativum - chemistry; Mechanical Phenomena; Microscopy, Electron, Scanning; Milnacipran HCl; Neurotransmitter Uptake Inhibitors - administration & dosage; Neurotransmitter Uptake Inhibitors - analysis; Neurotransmitter Uptake Inhibitors - chemistry; percolation theory; Plant Mucilage - chemistry; Seeds - chemistry; Solubility; Tablets
• ISSN: 0363-9045; 1520-5762
• DOI: 10.3109/03639045.2012.738686

The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 32 full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t50% = 5.92 h, t75% = 11.9 h, t90% = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.